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AIMS Whether renal mechanisms of hypertension primarily translate into increases in systemic vascular resistance (SVR) in all populations is uncertain. We determined whether renal mechanisms associate with either increases in SVR (and impedance to flow) or systemic flow in a community of African ancestry. METHOD In a South African community sampled across the full adult age range (n = 546), we assessed stroke volume (SV), peak aortic flow (Q), SVR, characteristic impedance (Zc) and total arterial compliance (TAC) from velocity and diameter measurements in the outflow tract (echocardiography) and central arterial pressures. Renal changes were determined from creatinine clearance (glomerular filtration rate, GFR) and fractional Na+ excretion (FeNa+) (derived from 24-h urine collections). RESULTS Independent of confounders (including MAP and pressures generated by the product of Q and Zc), SV (and hence cardiac output) (P

Hon-Chun Hsu,1,2 Gavin R Norton,1 Ferande Peters,1 Chanel Robinson,1 Noluntu Dlongolo,3 Ahmed Solomon,4 Gloria Teckie,5 Angela J Woodiwiss,1 Patrick H Dessein1,6,7 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 Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 5Division of Nephrology, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; 6Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa; 7Internal Medicine Department, Free University and University Hospital, Brussels, BelgiumCorrespondence: Patrick H DesseinCardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 80 Scholtz Road, Norwood, 2117, Johannesburg, South AfricaTel +27662491468Email patrick.dessein22@gmail.comIntroduction: We hypothesized that post transplantation anaemia and persistent secondary hyperparathyroidism are potential determinants of diastolic function in stable kidney transplant recipients.Methods: We assessed traditional and non-traditional cardiovascular risk factors and determined carotid artery intima-media thickness and plaque by ultrasound, arterial function by applanation tonometry using SphygmoCor software and diastolic function by echocardiography in 43 kidney transplant recipients with a transplant duration of ≥ 6 months, no acute rejection and a glomerular filtration rate of ≥ 15 mL/min/1.73m2.Results: Mean (SD; range) transplant duration was 12.3 (8.0; 0.5– 33.8) years. Post transplantation anaemia and persistent secondary hyperparathyroidism were identified in 27.9% and 30.8% of the patients, respectively; 67.5% of the participants were overweight or obese. In established confounder adjusted analysis, haemoglobin (partial R=− 0.394, p=0.01) and parathyroid hormone concentrations (partial R=0.382, p=0.02) were associated with E/e’. In multivariable analysis, haemoglobin (partial R=− 0.278, p=0.01) and parathyroid levels (partial R=0.324, p=0.04) were independently associated with E/e’. Waist–height ratio (partial R=− 0.526, p=0.001 and partial R=− 0.355, p=0.03), waist circumference (partial R=− 0.433, p=0.008 and partial R=− 0.393, p=0.02) and body mass index (partial R=− 0.332, p=0.04 and partial R=− 0.489, p=0.002) were associated with both e’ and E/A, respectively, in established confounder adjusted analysis. The haemoglobin-E/e’ (partial R=− 0.422, p=0.02), parathyroid hormone-E/e’ (partial R=0.434, p=0.03), waist–height ratio-e’ (partial R=− 0.497, p=0.007) and body mass index-E/A (partial R=− 0.386, p=0.04) relationships remained consistent after additional adjustment for left ventricular mass index and cardiac preload and afterload measures.Conclusion: Haemoglobin and parathyroid hormone concentrations as well as adiposity measures are independently associated with diastolic function in kidney transplant recipients. Whether adequate management of post transplantation anaemia, persistent secondary hyperparathyroidism and excess adiposity can prevent the development of heart failure with preserved ejection fraction in kidney transplant recipients merits further investigation.Keywords: haemoglobin, parathyroid hormone, obesity, diastolic function, kidney transplantation

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension (ISH) aimed at raising awareness of high BP and acting as a temporary solution to the lack of screening programmes worldwide. As part of MMM, screening in South Africa in 2017 and 2018 revealed that approximately one-third of adults had hypertension, that only half of hypertensives were receiving anti-hypertensive therapy and that only a third of those with hypertension had controlled BP. These data highlight the need for continued screening and awareness campaigns. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2019. Blood pressure measurements, the definition of hypertension and statistical analyses followed the MMM protocol. The sites screened were general populations, pharmacies, and university campuses in preference to hospitals and clinics, aiming to raise awareness, and allow access to screening to those less likely to be aware of their BP. Of the 4727 individuals (age 40.9 ± 18.1 years) screened, 31.9% had hypertension. Of those with hypertension, only 42.5% were aware and 36.1% were receiving treatment for hypertension. A large proportion (48.5%) of individuals receiving antihypertensive medication had uncontrolled BP. In conclusion, the high proportions of individuals unaware of their hypertension and with uncontrolled BP highlight the need for hypertension awareness campaigns and more rigorous management of hypertension.

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

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension (ISH) aimed at raising awareness of high BP and acting as a temporary solution to the lack of screening programmes worldwide. As part of MMM, screening in South Africa in 2017 revealed that 24.5% of adults (mean age = 31 years) have hypertension and only half of those with hypertension had controlled BP. These data highlight the need for continued screening and awareness campaigns. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2018. Blood pressure measurements, the definition of hypertension and statistical analyses followed the MMM protocol. The sites screened were general populations and university campuses in preference to hospitals and clinics, aiming to raise awareness and allow access to screening to those less likely to be aware of their BP. In total, 2965 individuals (age 40.5 ± 18.2 years) were screened. After multiple imputation for missing BP readings, 34.6% had hypertension, only 56.7% of those with hypertension were aware, 21.2% of those not receiving treatment for hypertension were hypertensive, and a large proportion (42.5%) of individuals receiving antihypertensive medication had uncontrolled BP. These results suggest that opportunistic screening campaigns can identify significant numbers with undiagnosed and uncontrolled hypertension. The high proportions of individuals with undiagnosed and treated uncontrolled hypertension highlight the need for hypertension awareness campaigns and more rigorous management of hypertension.

