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Grace Tade,1,* Hon-Chun Hsu,1,2,* Angela J Woodiwiss,1 Ferande Peters,1 Chanel Robinson,1 Noluntu Dlongolo,3 Gloria Teckie,4 Ahmed Solomon,5 Gavin R Norton,1 Patrick H Dessein1,5,6 1Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 2Nephrology Unit, Milpark Hospital, Johannesburg, South Africa; 3Rheumatology Unit, Rosebank Hospital, Johannesburg, South Africa; 4Division of Nephrology, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 5Rheumatology Department, University of the Witwatersrand, Johannesburg, South Africa; 6Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa*These authors contributed equally to this workCorrespondence: Patrick H Dessein, Departments of Medicine, Rheumatology and Physiology, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannnesburg, 2193, South Africa, Tel +27 662491468, Email patrick.dessein22@gmail.comIntroduction: Circulating uric acid, ferritin, albumin, intact parathyroid hormone and gamma-glutamyl transferase each participate in biochemical reactions that reduce or/and enhance oxidative stress, which is considered the final common pathway through which pathophysiological mechanisms cause uremic cardiomyopathy. We hypothesized that the respective biomarkers may be involved in the development of uremic cardiomyopathy characteristics and can be useful in their identification among chronic kidney disease patients.Methods: We assessed traditional and non-traditional cardiovascular risk factors including biomarker concentrations and determined central systolic blood pressure using SphygmoCor software and cardiac structure and function by echocardiography in 109 (64 non-dialysis and 45 dialysis) patients. Associations were evaluated in multivariate regression models and receiver operator characteristic (ROC) curve analysis.Results: Each biomarker concentration was associated with left ventricular mass beyond stroke work and/or inappropriate left ventricular mass in all, non-dialysis and/or dialysis patients. Ferritin, albumin and gamma-glutamyl transferase levels were additionally associated with E/e’ in all, non-dialysis and/or dialysis patients. Dialysis status influenced the relationship of uric acid concentrations with inappropriate left ventricular mass and those of gamma-glutamyl transferase levels with left ventricular mass and inappropriate left ventricular mass. In stratified analysis, low uric acid levels were related to inappropriate left ventricular mass in dialysis but not non-dialysis patients (interaction p=0.001) whereas gamma-glutamyl transferase concentrations were associated with left ventricular mass and inappropriate left ventricular mass in non-dialysis but not dialysis patients (interaction p=0.020 to 0.036). In ROC curve analysis, uric acid (area under the curve (AUC)=0.877), ferritin (AUC=0.703) and albumin (AUC=0.728) concentrations effectively discriminated between dialysis patients with and without inappropriate left ventricular hypertrophy, left ventricular hypertrophy, and increased E/e,’ respectively.Conclusion: Uric acid, ferritin, albumin, parathyroid hormone and gamma-glutamyl transferase were associated with uremic cardiomyopathy characteristics and could be useful in their identification. Our findings merit validation in future longitudinal studies.Keywords: uremic cardiomyopathy, uric acid, ferritin, albumin, parathyroid hormone and gamma-glutamyl transferase

OBJECTIVE To address to what extent central hemodynamic measurements, improve risk stratification, and determine outcome-based diagnostic thresholds, we constructed the International Database of Central Arterial Properties for Risk Stratification (IDCARS), allowing a participant-level meta-analysis. The purpose of this article was to describe the characteristics of IDCARS participants and to highlight research perspectives. METHODS Longitudinal or cross-sectional cohort studies with central blood pressure measured with the SphygmoCor devices and software were included. RESULTS The database included 10,930 subjects (54.8% women; median age 46.0 years) from 13 studies in Europe, Africa, Asia, and South America. The prevalence of office hypertension was 4,446 (40.1%), of which 2,713 (61.0%) were treated, and of diabetes mellitus was 629 (5.8%). The peripheral and central systolic/diastolic blood pressure averaged 129.5/78.7 mm Hg and 118.2/79.7 mm Hg, respectively. Mean aortic pulse wave velocity was 7.3 m per seconds. Among 6,871 participants enrolled in 9 longitudinal studies, the median follow-up was 4.2 years (5th–95th percentile interval, 1.3–12.2 years). During 38,957 person-years of follow-up, 339 participants experienced a composite cardiovascular event and 212 died, 67 of cardiovascular disease. CONCLUSIONS IDCARS will provide a unique opportunity to investigate hypotheses on central hemodynamic measurements that could not reliably be studied in individual studies. The results of these analyses might inform guidelines and be of help to clinicians involved in the management of patients with suspected or established hypertension., Graphical Abstract Graphical Abstract

