Aletta M.E. Millen

Reflected rather than forward wave pressures account for brachial pressure-independent relations between aortic pressure and end-organ changes in an African community.

Aims: To determine whether brachial blood pressure (BP)-independent relations between aortic pressure and cardiovascular damage are better explained by reflected (backward) (Pb) or forward (Pf) wave pressure effects. Methods: In 1174 participants from a community of African ancestry, we assessed central aortic pulse pressure (PPc), Pb, and Pf (radial applanation tonometry, SphygmoCor) as well as left ventricular mass index (LVMI) (n = 786), aortic pulse wave velocity (PWV) (n = 1019), carotid intima-media thickness (IMT) (n = 578), transmitral early-to-late left ventricular diastolic velocity (E/A) (n = 779) and estimated glomerular filtration rate (eGFR) (n = 1174). Results: Independent of mean arterial pressure and confounders, PPc, and both Pb and Pf were associated with end-organ measures or damage (P < 0.05 to P < 0.0001). With adjustments for brachial PP and confounders, Pb remained directly associated with LVMI (partial r = 0.09, P < 0.01), PWV (partial r = 0.28, P < 0.0001), and IMT (partial r = 0.28, P < 0.0001), and inversely associated with E/A (partial r = −0.31, P < 0.0001) and eGFR (partial r = −0.14, P < 0.0001). Similar relations were noted with the presence of end-organ damage (P < 0.05 to P < 0.0001). In contrast, with adjustments for brachial PP and confounders, Pf no longer retained direct relations with LVMI, PWV, and IMT or inverse relations with E/A and eGFR. Adjustments for Pb, but not Pf, diminished brachial PP-independent relationships between PPc and end-organ measures. Independent relations between Pb, but not Pf and end-organ measures, were largely attributed to Pb accounting for most of the variation in brachial-to-aortic PP amplification. Conclusions: In communities of African ancestry, brachial BP-independent relations between aortic pressure and end-organ changes are largely attributed to an impact of reflected rather than forward wave pressures.

Kidney Function, Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

Objective To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). Methods We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. Results The CKD-EPI eGFR was <90 ml/min/1.73m2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28–3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. Conclusion Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients.

Adiponectin and Atherosclerosis in Rheumatoid Arthritis

In the present study, we examined the potential impact of adiponectin on carotid ultrasound determined atherosclerosis in 210 (119 black and 91 white) RA patients in mixed regression models. Total adiponectin concentrations were smaller in patients with compared to those without the metabolic syndrome (MetS) defined waist criterion (median (range) = 6.47 (1.23–34.54) versus 8.38 (0.82–85.30) ng/mL, P = 0.02, resp.); both total and high molecular weight (HMW) adiponectin concentrations were larger in patients with compared to those without joint deformities (7.97 (0.82–85.30) and 3.51 (0.01–35.40) versus 5.36 (1.29–19.49) and 2.34 (0.01–19.49) ng/mL, P = 0.003 and 0.02, resp.). Total and HMW adiponectin concentrations were associated with carotid artery plaque in patients with MetS waist (odds ratio (95% CI) = 0.87 (0.76–0.99) and 0.92 (0.85–0.99) per 1-standard deviation increment, P = 0.02 for both) and those without joint deformities (odds ratio (95% CI) = 0.94 (0.88–0.99) and 0.94 (0.89–0.99), P = 0.03 for both). Plaque prevalence was lower in patients without compared to those with joint deformities (23.4% versus 42.6, P = 0.004 in multivariable analysis). In RA patients with abdominal obesity or no clinically evident joint damage, adiponectin concentrations are reduced but nevertheless associated with decreased carotid atherosclerosis.

Insulin Resistance and the Relationship Between Urinary Na+/K+ and Ambulatory Blood Pressure in a Community of African Ancestry