Although hypertension in groups of African ancestry is volume-dependent, the relative impact of systemic flow (stroke volume, peak aortic flow [Q]) versus vascular mechanisms (systemic vascular resistance, aortic characteristic impedance [Zc], total arterial compliance) components of arterial load has not been evaluated across the adult age range. In participants of African ancestry (n=824, age=16–99 years, 68.3% female), using central arterial pressure and aortic velocity and diameter measurements in the outflow tract, we determined the hemodynamic correlates of age-related increases in blood pressure. Strong independent positive relations between age and stroke volume or peak aortic Q were noted ( P P P P P P

The relative contribution of loading conditions at different ages across the full adult lifespan to decreases in left ventricular (LV) diastolic function is unclear. Using central arterial pressure and aortic velocity and diameter measurements in the outflow tract, we determined the contribution of systemic vascular resistance, compression wave pressures (characteristic impedance [Zc]×aortic flow [Q], [P Q×Zc ]) and backward wave pressures (Pb) to LV diastolic function (echocardiography) in a community sample across the full adult lifespan (n=605). Starting from early adulthood, stepwise age-related increases in LV filling pressures (E/e’) and decreases in myocardial relaxation (e’) were noted ( P Q×Zc positively correlates with age, Pb, but not systemic vascular resistance was independently associated with LV mass index ( P P P Q×Zc positively correlates with age, again Pb, but neither P QxZc nor systemic vascular resistance was independently associated with LV mass index ( P P P

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 β-coefficient = -0.13 ± 0.03, p < 0.0001) and plasma resistin concentrations (β-coefficient = -0.10 ± 0.02, p < 0.0001) were second only to age, and at least as strong as systolic blood pressure (β -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.

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.

AIM We hypothesized that arterial function and N-terminal natriuretic peptide (NT-proBNP) levels as a marker of volume overload, relate differently to E/e' as an index of diastolic function in dialysis compared with non-dialysis patients with chronic kidney disease. We further examined whether cardiovascular risk factors attenuated these relationships. METHODS We assessed cardiovascular risk factors and determined arterial function indices by applanation tonometry using SphygmoCor software and E/e' by echocardiography in 103 (62 non-dialysis and 41 dialysis) patients. RESULTS In established confounder adjusted analysis, dialysis status impacted the pulse wave velocity-E/e' relationship (interaction p = .01) but not the NT-proBNP level-E/e' association (interaction p = .1). Upon entering arterial function measures and NT-proBNP levels simultaneously in regression models, arterial function measures were associated with E/e' (p = .008 to .04) in non-dialysis patients whereas NT-proBNP levels were related to E/e' in dialysis patients (p = .009 to .04). Bivariate associations were found between diabetes (p

AIMS To determine whether the confounding influence of stroke work on left ventricular mass (LVM) limits the ability of LVM to detect hypertensive LV dysfunction in systemic flow-dependent hypertension. METHODS In a community with prevalent systemic flow-dependent hypertension (n = 709), arterial haemodynamics, LVM and LV function were determined using central arterial pressure, aortic velocity and diameter measurements in the outflow tract, and echocardiography with tissue Doppler imaging. RESULTS In multivariate models, stroke work showed markedly stronger relations with LVM index (LVMI) than blood pressure load [central arterial SBP (SBPc), backward wave pressure (Pb), 24-h SBP] (P

AIMS Although the development of left ventricular (LV) dysfunction in hypertension has traditionally been viewed as a transition process from a phase of structural LV remodelling to dysfunction, the extent to which LV mass (LVM) and remodelling account for blood pressure (BP)-associated alterations in LV diastolic function is uncertain. In product of coefficient mediation analysis, we aimed to determine the extent to which LVM index (LVMI) or relative wall thickness (RWT) account for relations between BP and LV diastolic function. METHODS In 709 randomly selected participants from a community sample with a high prevalence of hypertension (49.6%), we determined BP and LVMI, RWT and several indices of diastolic function from transmitral blood flow and myocardial tissue Doppler (E/A, e'/a', e' and E/e') and left atrial volume using standard echocardiographic techniques. RESULTS With adjustments for confounders, LVMI (P

Although chronic kidney disease (CKD) as determined from estimated glomerular filtration rate (eGFR) is recommended for risk prediction by current hypertension guidelines, the equations to derive eGFR may not perform well in black Africans. We compared whether across the adult lifespan, eGFR or CKD are as closely associated with noncardiac arterial vascular events, as carotid intima-media thickness (IMT), in Africa.In 1152 black South Africans [480 with noncardiac arterial events (294 with critical lower limb ischemia, 186 with stroke) of which 37% were premature] and 672 age, sex and ethnicity-matched controls from a randomly selected community sample, we assessed relations between eGFR, CKD or carotid IMT (B-mode ultrasound) and arterial events.From 20 years until old age, with or without adjustments, IMT was increased in those with as compared with without events (P 0.01 at each decade of age). However, at any decade of age across the adult lifespan neither creatinine concentrations, nor eGFR were altered in those with arterial events (P 0.28). Although IMT was strongly and independently associated with the odds of an event [odds ratio per 1 SD (0.171 mm) effect = 2.19, confidence interval = 1.75-2.78, P 0.0001], neither creatinine concentrations (P = 0.89), modification of diet in renal disease-derived (P = 0.07), nor Chronic Kidney Disease Epidemiology Collaboration-derived [odds ratio per 1 SD (22.5 ml/min per 1.73 m) effect = 1.06, confidence interval = 0.89-1.27, P = 0.51] eGFR were independently associated with the odds of an event. Although many with premature events had an increased IMT (63%), few with either premature events (8%) or with events at an older age (21%) had CKD and CKD had a poor performance (0.539 ± 0.011) and low sensitivity (16%) for event detection.In black South Africans, despite carotid IMT strongly associating with noncardiac arterial vascular events (stroke and critical lower limb ischaemia) consistently across the adult lifespan, few with events have CKD and CKD fails to associate with events.

Background Although obesity‐associated metabolic abnormalities (insulin resistance‐IR) may not play as marked a role in determining left ventricular (LV) diastolic dysfunction (DD) as hypertension, the impact of combinations of these risk factors on DD is unknown. Hypothesis We hypothesized that IR influences the impact of hypertension on DD. Methods In 704 randomly selected participants from a community sample with a high prevalence of hypertension (50.6%) and obesity (46.5%), we determined adiposity indices, IR from the homeostasis model (HOMA‐IR) and LV diastolic function using standard echocardiographic techniques. Results HOMA‐IR was independently associated with lateral wall e' and E/e' (P < 0.05 to P < 0.005) as well as a diagnosis of DD (P < 0.02). Importantly, however, an enhanced relationship between HOMA‐IR and E/e' in hypertensives (n = 356, partial r = 0.15, P < 0.005) as compared to normotensives (n = 348, partial r = 0.02 P = 0.75) was noted. Consequently, as compared to normotensives, with adjustments for confounders, hypertension was independently associated with DD only in those with the highest tertile of HOMA‐IR (odds ratio = 2.65, 95% confidence interval = 1.29‐5.42, P < 0.01), while in those with the lowest tertile of HOMA‐IR, hypertension failed to show a higher prevalence of DD (P = 0.22). Conclusions Insulin resistance enhances the impact of hypertension on LV DD. Thus, DD is more likely to occur with the combination of hypertension and IR.