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.

Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults ({greater than or equal to}18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally three blood pressure readings were measured for each participant, and data on lifestyle factors and co-morbidities were collected. Hypertension was defined as a systolic BP {greater than or equal to} 140 mmHg, and/or a diastolic BP {greater than or equal to} 90 mmHg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1,508,130 screenees 482,273 (32.0%) had never had a blood pressure measurement before and 513,337 (34.0%) had hypertension, of whom 58.7% were aware and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to

Background High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA). Methods To induce CIA, bovine type-II collagen emulsified in incomplete Freund’s adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA. Results Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e’ (early diastolic mitral annular velocity) and e’/a’ (early-to-late diastolic mitral annular velocity) and increased filling pressures as indexed by E/e’. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e’, e’/a’, radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e’. Conclusion High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats.

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 ​= ​798) BP. In separate models, waist circumference (p ​

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p ≥ 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p ≤ 0.05). In stratified analysis, apelin was associated with CSP (partial r = − 0.33, p = 0.01), CPP (partial r = − 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = − 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = − 0.24, p = 0.05) in those with a DAS28 joint

Objective.Arterial properties influence cardiovascular disease (CVD) risk. We identified potential determinants of arterial function in patients with rheumatoid arthritis (RA).Methods.Relationships of traditional cardiovascular risk factors and RA characteristics with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pulse pressure amplification, and forward wave pressure) were identified in multivariable backward regression models among 177 patients without established CVD (118 white, 32 Asian, 22 black, 5 mixed ancestry).Results.Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial function. These factors were particularly associated with wave reflection and pressure pulsatility: RA duration (p = 0.04), rheumatoid factor status (p = 0.01 to 0.03), leukocyte counts (p = 0.02 to 0.05), and total cholesterol (p < 0.01 to 0.03). Body mass index (p < 0.01 to 0.02) and insulin resistance (p < 0.01 to 0.01) were related to reduced wave reflection and peripheral pulse pressure. Exercise (p = 0.02) and alcohol consumption (p < 0.01) were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumor necrosis factor-α inhibition (p < 0.01) was related to reduced pulse wave velocity, and tetracycline use (p = 0.02) to decreased peripheral pulse pressure.Conclusion.Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The relative effect of arterial stiffness, wave reflection, and pressure pulsatility on CVD risk in RA needs further study.

This study compared the estimated prevalence and potential determinants of left ventricular (LV) diastolic dysfunction upon applying different classification criteria in rheumatoid arthritis (RA). LV diastolic function was assessed echocardiographically by pulsed Doppler (E/A), tissue Doppler (E/e′, lateral and septal e′), and left atrial volume index in 176 RA patients. Relationships of traditional cardiovascular risk factors and RA characteristics with LV diastolic function and dysfunction according to previous and current criteria were determined in multivariate regression models. Waist-hip ratio was associated with E/A (standardised β (SE) = -0.28±0.09, p=0.0002) and lateral e′ (standardised β (SE) = 0.26±0.09, p=0.01); low diastolic blood pressure was related to E/e′ (standardised β (SE) = -0.16±0.08, p=0.04). Diastolic dysfunction prevalence differed upon applying previous (59%) compared to current (22%) criteria (p<0.0001). One SD increase in waist-hip ratio was associated with diastolic dysfunction when applying current criteria (OR = 2.61 (95% CI = 1.51–4.52), p=0.0006), whereas one SD increase in diastolic blood pressure was inversely related to diastolic dysfunction upon using previous criteria (OR = 0.57 (95% CI = 0.40–0.81), p=0.002). In conclusion, application of current and previous diastolic dysfunction criteria markedly alters the prevalence and risk factors associated with diastolic dysfunction in RA.