BACKGROUND Although groups of African descent are particularly sensitive to blood pressure (BP) effects of salt intake, the role of obesity and insulin resistance in mediating this effect is uncertain. We determined whether obesity or insulin resistance is independently associated with urinary Na(+)/K(+)-BP relationships in a community sample of African ancestry. METHODS We measured 24-hour urinary Na(+)/K(+), homeostasis model assessment of insulin resistance (HOMA-IR), and nurse-derived conventional and 24-hour ambulatory BP in 331 participants from a South African community sample of black African descent not receiving treatment for hypertension. RESULTS With adjustments for diabetes mellitus and the individual terms, an interaction between waist circumference and urinary Na(+)/K(+) was associated with day diastolic BP (P < 0.05) and an interaction between log HOMA-IR and urinary Na(+)/K(+) was associated with 24-hour and day systolic (P < 0.05) and 24-hour, day, and night diastolic (P < 0.002; P < 0.001) BP. The multivariable-adjusted relationship between urinary Na(+)/K(+) and night diastolic BP increased across tertiles of HOMA-IR (tertile 1: β-coefficient = -0.79 ± 0.47; tertile 2: β-coefficient = 0.65 ± 0.35; tertile 3: β-coefficient = 1.03 ± 0.46; P < 0.05 tertiles 3 and 2 vs. 1). The partial correlation coefficients for relationships between urinary Na(+)/K(+) and 24-hour (partial r = 0.19; P < 0.02), day (partial r = 0.17; P < 0.05), and night (partial r = 0.18; P < 0.02) diastolic BP in participants with log HOMA-IR greater than or equal to the median were greater than those for relationships between urinary Na(+)/K(+) and 24-hour (partial r = -0.08; P = 0.29), day (partial r = -0.10; P < 0.22), and night (partial r = -0.06; P = 0.40) diastolic BP in participants with log HOMA-IR less than the median (comparisons of r values: P < 0.05). CONCLUSIONS Insulin resistance may modify the relationship between salt intake, indexed by urinary Na(+)/K(+), and ambulatory BP in groups of African descent.

Relative impact of blood pressure as compared to an excess adiposity on left ventricular diastolic dysfunction in a community sample with a high prevalence of obesity.

Aim: To determine whether blood pressure (BP) or an excess adiposity, both frequently observed comorbidities that independently relate to left ventricular diastolic dysfunction (LVDD), have a greater impact on LVDD at a community level. Methods: We assessed the relative independent impact of an excess adiposity versus BP on indices of LVDD as determined from the ratios of early-to-late transmitral blood flow velocity (E/A) and E/the mean of lateral and septal wall myocardial tissue lengthening at the level of the mitral annulus (e′; (E/e′) in 417 randomly recruited participants of a community-based study with a high prevalence of excess adiposity (43% obese and 25% morbidly obese). Results: In multivariate adjusted models, including adjustments for appropriate BP values (SBP for E/e′ and DBP for E/A), waist circumference was independently associated with E/A (partial r = −0.12, P < 0.02) and E/e′ (partial r = 0.15, P < 0.005). In contrast, BMI was independently associated with E/e′ (partial r = 0.11, P < 0.05), but not E/A (partial r = −0.09, P = 0.08). In multivariate models, SBP had a greater impact on E/e′ (standardized &bgr;-coefficient = 0.32 ± 0.05, P < 0.0001) than did waist circumference (standardized &bgr;-coefficient = 0.16 ± 0.05, P < 0.005; P < 0.05 for comparison), whereas DBP had a similar impact on E/A (standardized &bgr;-coefficient = −0.10 ± 0.03, P < 0.005) as did waist circumference (standardized &bgr;-coefficient = −0.10 ± 0.04, P < 0.05). Importantly, whereas SBP was the main factor independently associated with an increased E/e′ (≥10) (P < 0.0005), waist circumference was not independently associated with either a decreased E/A (⩽0.75) (P = 0.82) or an increased E/e′ (≥10; P = 0.15). Conclusion: In a community sample with a high prevalence of excess adiposity, BP exceeds obesity as the most important modifiable risk factor for LVDD. These data suggest that in communities with a high prevalence of obesity, if weight loss programmes fail to produce sustainable target body weights, rigorous BP management to lower than normal thresholds may be sufficient to prevent LVDD.

Cardiovascular Disease Risk amongst African Black Patients with Rheumatoid Arthritis: The Need for Population Specific Stratification

Rheumatoid arthritis (RA) enhances the risk of cardiovascular disease to a similar extent as diabetes. Whereas atherogenesis remains poorly elucidated in RA, traditional and nontraditional risk factors associate similarly and additively with CVD in RA. Current recommendations on CVD risk stratification reportedly have important limitations. Further, reported data on CVD and its risk factors derive mostly from data obtained in the developed world. An earlier epidemiological health transition is intrinsic to persons living in rural areas and those undergoing urbanization. It is therefore conceivable that optimal CVD risk stratification differs amongst patients with RA from developing populations compared to those from developed populations. Herein, we briefly describe current CVD and its risk factor profiles in the African black population at large. Against this background, we review reported data on CVD risk and its potential stratification amongst African black compared to white patients with RA. Routinely assessed traditional and nontraditional CVD risk factors were consistently and independently related to atherosclerosis in African white but not black patients with RA. Circulating concentrations of novel CVD risk biomarkers including interleukin-6 and interleukin-5 adipokines were mostly similarly associated with both endothelial activation and atherosclerosis amongst African black and white RA patients.