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.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.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 β-coefficient) of TNF-α on RWT (0.12 ± 0.03, p 0.0005) was at least as strong as age (0.13 ± 0.05, p 0.005), and second only to LVMI (0.27 ± 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 ± 0.8), circulating TNF-α concentrations (pg/ml) were increased as much in participants with concentric LV remodelling (16.8 ± 1.5, p 0.05) as in those with concentric LV hypertrophy (LVH) (17.0 ± 1.3, p 0.005), whilst eccentric LVH (13.7 ± 0.9) was not. No independent relations between inflammatory markers and LV diastolic function (trans-mitral and tissue Doppler) were noted.Independent of LVMI, a pro-inflammatory state rather than BP load is strongly associated with LV concentric remodelling.

BACKGROUND The contribution of steady-state pressures and the forward (Pf) and backward (reflected) (Pb) wave pressure components of pulse pressure to risk prediction have produced contrasting results. We hypothesized that the independent contribution of steady-state pressures (mean arterial pressure [MAP]), Pf and Pb, to cardiovascular damage is organ specific and age dependent. METHODS In 1,384 black South Africans from a community sample, we identified independent relations between MAP, Pf, or Pb (applanation tonometry and SphygmoCor software) and left ventricular mass index (LVMI) (n = 997) (echocardiography), carotid intima-media thickness (IMT) (n = 804) (B-mode ultrasound), or aortic pulse wave velocity (PWV) (n = 1,217). RESULTS Independent of risk factors, relations between Pf and IMT were noted in those over 50 years (P < 0.02), whereas in those less than 50 years, MAP (P < 0.005) was independently associated with IMT. Pb failed to show independent relations with IMT at any age (P > 0.37) In contrast, independent relations between Pb and LVMI were noted in those less than (P < 0.0001), and greater than (P < 0.02) 50 years, whereas MAP was not independently associated with LVMI at any age (P > 0.07) and Pf tended to show significant relations only in the elderly (P = 0.05). Moreover, although MAP (P < 0.005) and Pb (P < 0.01) showed independent relations with PWV at any age, Pf failed to show independent relations (P > 0.10). CONCLUSION Independent of confounders, steady-state and aortic Pf and Pb show associations with end-organ measures that are organ specific and age dependent.

BACKGROUND Whether in volume-dependent primary hypertension, concentric left ventricular (LV) remodeling beyond hypertrophy (LVH) represents the impact of a pressure rather than a volume overload, is unclear. METHODS Using central arterial pressure, and aortic velocity and diameter measurements in the outflow tract (echocardiography), we determined the factors that associate with concentric LVH or remodeling in a community of African ancestry (n = 709) with prevalent volume-dependent primary hypertension. RESULTS Both left ventricular mass index (LVMI) and relative wall thickness (RWT) were positively and independently associated with end diastolic volume (EDV), stroke volume (SV), and peak aortic flow (Q) (P < 0.05 to CONCLUSIONS In volume-dependent primary hypertension, concentric LVH is determined as much by volume-dependent increases in systemic flow and an enhanced BP as eccentric LVH. Concentric remodeling nevertheless reflects decreases in systolic function beyond LVH.

AIM We aimed to determine whether the impact of aortic stiffness on atherosclerotic or small vessel end organ damage beyond brachial blood pressure depends in-part on stiffness-induced increases in central arterial pressures produced by an enhanced resistance to flow (characteristic impedance, Zc). METHODS We studied 1021 participants, 287 with stroke or critical limb ischaemia, and 734 from a community sample with atherosclerotic or small vessel end organ measures. Central arterial haemodynamics were determined from arterial pressure (SphygmoCor) and velocity and diameter assessments in the outflow tract (echocardiography). RESULTS Although Zc and carotid-femoral pulse wave velocity (PWV) were correlated (P

Hon-Chun Hsu,1,2 Chanel Robinson,1 Gavin R Norton,1 Angela J Woodiwiss,1 Patrick H Dessein1,3,4 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; 3Internal Medicine Department, University of the Witwatersrand, Johannesburg, South Africa; 4Free University and University Hospital, Brussels, BelgiumCorrespondence: Patrick H Dessein 80 Scholtz Road, Norwood, Johannesburg 2117, South AfricaEmail patrick.dessein22@gmail.comIntroduction: It remains unclear why the optimal haemoglobin target is lower in patients with chronic kidney disease (CKD) than in non-CKD persons. Arteriosclerosis and consequent impaired arterial function comprise a central cardiovascular risk mechanism in CKD. We hypothesized that the optimal haemoglobin target depends on its opposing effects on arterial stiffness and pressure pulsatility in CKD.Methods: Arterial stiffness (aortic pulse wave velocity), wave reflection (augmentation index, reflected wave pressure and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pressure amplification and forward wave pressure) were assessed in 48 dialysis patients.Results: In established confounder and diabetes adjusted linear regression models, haemoglobin levels were directly associated with arterial stiffness (partial R=0.366, p=0.03) and inversely with central systolic pressure (partial R=− 0.344, p=0.04), central pulse pressure (partial R=− 0.403, p=0.01), peripheral pulse pressure (partial R=− 0.521, p=0.001) and forward wave pressure (partial R=− 0.544, p=0.001). The presence of heart failure and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and erythropoietin stimulating agents did not materially alter these relationships upon further adjustment for the respective characteristics in the models, and in sensitivity analyses. In receiver operator characteristic curve analysis, the optimal haemoglobin concentration cut-off values in predicting arterial stiffness and increased central pulse pressure were remarkably similar at 10.95 g/dl and 10.85 g/dl, respectively, and with clinically useful sensitivities, specificities and positive and negative predictive values. In logistic regression models, a haemoglobin value of > 10.9 mg/dl was associated with both arterial stiffness (> 10 m/sec; OR (95% CI) = 10.48 (1.57– 70.08), p=0.02) and normal central pulse pressure (> 50 mmHg; OR (95% CI) = 7.55 (1.58– 36.03), p=0.01).Conclusion: This study suggests that the optimal haemoglobin target in dialysis patients is ∼ 11g/dl and determined by its differential and contrasting effects on arterial stiffness and pressure pulsatility.Keywords: haemoglobin target, dialysis, arterial stiffness, pressure pulsatility