BACKGROUND: Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. METHODS: We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h) of RNaprox and RNadist. RESULTS: Independent of urinary sodium excretion, South Africans (n = 240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n = 737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (-5.40 +/- 0.58 vs. -0.78 +/- 0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (-3.84 +/- 0.19 vs. -13.71 +/- 1.30 units; P < 0.001). h of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally. CONCLUSION: Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks.

As acknowledged by all guidelines, left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular events independent of conventional risk factors and coronary artery disease. In addition, compared to a normal LV geometry, concentric LV remodeling (an increased relative wall thickness (RWT) without an increase in LV mass (LVM)) is associated with a worse prognosis.1–4 Although LVM rather than concentric LV remodeling predicts incident heart failure,3 concentric LV remodeling without LVH is associated with the development of diastolic dysfunction, and concentric rather than eccentric LVH is associated with greater increases in indices of LV filling pressures.5 Thus, the extent of concentric LV remodeling may determine whether progression from LVH to heart failure with a preserved rather than reduced systolic chamber function occurs. The factors that determine LV remodeling are therefore of considerable interest. Although the impact of age, sex, blood pressure, and obesity on LV geometric remodeling has been well described, there is nevertheless uncertainty as to the role of genetic factors independent of LVM, a major determinant of LV wall thickness, and a change that itself is well recognized as being inherited.6–14 Compared to age-, and sex-matched controls, siblings of those with LVH have a greater risk of concentric, but not eccentric LVH.9 However, in that study,9 whether siblings were also at risk for concentric LV remodeling is uncertain and hence LVM may have made a major contribution to the inheritance of concentric LVH. Moreover, in the Framingham Heart Study, the risk for concentric LV remodeling was only modestly increased in related compared to unrelated individuals, whereas the risk for concentric LVH was markedly augmented.15 Hence, again, LVM may have been the major determinant of the inheritance of LV remodeling. Although alternative studies indicate that RWT is indeed inherited,10–12,16 none of these studies reported on the inheritance of RWT independent of LVM. To address the aforementioned uncertainty as to the extent to which genetic factors contribute toward concentric LV remodeling beyond LVM, in the present study, we aimed to evaluate the intrafamilial aggregation and heritability of RWT independent of LVM and additional confounders. We hypothesized that RWT would show intrafamilial aggregation and heritability independent of LVM and additional confounders.

To the Editor: Leptin is an adipokine that regulates appetite and energy expenditure1. Both high and low leptin production can further increase cardiovascular (CV) risk1. Leptin is also produced in inflamed joints and implicated in the pathophysiology of rheumatoid arthritis (RA)2. Whether leptin increases CV risk in RA is currently uncertain. Two studies reported a lack of association between leptin concentrations and carotid artery intima-media thickness (cIMT) in RA3,4. Leptin concentrations were also found to be unrelated to coronary artery classification scores in RA5. However, we recently reported an independent relationship between leptin concentrations and surrogate markers of early atherogenesis in young patients with RA2. Importantly, in the present context, carotid artery plaque is a more reliable indicator of atherosclerosis than cIMT6. In our present study, we examined the independent relationships of leptin concentrations with cIMT and plaque in 217 (112 black and 105 white) patients with RA. Because the production and effects of adipokines on CV risk depend on pathophysiological context1,2,7, we also determined whether the presence of conventional and nonconventional CV risk factors modified leptin concentrations and their associations with atherosclerosis. … Address correspondence to Prof. P.H. Dessein, P.O. Box 1012, Melville 2109, Johannesburg, South Africa. E-mail: dessein{at}telkomsa.net

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.

