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Background: Whether systolic blood pressure (SBP) control in sustained volume-dependent primary hypertension is associated with blunted ANP (atrial natriuretic peptide) relationships with indexes of volume load is unknown. Methods: Systemic hemodynamics (central pressure, echocardiographic aortic velocity and diameter measurements in the outflow tract), circulating ANP concentrations (ELISA assays) and glomerular and tubular function (24-hour urine collections [n=519]) were determined in a community of African ancestry (n=772). Results: As compared with those with a controlled SBP, those with an uncontrolled SBP (n=198) showed lower ANP concentrations ( P P + excretion (FeNa + ; P P P P P P >0.25), cardiac output ( P >0.29), FeNa + ( P >0.77), or glomerular filtration rate ( P >0.47) and ANP concentrations were noted. Furthermore, in those with an uncontrolled SBP, no relationships between ANP concentrations and SVR or Zc were observed ( P >0.34). Conclusions: In a population where primary hypertension is strongly volume-dependent, those with an uncontrolled SBP have an attenuated relationship between ANP and both renal and hemodynamic indexes of volume overload and the vascular effects of ANP.

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.

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.

Alterations in sodium (Na + ) relative to potassium (K + ) intake increase systolic blood pressure, effects in-part attributed to enhanced pulsatile loads (pulse pressure) beyond steady-state pressures (mean arterial pressure). Whether this effect is through reversible changes (increases in blood volume and hence aortic flow [Q] or wave reflection [Pb]), or potentially irreversible structural changes in the proximal aorta, is unknown. In 581 black South Africans, we determined 24-hour urinary Na + and K + excretion and aortic function from central aortic pressure (radial pulse wave analysis [SphygmoCor software]), velocity, and diameter measurements. Proximal aortic function was assessed from characteristic impedance (Zc). Beyond mean arterial pressure and additional confounders, urinary Na + /K + was independently associated with Zc ( P P =0.30) or alternative aspects of Q or ejection volume. Although age was strongly associated with proximal aortic diameter, no independent relations between urinary Na + /K + and aortic diameter were noted ( P =0.17). Relations between urinary Na + /K + and Zc translated into independent relations with early systolic compression wave pressures (QxZc [P QxZc ]) and aortic forward wave pressures but not Pb. Moreover, neither reflected wave magnitude ( P =0.92) nor aortic pulse wave velocity were independently associated with urinary Na + /K + . In product of coefficient mediation analysis, the independent relations between urinary Na + /K + and peak aortic or brachial pulse pressure or systolic blood pressure were accounted for by Zc and P QxZc . In conclusion, abnormalities in Na + /K + intake determine pulse pressure or systolic blood pressure beyond mean arterial pressure mainly through potentially irreversible impacts on proximal aortic impedance rather than readily modifiable increases in aortic flow (blood volume) or wave reflection.

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.

Through both backward (Pb) and forward (Pf) wave effects, a lower heart rate (HR) associates with increased central (PPc), beyond brachial pulse pressure (PP). However, the relative contribution to Pf of aortic flow (Q) versus re-reflection of Pb, has not been determined. Using central pressure, aortic velocity and diameter measurements in the outflow tract (echocardiography), we constructed central pressure waveforms that account for the relative contribution of Q versus re-reflection to Pf. We thus evaluated the mechanisms of HR-PPc relations in a community sample (n=824) and the impact of age thereon. Inverse HR-PPc ( P P =0.064) relations were noted. The slope of HR-PPc relation was increased in older adults ( P P P P P P

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.

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.

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.

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.