AIMS Age-related increases in systemic blood flow [stroke volume (SV), cardiac output (CO), and aortic flow (Q)] contribute substantially to untreated or inadequately controlled (uncontrolled) blood pressure (BP) in Africa. We aimed to identify the haemodynamic determinants of uncontrolled systolic--diastolic (Syst--diast HT) versus uncontrolled isolated systolic (ISH) or diastolic (IDH) hypertension. METHODS Using central arterial pressure and aortic outflow tract velocity and diameter measurements (echocardiography), the haemodynamic correlates of BP were determined in 725 community participants of African ancestry (19.6% uncontrolled Syst--diast HT, 9.2% uncontrolled ISH, 11.3% uncontrolled IDH). RESULTS Independent of confounders, compared with those with a normotensive BP, those with uncontrolled Syst--diast HT had increases in SV, CO, Q, systemic vascular resistance (SVR) and aortic characteristic impedance (Zc) and decreases in total arterial compliance (TAC) (P

Objective: The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia). Approaches and Results: In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s, P P P P P Conclusions: Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.

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.

AIMS To determine the extent to which the adverse effects of blood pressure (BP) are mediated by pulsatile haemodynamic changes across the normotensive as compared with the hypertensive adult brachial BP range, and whether aortic rather than brachial pulsatile changes best index these effects. METHODS In 1307 community participants, the contribution of pulsatile haemodynamics (applanation tonometry and SphygmoCor software) to variations in left ventricular mass index (LVMI) (echocardiography) (n = 920), carotid intima-media thickness (IMT) (n = 712) and estimated glomerular filtration rate (eGFR) (n = 1164) were assessed. RESULTS In normotensive participants (50.5%) independent of steady-state pressure (mean arterial pressure), significant relations between aortic backward wave pressure and LVMI (partial r = 0.16, P

Although nitric oxide (NO) plays an important role in blood pressure (BP) control, whether variation of genes involved in regulating the synthesis of NO infl uences BP is uncertain. As the heritability of BP is stronger for ambulatory than it is for conventional BP, we assessed the independent association of the well described functional exon 7 Glu298Asp variant of the eNOS gene with the presence of hypertension in 511 randomly selected normotensive control participants and 503 hypertensives with a diagnosis of hypertension confi rmed with 24-hour ambulatory BP profiles whilst off therapy. We also assessed the relationship between eNOS genotype and 24 hour ambulatory BP. Comparisons of genotype and allele frequencies indicated a lack of association of the exon 7 Glu298Asp gene variant with hypertension (Odds ratio of genotype predicting the presence of hypertension=0.97, confidence interval=0.70-1.30, p=0.92). However, patients with the Glu/Glu genotype of the Glu298Asp variant (n=424) had increased 24-hour systolic and diastolic blood pressures (152±1/97±1 mm Hg) in comparison to patients heterozygous for the Glu298Asp variant or homozygous for the 298Asp allele (n=79) (145±1/94±1 mm Hg, p‹0.005 for systolic BP and p‹0.001 for diastolic BP after multiple adjustments including age, gender, body mass index and the presence of diabetes mellitus). Differences in systolic and diastolic BP between genotype groups were noted during the day as well as at night. The association of eNOS genotype with ambulatory BP translated into an increased risk of more severe grades of hypertension in patients with the Glu/Glu genotype (grade II and III vs. grade I, Odds ratio=2.20, confidence interval=1.34-3.59, p‹0.0002). In conclusion, a functional gene variant (Glu298Asp) at the eNOS locus contributes ~1.4-2.5% to the variation in ambulatory blood pressure within hypertensives, but is not associated with the presence of hypertension in patients in whom the diagnosis has been confirmed by 24-hour ambulatory BP values. The relationship between eNOS genotype and 24-hour ambulatory BP and the severity of hypertension warrants further study.

BACKGROUND Aortic reflected wave magnitude (RM) may not account for sex-specific differences in aortic pressure augmentation in Caucasians. However, aortic reflected waves are greater in groups of African descent than other ethnic groups. We determined whether RM or alternative factors explain the impact of sex on aortic augmented pressure (Pa) in participants of African ancestry. METHODS We assessed aortic function (radial applanation tonometry, SphygmoCor) in 1,197 randomly recruited community participants of African ancestry (age ≥ 16 years). Aortic forward (Pf) and backward (Pb) wave separation was performed assuming an aortic triangular flow wave validated against aortic velocity measurements. RESULTS Across the adult lifespan, women had greater multivariate-adjusted augmentation index (AIx) and Pa. This was associated with multivariate-adjusted age-related increases in Pb, RM (Pb/Pf), and time to the peak of Pf and decreases in backward wave foot time; but not increases in Pf. With adjustors, Pa was associated with female gender (β-coefficient = 3.81 ± 0.34), a relationship which was markedly attenuated by adjustments for RM (β-coefficient = 1.78 ± 0.31, P < 0.0001 vs. without adjustments for RM), and Pb (β-coefficient = 2.05 ± 0.19, P < 0.0001 vs. without adjustments for Pb), but not by adjustments for Pf, time to the peak of Pf, or backward wave foot time. Similarly, AIx was associated with female gender, a relationship which was markedly attenuated by adjustments for RM, Pb, and backward wave foot time, but not alternative factors. CONCLUSIONS In contrast to reports in alternative populations, the relationship between aortic pressure augmentation and female gender in participants of African descent is accounted for mainly by increases in RM.