Background Retinol binding protein 4 (RBP) enhances metabolic risk and atherogenesis. Whether RBP4 contributes to cardiovascular risk in rheumatoid arthritis (RA) is unknown. Methods We assessed RBP4 concentrations and those of endothelial activation molecules including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 by ELISA, and the common carotid artery intima-media thickness (cIMT) and carotid artery plaque by ultrasound in 217 (112 black and 105 white) patients with RA. Relationships were identified in potential confounder and mediator adjusted mixed regression models. Results RBP4 concentrations were associated with systolic and mean blood pressure, and those of glucose and E-selectin (partial R = −0.207 (p = 0.003), −0.195 (p = 0.006), −0.155 (p = 0.03) and −0.191 (p = 0.007), respectively in all patients); these RBP4-cardiovascular risk relations were mostly reproduced in patients with but not without adverse traditional or non-traditional cardiovascular risk profiles. RBP4 concentrations were not associated with atherosclerosis in all patients, but related independently to cIMT (partial R = 0.297, p = 0.03) and plaque (OR (95%CI) = 2.95 (1.31–6.68), p = 0.008) in those with generalized obesity, as well as with plaque in those with abdominal obesity (OR (95%CI) = 1.95 (1.12–3.42), p = 0.01). Conclusion In the present study, RBP4 concentrations were inversely associated with metabolic risk and endothelial activation in RA. This requires further investigation. RBP4 concentrations were related to enhanced atherosclerosis in patients with generalized or/and abdominal obesity.

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=0.003and 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=0.02for both) and those without joint deformities (odds ratio (95% CI) = 0.94 (0.88–0.99) and 0.94 (0.89–0.99),P=0.03for both). Plaque prevalence was lower in patients without compared to those with joint deformities (23.4% versus 42.6,P=0.004in 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.

We examined the potential impact of demographic characteristics on the independent leptin-metabolic cardiovascular risk factor and leptin–endothelial activation relationships in black and white patients with RA. Leptin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were measured in 217 RA patients (51.6 % black). We determined associations in potential confounder and mediator-adjusted mixed regression models. No independent associations between leptin concentrations and cardiovascular risk were present in all patients and either women and men or black and white patients. However, age impacted on several leptin–cardiovascular risk relations (interaction P < 0.05). In patients aged

Background. Primary healthcare is the foundation of a country’s healthcare system. Without an efficient and cost-effective programme, the level of healthcare offered across all levels of health management is adversely affected. Objective. To analyse the effectiveness of the management of hypertension and diabetes mellitus (DM) among two distinct patient populations, one with significant cardiovascular risk factors and the other without. Method. We performed a case control study of a high-risk group of patients presenting with chronic critical limb ischaemia (CLI) to the Divisions of Vascular Surgery at Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital, and a randomly selected group of ‘healthy’ community participants from Johannesburg’s South Western Townships (Soweto). Results. We assessed 217 patients with CLI and 1 030 participants from the community. We assessed the number of patients who were not achieving their therapeuatic targets, among those known to be hypertensive (CLI: 44.7%; community: 59.9%) and diabetic (CLI: 83.5%; community: 66%). Undiagnosed diabetes affected 10.8% of patients with CLI and 11% of the community sample. Conclusion. Traditional vascular risk factors are managed poorly at both primary healthcare and at tertiary care levels. There is a need to identify factors that will address this issue.

