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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

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.

Although peak aortic flow (Q) is now recognized as a major determinant of hypertension in Africa, current therapy has no proven ability to target this change. The mechanisms of this effect, therefore, require elucidation. We compared the intrafamilial aggregation and heritability of Q to that of the vascular determinants of pulse pressure (PP) and SBP in Africa.The intrafamilial aggregation and heritability of Q and aortic characteristic impedance (Zc) or total arterial compliance (TAC) was determined in 669 participants of 194 families (69 father-mother, 385 parent-child, 157 sibling-sibling pairs) in a community in Africa with prevalent flow-dependent primary hypertension. Haemodynamics were determined from velocity and diameter measurements in the outflow tract (echocardiography) and central arterial pressures.No mother-father correlations were noted for either Q or Zc. However, with adjustments for confounders, parent-child (P 0.0001) and sibling-sibling (P 0.0001) correlations were noted for Q. Parent-child and/or sibling-sibling correlations were also noted for Zc or TAC but were weaker for Zc and mother-father correlations were noted for TAC. Moreover, Q showed markedly stronger multivariate adjusted heritability estimates (h2 = 0.82 ± 0.07, P 0.0001) than Zc (h2 = 0.44 ± 0.10, P 0.0001)(P 0.005 for comparisons) and TAC (h2 = 0.47 ± 0.08, P 0.0001)(P 0.005 for comparisons). Importantly, the heritability of Q was also greater than that for PP (h2 = 0.12 ± 0.09, P = 0.11) (P 0.0001 for comparisons), or SBP (h2 = 0.13 ± 0.10, P = 0.08) (P 0.0001 for comparisons).Of the haemodynamic determinants of SBP, peak aortic flow is the most strongly inherited in Africa. Peak aortic flow, therefore, represents an important target for identifying novel therapeutic approaches to controlling SBP in Africa.

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

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

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 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

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.

Alterations in sodium (Na

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 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

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.

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

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.

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.

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.

Reports on the contribution of aortic forward (Pf) and backward (Pb) wave pressures to age-related increases in central aortic pulse pressure (PPc) have been confounded by the use of participants receiving antihypertensive therapy. We assessed the relative contribution of Pf and Pb to age-related increases in PPc (radial applanation tonometry and SphygmoCor software using an assumed triangular wave for wave separation analysis) in 892 community participants not receiving antihypertensive therapy. We validated our results using aortic flow waves (echocardiography) for wave separation analysis in 254 of these participants. In multivariate regression models in those aged50 years, adjustments for both Pb and a Pf-independent measure of reflected wave function (RM = Pb/Pf), but not Pf abolished the impact of age on PPc. However, in those aged50 years, adjustments for Pf (β-coefficient: 0.25 ± 0.06 vs. 0.74 ± 0.08; P .0001) and Pb (0.04 ± 0.04 vs. 0.74 ± 0.08; P .0001), but not RM markedly decreased the relationship between age and PPc. On product of coefficient mediation analysis, whether assessed in men or in women, in those participants aged50 years, independent of several confounders and mean arterial pressure, Pb (P .005), but not Pf contributed to age-related increases in PPc. In contrast, in those participants aged ≥50 years, independent of several confounders and mean arterial pressure, Pb (P .005) and Pf (P .01) contributed to age-related increases in PPc, and Pb effects were markedly diminished by adjustments for Pf (0.26 ± 0.002 vs. 0.52 ± 0.003 mm Hg per year, P .0001 for comparison). In conclusion, independent of the effects of antihypertensive therapy, aortic backward waves contribute to age-related increases in aortic PPc across the adult lifespan, but at an older age, this effect may be attributed in part to the impact of forward on backward wave pressures.

Aims A reduced average leucocyte telomere length is associated with ischaemic heart failure. Whether this relationship represents a cause or consequence of heart failure or is attributed to associated risk factors and coronary artery disease is uncertain. We evaluated if average leucocyte telomere length is associated with idiopathic dilated cardiomyopathy (IDC) or its severity. Methods and results We compared average leucocyte telomere length in 223 patients with heart failure due to IDC and 227 healthy controls of black African ancestry. We also evaluated the relationship between average leucocyte telomere length and left ventricular ejection fraction (LVEF). LVEF was determined using echocardiography and radionuclide multiple-gated acquisition (MUGA) scan in patients with IDC. Relative leucocyte telomere length (T/S) was measured using a quantitative real-time polymerase chain reaction assay. Log T/S was negatively correlated with age in patients with IDC (P = 0.0007) and in controls (P = 0.030), and with alcohol consumption (P = 0.032) and regular smoking (P = 0.021) in patients with IDC. Log T/S did not differ between IDC and control groups either before (P = 0.11) or after (IDC = 0.071 ± 0.187, control = 0.071 ± 0.187, P = 0.99) adjustments for confounders. Log T/S was not associated with echocardiographic (P = 0.47) or MUGA (P = 0.99) LVEF or LV end-diastolic diameter (LVEDD) (P = 0.34) in patients with IDC. With adjustments for age, sex, alcohol consumption, and smoking, log T/S was similarly not associated with echocardiographic (P = 0.60) or MUGA (P = 0.91) LVEF or LVEDD (P = 0.53) in patients with IDC. Conclusions Average relative leucocyte telomere length is not associated with IDC or its severity in groups of black African ancestry.