AIM To determine the degree to which an extended time to the peak of the aortic forward wave or early wave reflection time enhance associations between aortic backward wave pressure and hence central aortic pulse pressure (PPc) and left ventricular mass index (LVMI). METHODS In 701 adult participants from a community sample either receiving no antihypertensive therapy or receiving low-dose thiazide diuretic monotherapy for at least a year (the major therapy employed), we assessed aortic haemodynamics (SphygmoCor software and wave separation analysis; AtCor Medical, West Ryder, New South Wales, Australia) and LVMI (echocardiography). RESULTS An interaction between time to the peak of the aortic forward wave and aortic backward wave pressure was independently associated with aortic augmented pressure (P

Whether excess adiposity, associated metabolic abnormalities or alternative risk factors for left ventricular (LV) diastolic function are modified rather than mediated by geometric LV remodeling, is uncertain.Echocardiographic LV mass index (LVMI), relative wall thickness (RWT) and diastolic function (lateral and septal wall myocardial tissue lengthening at the level of the mitral annulus [e'] [n=430], ratio of early-to-late transmitral blood flow velocity (E/A), and E/e' [n=430]) were determined in 737 randomly recruited participants of a community-based study (43% obese).Independent of LVMI and confounders, indexes of adiposity and the homeostasis model of insulin resistance (HOMA-IR) were independently associated with LV diastolic function (p0.05). In addition, RWT was independently associated with LV diastolic function (p0.002). Importantly, an independent interaction between HOMA-IR and RWT, but not between blood pressure or age and RWT, was related to LV diastolic function (p0.05). This translated into an independent relationship between HOMA-IR and lateral e' (partial r=-0.17, p0.02), septal e' (partial r=-0.14, p=0.05), E/A (partial r=-0.17, p0.005) and E/e' (partial r=0.19, p0.01) in those with RWT above, but a lack of relationship between HOMA-IR and LV diastolic function (p0.59) in those with RWT below the median for the sample. Similarly, HOMA-IR was independently associated with LV diastolic dysfunction in those with RWT above (p0.05) but not below (p0.19) the median for the sample.The relationship between insulin resistance, but not alternative risk factors and LV diastolic function is markedly modified by the presence of a more concentrically remodeled LV.

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 ​

The ability of carotid intima–media thickness (IMT) to predict risk beyond plaque is controversial. In 952 participants (critical limb ischemia [CLI] or stroke, n = 473; community, n = 479), we assessed whether relationships with events for IMT complement the impact of plaque in young patients depending on the extent of thrombotic versus atherosclerotic disease. The extent of atherosclerotic versus thrombotic occlusion was determined in 54 patients with CLI requiring amputations. Thrombotic occlusion in CLI was associated with younger age ( P < .0001) and less plaque ( P = .02). Independent relations between plaque and CLI were noted in older (>50 years; P < .005 to .38) participants, while independent relations between plaque and stroke ( P < .005 to

Background Aberrant hemostasis is implicated in the increased CVD risk experienced by patients with rheumatoid arthritis (RA) (1). Large circulating concentrations of plasminogen activator inhibitor-1 (PAI-1) predict cardiovascular event rates (2). PAI-1 levels are markedly smaller in American and African black populations than in those of European descent (3,4). Whether this protection persists in black persons who have RA is unknown. Objectives This study compared hemostasis factors among African black and white RA patients Methods PAI-1, tissue factor pathway inhibitor (TFPI) and tissue plasminogen activator (t-PA) levels were measured by ELISA in 236 (114 black; 122 white) African RA patients. Data were analysed in mixed regression models. Results In age and sex adjusted analysis, PAI-1 concentrations were larger in black compared to white patients with RA (median (interquartile range (IQR))=12.4 (3.1-28.7) versus 5.4 (1.5-25.0) ng/ml, p=0.006). In all patients, body mass index (BMI) (β (SE)=0.022 (0.007), p=0003), waist circumference (β (SE)=0.007 (0.003), p=0.04) and tetracycline use (β (SE)=0.291 (0.133), p=0.03) were associated with logarithmically transformed PAI-1 levels. Population grouping did not influence these relationships (interaction p>/=0.8) but impacted rheumatoid factor (RF) positivity- and azathioprine use-PAI-1 level associations (interaction p=0.03 and 0.004, respectively). In stratified analysis, RF positivity was associated with PAI-1 levels in white (β (SE)=0.344 (0.139), p=0.01) but not black patients (β (SE)=-0.102 (0.143), p=0.5), and azathioprine use was associated with PAI-1 levels in black (β=0.400 (0.155), p=0.01) but not white patients (β (SE)=0.305 (0.184), p=0.1). In age, sex, BMI, RF positivity and azathioprine and tetracycline use adjusted analysis, black population origin remained associated with PAI-1 levels (β (SE)=0.175 (0.091), p=0.05). In age and sex adjusted analysis, TFPI and t-PA levels did not differ in black compared to white RA patients (median (IQR)=221.0 (149.8-410.5) versus 225.0 (130.4-357.2) pg/ml, p=0.6, and 6.7 (4.9-9.1) versus 7.4 (4.4-10.0) pg/ml, p=0.3). Conclusion PAI-1 concentrations are substantially larger in African black compared to white patients with RA. References [1] Van den Hoever IAM, Sattar N, Nurmohamed MT. Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis 2014;73:954-7. [2] Jung RG, Motazedian P, Ramirez FD, et al. Association between plasminogen activator-1 and cardiovascular events: a systematic review and meta-analysis. Thrombosis J (2018) 16:12. [3] Festa A, D’Agostino R, Rich SS, et al. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics and non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. Circulation 2003;107:2422-7. [4] De Lange Z, Rijken DC, Hoekstra T, et al. In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time. PLoS One 2013;8 (12): e83151. Disclosure of Interests None declared

Rheumatoid arthritis (RA) impacts arterial and diastolic function. This study examined whether arterial properties can determine diastolic function in RA. In 173 RA patients, arterial function measures including carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification, and the magnitude and timing of the forward and reflected waves were measured using applanation tonometry. Diastolic function parameters including the ratio of early-to-late transmitral velocity (E/A) and ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening (e') were measured using echocardiography. The timing of the reflected wave was associated with E/A; PWV was related to E/e'. The timing of the reflected wave, forward wave magnitude, and pulse pressure amplification were associated with impaired relaxation; PWV was related to increased left ventricular (LV) filling pressure. Early wave reflection and PWV are associated with LV-impaired relaxation and increased filling pressure, respectively, in RA.