Adiponectin and leptin are likely involved in the pathophysiology of rheumatoid arthritis (RA) and therefore potential new therapeutic targets. Adiponectin inhibition could be expected to enhance cardiovascular metabolic risk. However, it is unknown whether RA changes the influence of adipokines on cardiovascular metabolic risk. We determined whether RA impacts on the independent relationships of circulating leptin and adiponectin concentrations with cardiovascular risk factors and carotid intima-media thickness (cIMT) in 277 black African subjects from a developing population; 119 had RA. RA impacted on the relationships of adiponectin concentrations with lipid concentrations and blood pressure, independent of confounders including adiposity (interactionP<0.05). This translated into an association of adiponectin concentrations with more favorable lipid variables including HDL cholesterol (P=0.0005), non-HDL cholesterol (P=0.007), and triglyceride (P=0.005) concentrations, total cholesterol-HDL cholesterol (P=0.0002) and triglycerides-HDL cholesterol (P=0.0003) ratios, and higher systolic (P=0.0006), diastolic (P=0.0004), and mean blood pressure (P=0.0007) in RA but not non-RA subjects. Leptin was not associated with metabolic risk after adjustment for adiposity. The cIMT did not differ by RA status, and adipokine concentrations were unrelated to atherosclerosis. This study suggests that leptin and adiponectin inhibition may not alter overall cardiovascular risk and disease in RA.

Objective.Black Africans currently experience a distinctly low frequency of atherosclerotic cardiovascular disease. Whether this protection persists in those with rheumatoid arthritis (RA) is unknown. We compared the carotid atherosclerosis burden and its relationships with cardiovascular (CV) risk factors between Africans with RA from a developing black and developed CV population.Methods.We performed high resolution B-mode ultrasonography and assessed CV risk factors in 243 patients with established RA, of whom 121 were black and 122 white. Data were analyzed in age, sex, and healthcare center-adjusted regression models.Results.The mean ± SD common carotid intima-media thickness (cIMT) was 0.694 ± 0.097 mm in black and 0.712 ± 0.136 mm in white patients (adjusted p = 0.8). Plaque prevalence was also similar in black compared to white cases (35.5% and 44.3%, respectively; adjusted OR 0.83, 95% CI 0.32–2.20, p = 0.7). Interactions between population grouping and several CV risk factors were independently associated with cIMT and plaque. In stratified analysis, that is, in each population group separately, risk factors associated with cIMT or/and plaque comprised the systolic blood pressure (p = 0.02), serum cholesterol/high-density lipoprotein cholesterol ratio (p = 0.004), C-reactive protein concentrations (p = 0.01), and the presence of extraarticular manifestations (p = 0.01) in whites but, contrastingly, the Arthritis Impact Measurement Scales tension score (p = 0.04) and use of nonsteroidal antiinflammatory agent (p = 0.03) in black patients. The Framingham score was significantly associated with atherosclerosis only in whites (p < 0.0001).Conclusion.The carotid atherosclerosis burden is similar in black compared to white Africans with RA, but relationships between modifiable CV risk factors and atherosclerosis vary substantially among Africans with RA.

