Impact of metabolic and inflammatory changes on glomerular function beyond conventional risk factors in an urban South Africa community with prevalent obesity.

OBJECTIVES: To determine the extent to which metabolic and inflammatory changes are associated with renal damage beyond conventional risk factors in a community sample with a high prevalence of obesity in urban South Africa. METHODS: This was a cross-sectional, community-based study in 1 010 (n = 872 without diabetes mellitus, DM) randomly selected participants over 16 years of age in an urban, developing community (Soweto, Johannesburg) with a high prevalence of obesity (41.8%). We assessed estimated glomerular filtration rate (eGFR), conventional risk factors including adiposity indices, and metabolic changes and plasma resistin concentrations (ELISA) and the homeostasis model of insulin resistance (HOMA-IR). Relationships independent of haemodynamic loads were confirmed using ambulatory blood pressure and central arterial haemodynamics. RESULTS: In multivariate regression models conducted in those without DM, HOMA-IR (standardised ß-coefficient = -0.13 ± 0.03, p < 0.0001) and plasma resistin concentrations (ß-coefficient = -0.10 ± 0.02, p < 0.0001) were second only to age, and at least as strong as systolic blood pressure (ß -coefficient = -0.04 ± 0.03, p = 0.19) in the impact on eGFR, while alternative conventional risk factors including adiposity indices and the metabolic syndrome features contributed little to eGFR. Similar results were obtained in relationships with chronic kidney disease (CKD) and in the whole group including those with DM. Adjustments for ambulatory blood pressure or central arterial loads did not influence these relationships. CONCLUSIONS: The impact on glomerular function of insulin resistance and inflammatory changes is well beyond modifiable conventional risk factors, including the metabolic syndrome. Targeting conventional risk factors alone is likely to result in a marked residual risk of renal damage produced by insulin resistance and inflammation.

Associations between circulating resistin concentrations and left ventricular mass are not accounted for by effects on aortic stiffness or renal dysfunction.

BACKGROUND: Although, in-part through an impact on left ventricular mass (LVM), resistin (an adipokine) may contribute to heart failure, whether this is explained by the adverse effects of resistin on aortic stiffness and renal function is unknown. METHODS: Relationships between circulating resistin concentrations and LVM index (LVMI), and LVM beyond that predicted by stroke work (inappropriate LVM [LVMinappr]) (echocardiography) were determined in 647 randomly selected community participants, and in regression analysis, the extent to which these relations could be explained by aortic pulse wave velocity (PWV) or estimated glomerular filtration rate (eGFR) was evaluated. RESULTS: Independent of confounders, resistin concentrations were independently associated with LVMI, LVMinappr, LV hypertrophy (LVH), PWV and eGFR. Furthermore, independent of confounders, LVMI, LVMinappr and LVH were independently associated with PWV and eGFR. However, adjustments for either PWV or eGFR failed to modify the relationships between resistin concentrations and LVMI, LVMinappr or LVH. Moreover, in multivariate regression analysis neither PWV nor eGFR significantly modified the contribution of resistin to LVMinappr or LVMI. CONCLUSIONS: Independent relationships between circulating concentrations of the adipocytokine resistin and LVM are not explained by the impact of resistin on ventricular-vascular coupling or renal dysfunction. Resistin's effects on LVM are therefore likely to be through direct actions on the myocardium.

Limited contribution of insulin resistance and metabolic parameters to obesity-associated increases in ambulatory blood pressure in a black African community.

Although accounting for a striking proportion of obesity effects on blood pressure (BP) in other populations, the extent to which obesity-associated increases in BP are explained by insulin resistance and metabolic changes in populations of African ancestry is uncertain. We determined the contribution of insulin resistance and associated metabolic abnormalities to variations in office or ambulatory BP in a black African community with prevalent obesity and hypertension. In 1225 randomly selected participants of black South African ancestry (age>16years, 43.1% obese, 47.4% abdominal obesity), we assessed adiposity indexes, the homeostasis model of insulin resistance (HOMA-IR) and associated metabolic abnormalities and office or ambulatory (n â€‹= â€‹798) BP. In separate models, waist circumference (p â€‹< â€‹0.0005-<0.0001) and HOMA-IR (p â€‹< â€‹0.51-0.005), were independently associated with office, 24 â€‹h, day or night systolic (SBP) or diastolic (DBP) BP. However, whilst a one standard deviation increase in waist circumference translated into a 1.47-3.08 â€‹mm Hg increased in office, 24-h SBP or DBP, in mediation analysis HOMA-IR accounted for only 0.12-0.30 â€‹mm Hg of the impact of a one standard deviation effect of waist circumference on office, and 24-h SBP and 0.003-0.17 â€‹mm Hg of the impact of a one standard deviation effect of waist circumference on office and 24-h DBP. In conclusion, in a black African community, insulin resistance accounts for a negligible proportion of the impact of obesity on office or ambulatory BP.

Independent of left ventricular mass, circulating inflammatory markers rather than pressure load are associated with concentric left ventricular remodelling.