Clinical data advocating an adverse effect of obesity on left ventricular (LV) systolic function independent of comorbidities is controversial. We hypothesized that in obesity with prediabetic insulin resistance, circulating fatty acids (FAs) become a valuable fuel source in the maintenance of normal systolic function.Male Wistar rats were fed a high caloric diet for 32 weeks to induce obesity. Myocardial LV systolic function was assessed using echocardiography and isolated heart preparations.Aortic output was reduced in obese rat hearts over a range of filling pressures (for example: 15 cmH2O, obese: 32.6 ± 1.2 ml/min vs control: 46.2 ± 0.9 ml/min, P .05) when perfused with glucose alone. Similarly, the slope of the LV end-systolic pressure-volume relationship decreased, and there was a right shift in the LV end-systolic stress-strain relationship as determined in Langendorff perfused, isovolumic rat heart preparations in the presence of isoproterenol (10(-8)M) (LV systolic stress-strain relationship and a reduced load-independent intrinsic systolic myocardial function, obese: 791 ± 62 g/cm(2) vs control: 1186 ± 74 g/cm(2), P .01). The addition of insulin to the perfusion buffer improved aortic output, whereas the addition of FAs completely normalized aortic output. LV function was maintained in obese animals in vivo during an inotropic challenge.Elevated circulating FA levels may be important to maintain myocardial systolic function in the initial stages of obesity and insulin resistance.

Background Electrocardiographic (ECG) QRS voltages used to generate criteria for left ventricular hypertrophy (LVH) detection are considerably attenuated by obesity. This effect renders the utility of ECG criteria to detect LVH in obese individuals of African ancestry to be of limited value. Hypothesis A novel approach to correcting QRS voltages for the attenuating effect of body mass index (BMI) will improve the ability of ECG criteria to detect LVH in a group of African descent. Methods Left ventricular mass was determined from echocardiography in 661 randomly selected participants (43.0% obese) of black African ancestry in South Africa. Results As compared with Cornell and Sokolow-Lyon voltage criteria, BMI best correlated with RaVL, Gubner-Ungerleider, and Lewis QRS complex voltages, but these relations were noted only in those with BMI

AIM: To identify whether the more recently developed equation for estimated glomerular filtration rate (eGFR) [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] is more closely associated with end-organ changes than previous equations in a group of black African descent. METHODS: In 1221 randomly recruited participants of black African ancestry in South Africa, we evaluated serum creatinine concentrations, echocardiographic left ventricular mass index (n = 833), carotid-femoral (aortic) pulse wave velocity (PWV) (n = 1053) and carotid intima-media thickness (n = 633). We calculated eGFR from the Jelliffe, five Cockcroft-Gault, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations. RESULTS: After multivariate adjustments, eGFR calculated from all formulae was inversely associated with left ventricular mass index (P 0.08). However, although eGFR determined from all equations except Cockcroft-Gault lean body weight or adjusted body weight was independently associated with left ventricular hypertrophy (n = 390 of 833), CKD-EPI-derived eGFR, but not eGFR determined from alternative equations, was independently associated with an increased PWV (n = 88 of 1053). eGFR derived from the CKD-EPI and MDRD equations showed a better performance (area under the receiver operator characteristic curve) for the detection of left ventricular hypertrophy (P

BACKGROUND Whether the impact of backward wave pressures (Pbs) on left ventricular (LV) diastolic dysfunction (DD) antedates the effects of aortic stiffness is uncertain. We compared the relative contribution of various aortic hemodynamic parameters to preclinical DD in a predominantly young-to-middle-aged community-based sample. METHODS In 524 randomly selected participants of African ancestry (mean age = 46.8±18.4 years), we assessed central aortic pulse pressure (PPc), forward wave pressure (Pf), Pb, augmented pressure (Pa), the time-to-wave reflection (Rt), and aortic pulse wave velocity (PWV) using applanation tonometry (SphygmoCor software). LV mass index (LVMI), early to late transmitral velocity (E/A), and E/velocity of myocardial tissue lengthening (E/e') were determined using echocardiography. RESULTS Independent of age, sex, mean arterial pressure, body mass index, diabetes mellitus and/or HbA1c > 6.1%, regular smoking, regular alcohol intake, treatment for hypertension, pulse rate, and LVMI; PPc (P < 0.002), Pb (P < 0.0005), Pa (P < 0.002), and Pf (P < 0.02), but not Rt or PWV were independently associated with E/e' (but not with E/A). With adjustments for confounders, PPc (P < 0.005), Pb (P < 0.002), and Pa (P < 0.001), but not Pf, Rt, or PWV were independently associated with E/e' ≥ 12 (moderate-to-severe DD, n = 69). The independent relations between PPc and E/e' or moderate-to-severe DD were not affected by adjustments for PWV, Pf, or Rt, but were abolished with adjustments for Pb. CONCLUSIONS In a predominantly young-to-middle-aged community sample, the impact of Pbs on LV DD antedates the effects of aortic stiffness, the time-to-wave reflection, or Pfs.

Aim The aim of this work was to determine whether ethanol-associated myocardial apoptosis and cardiac dilation are related to myocardial telomere shortening in rats. Methods and Results Sprague-Dawley (SD) rats received either drinking water with (ethanol: n = 19) or without (control: n = 19) 5% (v/v) ethanol ad libitum, for 4 months. Left ventricular (LV) dimensions and function (echocardiography and isolated perfused heart preparations), cardiomyocyte apoptosis (terminal deoxynucleotide transferase–mediated dUTP nick-end labeling), and leukocyte and myocardial telomere length (real-time polymerase chain reaction) were determined at the end of the study. Ethanol administration resulted in a marked increase in cardiomyocyte apoptosis (ethanol 0.85 ± 0.13% vs control 0.36 ± 0.06%; P = .0021) and LV dilation (LV end-diastolic diameter: ethanol 8.20 ± 0.14 mm vs control 7.56 ± 0.11 mm [ P = .0014]; volume intercept at 0 mm Hg (V 0 ) of the LV end-diastolic pressure-volume relationship: ethanol 0.40 ± 0.03 mL vs control 0.31 ± 0.02 mL [ P = .020]). However, there were no changes in systolic chamber function as indexed by LV endocardial fractional shortening or the slope of the LV systolic pressure-volume relationship (end systolic elastance). The percentage of myocardial apoptosis was correlated with the degree of LV dilation (% apoptosis vs LV EDD: r = 0.39; n = 38; P = .021; vs V 0 : r = 0.44; n = 19; P = .046). No differences in leukocyte or cardiac telomere length were noted between the ethanol and control groups. Furthermore, cardiac telomere length was not associated with indexes of LV dilation (LVEDD and V 0 ) or cardiomyocyte apoptosis. Conclusions Chronic ethanol-associated myocardial apoptosis and adverse remodeling occurs independently from changes in cardiac telomere length. Telomere shortening may not be a critical mechanism responsible for cardiomyocyte apoptosis and adverse cardiac remodeling.