Background Serum aminotransferase concentrations are reportedly strongly associated with insulin resistance, an established cardiovascular risk factor that is not routinely assessed in clinical practice. We therefore explored the possibility that serum aminotransferase concentrations are as closely related to large artery disease as insulin resistance in rheumatoid arthritis (RA). Methods Carotid artery plaque (ultrasonography), insulin resistance and liver enzymes (prior to methotrexate (MTX) were determined in 77 consecutive patients with RA (43 with and 34 without MTX). Results Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were associated with insulin resistance in univariate analysis (R = 0.54, p < 0.0001 and R = 0.36, p = 0.001, respectively) and after adjustment for age, gender and waist circumference (partial R = 0.43, p = 0.0001 and partial R = 0.37, p = 0.001, respectively). ALT and AST concentrations were higher in patients with plaque as compared to in those without plaque (ALT (u/l): 27 2223242526272829303132 versus 20 181920212223, p = 0.02; AST (u/l): 25 2122232425262728 versus 20 19202122, p = 0.02). The odds ratios [95% CI] for plaque were 1.92 [1.14–3.24] (p = 0.01), 1.93 [1.17–3.16] (p = 0.009) and 1.82 [1.13–2.93] (p = 0.01) for 1 SD increase in ALT (~10 u/l) and AST (~6 u/l) concentrations and in logarithmically transformed homeostasis model assessment of insulin resistance (HOMA-IR) (~0.2 uU.mmol/ml.l), respectively. After adjustment for the potentially confounding characteristics of age, sex, hypertension and hypothyroidism in logistic regression models, ALT (p = 0.049) and AST concentrations (p = 0.027) remained associated with plaque whereas the HOMA-IR did not (p = 0.08). AST concentrations (p = 0.049) were associated with plaque independent of insulin resistance whereas the HOMA-IR (p = 0.1) was not associated with plaque independent of AST concentrations. Conclusion Within currently recommended reference ranges, serum aminotransferase concentrations may be strongly associated with insulin resistance and atherosclerosis in patients with RA. The measurement of aminotransferase concentrations could be a useful tool in cardiovascular risk stratification in patients with RA.

To the Editor: As reported previously in this journal, the endogenous lithium clearance is a marker of proximal tubular sodium handling.1,2 To investigate the context dependency of the endogenous lithium clearance, we measured by electrothermal atomic absorption spectrophotometry the lithium concentrations in serum and in exactly timed urine samples in 745 whites (51.5% women) and …

Objectives The purpose of this research was to evaluate the therapeutic value of initiating a beta-blocker before an angiotensin-converting enzyme inhibitor (ACEI) in the treatment of heart failure. Background Although ACEI and carvedilol produce benefits in heart failure, whether the order of initiation of therapy determines the impact on left ventricular (LV) function and New York Heart Association functional class (NYHA FC) has not been determined. Methods A single-center, prospective, randomized, open-label study was performed. We evaluated whether initiation of therapy with carvedilol either before (n = 38) or after (n = 40) perindopril therapy in newly diagnosed patients in NYHA FC II to III heart failure with idiopathic dilated cardiomyopathy, with the addition of the alternative agent after six months, determined subsequent changes in NYHA FC and LV function (echocardiography and radionuclide ventriculography). Study drugs were titrated to maximum tolerable doses. Results There were no differences in baseline characteristics between the study groups. After 12 months 11 patients died (6 in the group where the ACEI was initiated). At 12 months the group receiving carvedilol as initial therapy achieved a higher tolerable dose of carvedilol (43 ± 17 mg vs. 33 ± 18 mg, p = 0.03); a lower dose of furosemide (p l 0.05); and better improvements in symptoms (NYHA FC, p l 0.002), LV ejection fraction (radionuclide: 15 ± 16% vs. 6 ± 13%, p l 0.05; echocardiographic, p l 0.01), and plasma N-terminal pro-brain natriuretic peptide concentrations (p l 0.02). Conclusions As opposed to the conventional sequence of drug use in the treatment of heart failure, initiation of therapy with carvedilol before an ACEI results in higher tolerable doses of carvedilol and better improvements in FC and LV function.