BACKGROUND: A reason for concentric left ventricular (LV) remodelling predicting cardiovascular outcomes independent of conventional risk factors and LV mass (LVM) has not been provided. We hypothesized that independent of LVM, concentric LV remodelling is associated with inflammatory changes rather than a pressure load on the LV. METHODS: In 764 randomly selected community participants, we assessed relations between several inflammatory markers (ELISA) and LV relative wall thickness (RWT) (echocardiography), LV mass index (LVMI), and indexes of diastolic function. RESULTS: No independent relations were noted between circulating concentrations of inflammatory markers and LVM index (LVMI) (p > 0.13 for all). However, independent of confounders including LVMI and blood pressure (BP), circulating tumour necrosis factor-α (TNF-α) (partial r = 0.14, p < 0.0005) and to a lesser degree interleukin-6 (partial r = -0.09, p < 0.02) were associated with RWT. The impact (standardized ß-coefficient) of TNF-α on RWT (0.12 ±â€¯0.03, p < 0.0005) was at least as strong as age (0.13 ±â€¯0.05, p < 0.005), and second only to LVMI (0.27 ±â€¯0.04, p < 0.0001), whilst neither office, 24-hour, central aortic BP, nor aortic stiffness were associated with RWT independent of LVMI. With adjustments, as compared to participants with a normal LVMI and geometry (12.7 ±â€¯0.8), circulating TNF-α concentrations (pg/ml) were increased as much in participants with concentric LV remodelling (16.8 ±â€¯1.5, p < 0.05) as in those with concentric LV hypertrophy (LVH) (17.0 ±â€¯1.3, p < 0.005), whilst eccentric LVH (13.7 ±â€¯0.9) was not. No independent relations between inflammatory markers and LV diastolic function (trans-mitral and tissue Doppler) were noted. CONCLUSIONS: Independent of LVMI, a pro-inflammatory state rather than BP load is strongly associated with LV concentric remodelling.

Limited Impact of ß-Adrenergic Receptor Activation on Left Ventricular Diastolic Function in Rat Models of Hypertensive Heart Disease.

BACKGROUND: Hypertension is a major cause of left ventricular (LV) diastolic dysfunction. Although ß-adrenergic receptor (ß-AR) blockers are often used to manage hypertension, the impact of ß-AR activation on LV lusitropic effects and hence filling pressures in the hypertensive heart with LV diastolic dysfunction is uncertain. METHODS: Using tissue Doppler imaging and Speckle tracking software, we assessed LV function in isoflurane anesthetised spontaneously hypertensive (SHR) and Dahl salt-sensitive (DSS) rats before and after ß-AR activation [isoproterenol (ISO) administration]. RESULTS: As compared to normotensive Wistar Kyoto control rats, or DSS rats not receiving NaCl in the drinking water, SHR and DSS rats receiving NaCl in the drinking water had a reduced myocardial relaxation as indexed by lateral wall e' (early diastolic tissue velocity at the level of the mitral annulus) and an increased LV filling pressure as indexed by E/e'. However, LV ejection fraction and deformation and motion were preserved in both SHR and DSS rats. The administration of ISO resulted in a marked increase in ejection fraction and decrease in LV filling volumes in all groups, and an increase in e' in SHR, but not DSS rats. However, after ISO administration, although E/e' decreased in DSS rats in association with a reduced filling volume, E/e' in SHR remained unchanged and SHR retained greater values than Wistar Kyoto control. CONCLUSIONS: The hypertensive heart is characterized by reductions in myocardial relaxation and increases in filling pressures, but ß-AR activation may fail to improve myocardial relaxation and when this occurs, it does not reduce LV filling pressures.

Circulating resistin concentrations are independently associated with aortic pulse wave velocity in a community sample.

AIMS: The role of the adipokine, resistin in mediating increases in aortic stiffness is uncertain. We aimed to determine independent relations between circulating resistin concentrations and aortic pulse wave velocity (PWV) and wave reflection in a community-based sample with a high prevalence of untreated hypertension and obesity. METHODS: Plasma resistin, adiponectin, and C-reactive protein concentrations (ELISA); carotid-femoral (aortic) PWV and the aortic reflected wave index (applanation tonometry and SphygmoCor software) were determined in 683 randomly selected participants of African ancestry from SOWETO, South Africa who had never received antihypertensive therapy. RESULTS: Resistin concentrations were not independently associated with office or 24-h (n = 492) blood pressure (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 sex (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 C-reactive protein concentrations (P < 0.005), and the homeostasis model of insulin resistance (P < 0.02). Similar relations were noted with waist circumference rather than BMI in the model. Resistin concentrations were not independently associated with aortic reflected wave index or aortic BP. CONCLUSION: Resistin is independently and directly associated with aortic stiffness and these effects occur beyond BP, insulin resistance, and general inflammation.

Independent associations between resistin and left ventricular mass and myocardial dysfunction in a community sample with prevalent obesity.

BACKGROUND: Although the adipokine resistin may play a role in heart failure, the mechanisms of this effect are uncertain. Relations with left ventricular mass (LVM) and function are uncertain. METHODS: In 739 randomly selected participants from a community sample (43.6% obese), we assessed relations between circulating resistin concentrations and LVM index (LVMI), LVM beyond that predicted by stroke work (inappropriate LVMI [LVMinappr]) and systolic and diastolic LV function (echocardiography). RESULTS: Resistin concentrations were not independently associated with blood pressure (BP). However, resistin concentrations were associated with LVMI (partial r=0.12, p<0.0005), LVMinappr (partial r=0.18, p<0.0001) and LV hypertrophy (partial r=0.13, p<0.001) independent of BP, BMI, the homeostasis model of insulin resistance and additional confounders. Independent relations between resistin concentrations and LVMI and LVMinappr persisted with further adjustments for C-reactive protein concentrations. Resistin concentration (partial r=-0.12, p<0.002 in all and partial r=-0.15, 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. Resistin was not independently associated with transmitral and myocardial tissue Doppler indices of LV diastolic function. CONCLUSIONS: Resistin in-part explains variations in LVM, hypertrophy and myocardial systolic dysfunction, and these effects are independent of insulin resistance and general inflammatory changes.