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

Objective.We determined the performance of the Framingham score and the Systematic COronary Risk Evaluation (SCORE) in assessing high-risk atherosclerosis in patients with rheumatoid arthritis (RA).Methods.We assembled 330 cases without established cardiovascular disease (CVD), diabetes, and moderate or severe chronic kidney disease among 451 consecutive Spanish patients who underwent CVD risk screening and carotid ultrasound-determined plaque assessment. The findings were validated in 90 black and 97 white African patients.Results.When sensitivity for the Framingham score was set at 80% in receiver-operator curve analysis [area under the curve (AUC) = 0.799], the corresponding cutoff value and specificity were 7.3% and 63%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 10.8% and 65%, respectively. When sensitivity for SCORE (AUC = 0.747) was set at 80%, the cutoff value and specificity were 0.5% and 58%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 1.5% and 50%, respectively. Upon applying a cutoff value of 7.3% for the Framingham and 0.5% for SCORE in African white patients with RA, the corresponding sensitivities and specificities were 67% and 72%, and 67% and 55%, respectively. CVD risk equations did not discriminate between black African patients with and without plaque (AUC = 0.544 and 0.549 for Framingham score and SCORE, respectively).Conclusion.The Framingham score and SCORE at markedly low cutoff values of 7.3% to 10.8% and 0.5% to 1.5%, respectively, can usefully estimate plaque presence in RA. Effective population-specific CVD risk assessment strategies are needed in black African patients with RA.

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.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).Resistin concentrations were not independently associated with blood pressure (BP). However, resistin concentrations were associated with LVMI (partial r=0.12, p0.0005), LVMinappr (partial r=0.18, p0.0001) and LV hypertrophy (partial r=0.13, p0.001) 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, p0.002 in all and partial r=-0.15, p0.0005 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.Resistin in-part explains variations in LVM, hypertrophy and myocardial systolic dysfunction, and these effects are independent of insulin resistance and general inflammatory changes.

We determined the role of high-grade inflammation on endothelial function and its association with biomarkers of endothelial dysfunction in collagen-induced arthritis. Sprague-Dawley rats were divided into a control (n = 12) or collagen-induced arthritis (CIA; n = 21) group. To induce arthritis, Bovine-type-II collagen emulsified in incomplete Freund's adjuvant was injected at the base of the tail. Nine-weeks after the primary immunisation, vascular reactivity in mesenteric and saphenous arteries was assessed using a wire-myograph. Serum concentrations of inflammatory markers (tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), C-reactive protein (CRP)) and biomarkers of endothelial dysfunction (vascular cell adhesion molecule-1 (VCAM-1) and asymmetric dimethylarginine (ADMA)) were measured by ELISA. Acetylcholine-induced relaxation in mesenteric and saphenous arteries was impaired in CIA compared to controls (P 0.05). Responses to sodium nitroprusside were similar between controls and CIA in mesenteric arteries and marginally impaired in saphenous arteries of CIA rats. Compared to controls, TNF-α, IL-6, IL-1β, CRP (all P 0.00001) and VCAM-1 (P = 0.02) were elevated in CIA. TNF-α (std β(SE) = 0.39(0.16); P = 0.03), IL-6 (std β(SE) = 0.37(0.17); P = 0.03), IL-1β (std β(SE) = 0.41(0.16); P = 0.02) and CRP (std β(SE) = 0.36(0.17); P = 0.04) were associated with VCAM-1. Associations between inflammatory markers and the maximal relaxation (E

Background Patients with rheumatoid arthritis (RA) experience an increased frequency of heart failure with a preserved ejection fraction (HFpEF) (1). The treatment of HFpEF is currently suboptimal. Elucidation of the underlying pathophysiological mechanisms of HFpEF may provide potential targets for its management. Diastolic dysfunction often precedes the progression to HFpEF (2). Abnormalities in aortic function contribute to diastolic dysfunction in non-RA populations (3,4). Objectives The aim of this study was to determine whether impaired aortic function is associated with left ventricular diastolic dysfunction in RA. Methods Arterial function was determined by applanation tonometry using SphygmoCor software and left ventricular diastolic function was assessed by echocardiography in 176 patients with RA. Markers of arterial function included carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification and the magnitude and timing of the forward and reflected waves. Markers of diastolic function included the ratio of early-to-late transmitral blood flow velocity (E/A), the ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (e’)(E/e’) and the septal and lateral e’. Relationships of comprehensively evaluated arterial function with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results The timing of the forward (Ft) and reflected (Rt) waves were each associated with E/A (Ft: partial r=0.20, p=0.02; Rt: partial r=0.30, p=0.001) and Rt was further associated with lateral e’ (partial r=0.36, p 12: OR (95% CI)=1.58 (1.04-2.38), p=0.03). Conclusions Aortic stiffness and time to wave reflection are associated with increased filling pressure and impaired relaxation of the left ventricle, respectively. The development of diastolic dysfunction in RA may be partly mediated by changes in large artery function. References: [1] Davis JM, Roger VL, Crowson CS, et al. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheumatol 2008;58:2603-11. [2] Aurigemma GP, Gottdiener JS, Shemanski L, et al. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042-8. [3] Peterson VR, Woodiwiss AJ, Libhaber CD, et al. Cardiac diastolic dysfunction is associated with aortic wave reflection, but not stiffness in a predominantly young-to-middle-aged community sample. Am J Hypertens 2016;29:1148-57. [4] Cauwenberghs N, Knez J, Tikhonoff V, et al. Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population. J Hypertens 2016;34:762-71. Disclosure of Interest: None declared

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

BACKGROUND Blunted nocturnal blood pressure (BP) dipping (nondipping) predicts cardiovascular morbidity and mortality, and is associated with heart failure (HF) independent of office BP. Whether nondipping is independently associated with cardiac systolic function prior to the development of HF is uncertain. METHODS We assessed whether nocturnal BP dipping pattern and nocturnal BP were associated with indexes of cardiac systolic function [endocardial fractional shortening (endFS), midwall FS (mFS), ejection fraction (EF)] independent of left ventricular mass index (LVMI) and relative wall thickness (RWT) in 491 randomly selected community participants not receiving antihypertensive therapy. Nocturnal BP and dipping pattern were determined from 24-hour BP monitoring where nighttime was defined from fixed-clock time intervals. BP dipping was defined as night-to-day BP ratio. Pulse wave velocity (PWV) was determined using SphygmoCor, and total peripheral resistance (TPR) was calculated from echocardiographic data. RESULTS On bivariate analyses, nocturnal BP and BP dipping but not day BP were correlated with indexes of cardiac systolic function (P < 0.005). After adjustments for potential confounders including age, LVMI (or RWT) and 24 hour (or day) BP, endFS (P < 0.01), mFS (P < 0.05), and EF (P < 0.01) were associated with nocturnal BP and BP dipping. These relationships survived further adjustments for PWV, and the homeostasis model of insulin resistance. The decreased mFS in reverse dippers was in-part explained by an increased TPR. CONCLUSIONS In an untreated community sample, blunted nocturnal BP dipping is independently and inversely associated with cardiac systolic function. Hence, nondipping is related to a reduced cardiac systolic function prior to the development of HF.