INTRODUCTION: Whether adiponectin levels associate with atherogenesis in RA is uncertain. We examined the independent relationships of total and high molecular weight (HMW) adiponectin concentrations with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with RA. METHODS: We determined total and HMW adiponectin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), in 210 (119 black and 91 white) RA patients. Associations were determined in potential confounder and mediator adjusted mixed regression models. RESULTS: Total and HMW adiponectin concentrations related similarly to metabolic risk factors and endothelial activation. In all patients, total and HMW adiponectin concentrations associated paradoxically with high systolic, diastolic and mean blood pressure (partial R = 0.155 to 0.241, P ≤ 0.03). Ethnic origin did not impact on these relationships (interaction P ≥ 0.09). Total and HMW adiponectin concentrations associated with those of glucose in white and black patients respectively (partial R = -0.304, P = 0.006 and -0.246, P = 0.01). In black but not white participants, total and HMW adiponectin concentrations also related favorably to lipid profiles (partial R = 0.292 to 0.360, P ≤ 0.003 for HDL cholesterol concentrations, -0.269 to -0.299, P ≤ 0.006 for triglyceride concentrations and -0.302 to -0.390, P ≤ 0.002 for total-HDL cholesterol ratio) and the number of metabolic risk factors (partial R = -0.210 to -0.238, P ≤ 0.03). In white but not black patients, total and HMW adiponectin concentrations associated paradoxically with overall endothelial activation as estimated by a standard z-score of endothelial activation molecule concentrations (partial R = 0.262, P = 0.01 and 0.252, P = 0.02); in the respective models, the extent of effect of total and HMW adiponectin concentrations on endothelial activation was larger in white compared to black participants (standardized β (SE) = 0.260 (0.107) versus -0.106 (0.107), P = 0.01 and 0.260 (0.120) versus -0.100 (0.111), P = 0.02). The HMW-total adiponectin ratio related inconsistently to metabolic risk factors and not to endothelial activation. CONCLUSION: In this study, total and HMW adiponectin concentrations associated with increased blood pressure parameters, and in white patients additionally with endothelial activation. The potential mechanism(s) underlying these paradoxical relationships between adiponectin concentrations and cardiovascular risk in RA merit further investigation.

INTRODUCTION: Rheumatoid arthritis (RA) is characterized by inflamed joint-derived cytokine-mediated high-grade systemic inflammation that enhances cardiovascular metabolic risk and disease in developed populations. We investigated the potential impact of RA on cardiovascular risk factors including systemic inflammation and atherosclerosis, and their relationships in black Africans from a developing population. METHODS: We evaluated demographic features, adiposity indices, major traditional cardiovascular risk factors, circulating C-reactive protein and interleukin-6 concentrations and ultrasound determined carotid intima-media thickness (cIMT) in 274 black Africans; 115 had established RA. Data were analyzed in confounder-adjusted mixed regression models. RESULTS: The body mass index and waist-height ratio were lower in RA compared to non-RA subjects (29.2 (6.6) versus 33.7 (8.0), P < 0.0001 and 0.58 (0.09) versus 0.62 (0.1), P = 0.0003, respectively). Dyslipidemia was less prevalent in patients with RA (odds ratio (OR) (95% confidence interval (CI) = 0.54 (0.30 to 1.00)); this disparity was no longer significant after further adjustment for reduced adiposity and chloroquine use. RA was also not associated with hypertension, current smoking and diabetes. The number of major traditional risk factors did not differ by RA status (1.1 (0.8) versus 1.2 (0.9), P = 0.7). Circulating C-reactive protein concentrations were similar and serum interleukin-6 concentrations reduced in RA (7.2 (3.1) versus 6.7 (3.1) mg/l, P = 0.7 and 3.9 (1.9) versus 6.3 (1.9) pg/ml, P < 0.0001, respectively). The cIMT was 0.700 (0.085) and 0.701 (0.111) mm in RA and non-RA subjects, respectively (P = 0.7). RA disease activity and severity parameters were consistently unrelated to systemic inflammation, despite the presence of clinically active disease in 82.6% of patients. In all participants, adiposity indices, smoking and converting angiotensin inhibitor non-use were associated with increased systemic inflammation, which related to more atherogenic lipid profiles, and circulating low density lipoprotein concentrations were associated with cIMT (partial R = 0.153, P = 0.032); RA did not impact on these relationships (interaction P ≥0.1). CONCLUSIONS: Among black Africans, patients with established RA experience reduced overall and abdominal adiposity but no enhanced major traditional risk factor and atherosclerosis burden. This study further suggests that an absent interleukin-6 release by inflamed RA joints into the circulation may account for this unaltered cardiovascular disease risk.