Relationship between inappropriate left ventricular hypertrophy and ejection fraction independent of absolute or indexed mass in a community sample of black African ancestry.

Aim: We determined whether left ventricular hypertrophy (LVH) which exceeds that predicted from workload [inappropriate LV mass (LVMinappr)] is associated with reduced left ventricle (LV) systolic chamber function independent of and more closely than absolute or indexed left ventricular mass (LVM). Methods: In 626 randomly selected adult participants from a community sample of black Africans, using echocardiography we assessed absolute LVM, LVM indexed to height2.7 (LVMI), LVMinappr, LV wall stress, ejection fraction, and midwall fractional shortening (FSmid). LVMinappr was determined as percentage of observed/predicted LVM. Predicted LVM was calculated from a previously validated formula that incorporates stroke work. LVMIinappr more than 150% was considered to be inappropriate LVH. This threshold was identified from the upper 95% confidence interval for LVMIinappr determined in 140 healthy participants. Results: A total of 21.7% of participants had LVH (LVMI > 51 g/m2.7) and 18.5% had inappropriate LVH. With adjustments for LV stress and other confounders there was a strong inverse relationship between LVMinappr and ejection fraction (partial r = −0.41, P < 0.0001), whereas only modest inverse relations between LVM or LVMI and ejection fraction were noted (partial r = −0.07 to −0.09, P < 0.05–0.09) (P < 0.0001, comparison of partial r values). The independent relationship between LVMinappr and ejection fraction persisted with further adjustments for LVM or LVMI (partial r = −0.52, P < 0.0001). LVMinappr and FSmid were similarly inversely related (P < 0.0001) and these relations were also stronger and independent of LVM or LVMI. Conclusion: Inappropriate LVH is strongly and inversely related to variations in ejection fraction independent of and more closely than LVM or LVMI in a community sample of black African ancestry. These data suggest that LVH is a compensatory response to workload, but when exceeding that predicted by workload, is associated with LV systolic chamber decompensation.

Nesfatin-1 and visfatin expression is associated with reduced atherosclerotic disease risk in patients with rheumatoid arthritis

HIGHLIGHTSVisfatin levels were associated with cardio‐metabolic risk in RA.Nesfatin concentrations were related to reduced carotid IMT in RA.Nesfatin and visfatin associated with the plaque stability mediator MMP‐2 in RA.Nesfatin and visfatin concentrations were directly correlated in RA.MMP‐2 expression in relation to visfatin may represent a compensatory mechanism in RA. ABSTRACT Nesfatin is an anti‐inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro‐inflammatory properties and is pro‐atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (&bgr;=0.650, p<0.0001) and visfatin levels (&bgr;=0.157, p=0.03). Visfatin concentrations were related to increased diastolic blood pressure (&bgr;=4.536, p=0.01) and diabetes prevalence (&bgr;=0.092, p=0.04). Nesfatin levels were associated with reduced carotid intima‐media thickness (&bgr;=−0.017, p=0.008). Nesfatin (&bgr;=0.116, p=0.001) and visfatin concentrations (&bgr;=0.234, p=0.001) were related to those of matrix metalloproteinase‐2 (MMP‐2), a plaque stability mediator. Nesfatin and visfatin concentrations were directly correlated (Spearmans rho=0.516). The nesfatin‐MMP‐2 and visfatin‐MMP‐2 relations were both stronger in RF negative compared to RF positive patients (interaction p=0.01 and p=0.04, respectively). Nesfatin is associated with reduced atherosclerosis and increased plaque stability mediator levels in RA. Visfatin is related to adverse cardio‐metabolic risk in RA. Increased MMP‐2 expression in relation to visfatin may represent a compensatory mechanism aimed at reducing cardiovascular risk in RA.

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.