BACKGROUND Through the impact of conventional risk factors on arteries, several changes in aortic function contribute to cardiovascular events. It is nevertheless uncertain whether these effects are accurately reflected by changes in central aortic pulse pressure (PPc). We, therefore, aimed to determine the extent to which relations between modifiable risk factors and aortic function translate into increases in PPc. METHODS In 1,232 black South Africans from the South West Township (SOWETO) of Johannesburg, we determined risk factors and aortic function from carotid-femoral pulse wave velocity (PWV), aortic PPc, forward wave pressures (Pf), and reflected (backward) wave pressures (Pb) (applanation tonometry and SphygmoCor software). RESULTS With adjustments for alternative risk factors and distending pressure (mean arterial pressure (MAP)), diabetes mellitus (treatment or HbA1c > 6.5%, n = 151) was associated with an increased PWV (7.10 ± 2.09 vs. 6.17 ± 2.00 m/s, P < 0.0001), and Pf (26 ± 8 vs. 24 ± 8 mm Hg, P < 0.005), but neither brachial PP (46 ± 14 vs. 45 ± 13, P = 0.19), PPc (36 ± 12 vs. 35 ± 11 mm Hg, P = 0.48), nor Pb (17 ± 6 vs. 17 ± 6 mm Hg, P = 0.83). Moreover, independent of alternative risk factors and MAP, uncontrolled hypertension (office blood pressure > 140/90 mm Hg, n = 433) was associated with an increased Pf (26 ± 12 vs. 24 ± 10 mm Hg, P < 0.01), but not with changes in brachial PP (45 ± 19 vs. 44 ± 17, P = 0.75), PPc (35 ± 16 vs. 35 ± 15 mm Hg, P = 0.93), or Pb (18 ± 8 vs. 17 ± 8 mm Hg, P = 0.46). CONCLUSIONS Neither brachial nor aortic PP are adequate indexes of relations between the modifiable conventional risk factors, uncontrolled hypertension or diabetes mellitus, and risk-related aortic functional changes.

Cardiovascular disease (CVD) constitutes a major public health problem both in the developed and developing countries. Africa is characterized by a lack of good registries on incidence and mortality of non-communicable diseases (NCDs). Nevertheless, the Global Burden of Disease group, with the data available, showed recently that among the estimated 422 million cases of existing cardiovascular disease in the world in 2015, the age-adjusted higher prevalence of cases were from western and eastern Africa. Specifically, hypertensive heart disease was more prevalent in Africa, and this was accompanied by a higher mortality rate of this condition in this continent compared with other parts of the world.

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 (β = 0.650, p

Although aortic wave reflection may be inherited, the extent to which indexes of wave reflection derived from wave separation analysis (reflected (backward) wave index (RI) and pressure (Pb)) show intrafamilial aggregation and heritability is uncertain. We therefore aimed to determine the intrafamilial aggregation and heritability of RI and Pb and compare these with indexes of pressure augmentation.Aortic Pb, RI, augmented pressure (Pa), and augmentation index (AIx) were determined using radial applanation tonometry and SphygmoCor software in 1,152 participants of 315 families (111 father-mother, 705 parent-child, and 301 sibling-sibling pairs) from an urban developing community of black Africans. Heritability estimates were determined from Statistical Analysis for Genetic Epidemiology software.With appropriate adjustments, significant correlations were noted between parent-child pairs for Pb and Pa (P0.05 for all), but not for RI (P = 0.50) or AIx (P = 0.90) and between sib-sib pairs for Pb and Pa (P0.05), but not for RI (P = 0.54) or AIx (P = 0.14). No correlations for indexes of wave reflection were noted between fathers and mothers (P0.57). After adjustments, Pb (h2 = 0.24±0.07) and Pa (h2 = 0.23±0.07) (P0.001 for both) but not RI (h2 = 0.04±0.06, P = 0.27) or AIx (h2 = 0.10±0.07, P = 0.07) showed significant heritability.Aortic reflected (backward) waves derived from either wave separation (Pb) or pulse wave analysis (Pa) show a similar degree of intrafamilial aggregation and heritability, but the use of RI or AIx may underestimate reflected wave effects.

BACKGROUND Telomere length predicts cardiovascular disease (CVD) possibly through an impact of telomere attrition on aortic stiffness. Whether reduced biological aging and a lack of telomere length-aortic stiffness relationships in women contribute to the lower prevalence of CVD in women, prior to menopause, is uncertain. METHODS We evaluated the relationship between telomere length and carotid-femoral (aortic) pulse wave velocity (PWV) in 580 randomly recruited participants of Black African descent (age = 44 ± 19 years; women: n = 361; premenopausal: n = 195). PWV was determined using carotid and femoral applanation tonometry (SphygmoCor). Relative leukocyte telomere length (T/S) was measured using quantitative real-time polymerase chain reaction assays. RESULTS Men and women had similar T/S. T/S was inversely correlated with age (r = -0.14, P < 0.001) and this association was similar in all (r = -0.14, P < 0.01) and premenopausal (r = -0.17, P < 0.05) women as in men (r = -0.14, P < 0.05). An inverse relationship between T/S and PWV was noted both before (r = -0.20, P < 0.0001) and after (partial r = -0.14, P < 0.001) adjustments for confounders. No interaction between T/S and either sex or menopausal status was independently associated with PWV, and T/S was independently correlated with PWV in all (partial r = -0.14, P < 0.01) and premenopausal (partial r = -0.18, P < 0.05) women and in men (partial r = -0.15, P < 0.05). CONCLUSIONS Gender and premenopausal status do not affect age-related decreases in T/S and associations between T/S and PWV. In participants of African descent in whom telomere length did not differ by gender, the impact of gender prior to menopause on CVD is unlikely to be attributed to differences in the effect of biological aging on aortic stiffness.

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.