Aortic pulse wave velocity (PWV) and backward waves, as determined from wave separation analysis, predict cardiovascular events beyond brachial blood pressure. However, the extent to which these aortic hemodynamic variables contribute independent of each other is uncertain. In 749 randomly selected participants of African ancestry, we therefore assessed the extent to which relationships between aortic PWV or backward wave pressures (Pb) (and hence central aortic pulse pressure [PPc]) and left ventricular mass index (LVMI) occur independent of each other. Aortic PWV, PPc, forward wave pressure (Pf), and Pb were determined using radial applanation tonometry and SphygmoCor software and LVMI using echocardiography; 44.5% of participants had an increased left ventricular mass indexed to height1.7. With adjustments for age, brachial systolic blood pressure or PP, and additional confounders, PPc and Pb, but not Pf, were independently related to LVMI and left ventricular hypertrophy (LVH) in both men and women. However, PWV was independently associated with LVMI in women (partial r = 0.16, P < .001), but not in men (partial r = 0.03), and PWV was independently associated with LVH in women (P < .05), but not in men (P = .07). With PWV and Pb included in the same multivariate regression models, PWV (partial r = 0.14, P < .005) and Pb (partial r = 0.10, P < .05) contributed to a similar extent to variations in LVMI in women. In addition, with PWV and Pb included in the same multivariate regression models, PWV (P < .05) and Pb (P < .02) contributed to LVH in women. In conclusion, aortic PWV and Pb (and hence pulse pressure) although both associated with LVMI and LVH produce effects which are independent of each other.

A decreased aortic-to-brachial pulse pressure (PP) amplification, which is independently associated with cardiovascular outcomes, may index several aortic functional changes. However, that aortic functional change most likely to account for this effect is uncertain. In 706 randomly selected community participants of African ancestry with a mean age of 44.4 ± 18.2 years, we assessed aortic function using radial applanation tonometry and SphygmoCor software (including forward [Pf] and backward [Pb] wave separation analysis assuming a triangular flow waveform) and left ventricular mass index (LVMI) (echocardiography). In multivariate models with the inclusion of brachial PP, 1/PP amplification (partial r = 0.12, P .005), reflected wave pressures (partial r = 0.09, P .05), and aortic pulse wave velocity (PWV; partial r = 0.09, P .05) were independently associated with LVMI. Similarly, in multivariate models with the inclusion of brachial PP, 1/PP amplification (P .005), the reflected wave pressure (P .01), and aortic PWV (P .01) were independently associated with LVH. With adjustments for reflected wave pressures, the brachial PP-independent relationships between 1/PP amplification and LVMI or LVH were abolished (P .08 for both). However, adjustments for PWV failed to modify brachial PP-independent relations between 1/PP amplification and LVMI or LVH. Similar results were noted when brachial systolic blood pressure rather than PP was included in regression models and in sensitivity analysis conducted in participants not receiving antihypertensive therapy. In conclusion, the independent relations between the reciprocal of aortic-to-brachial PP amplification and LVMI or LVH in a largely young to middle-aged sample are accounted for by variations in backward wave pressures rather than aortic stiffness.

Although in cross-sectional studies left ventricular mass (LVM), which exceeds that predicted by workload (inappropriate LVM [LVM inappr ]) but not absolute LVM or LVM index (LVMI), is inversely related to LV ejection fraction (EF), whether on-treatment decreases in LVM inappr (%observed/predicted LVM) account for increases in EF beyond LVM or LVMI is unclear. Echocardiography was performed in 168 mild-to-moderate hypertensives treated for 4 months. Although in patients with an LVMI >51 g/m 2.7 (n=112; change in LVMI, −13.7±14.0 g/m 2.7 ; P 2.7 (n=56; change in LVMI, 1.3±9.3 g/m 2.7 ) LVMI decreased with treatment, treatment failed to increase EF in either group (1.2±10.8% and 2.7±10.7%, respectively). In contrast, in patients with inappropriate LV hypertrophy (LVM inappr >150%; n=33) LVM inappr decreased (−32±27%; P P inappr ≤150% (n=135), neither LVM inappr (−0.5±23%) nor EF (0.9±10.3%) changed with therapy. With adjustments for circumferential LV wall stress and other confounders, whereas on-treatment decreases in LVM or LVMI were weakly related to an attenuated EF (partial r =0.17; P inappr were strongly related to increases in EF even after further adjustments for LVM or LVMI (partial r =−0.63 [CI, −0.71 to −0.52]; P inappr are strongly related to on-treatment increases in EF beyond changes in LVM and LVMI. LV hypertrophy can, therefore, be viewed as a compensatory change that preserves EF, but when in excess of that predicted by stroke work, it can be viewed as a pathophysiological process accounting for a reduced EF.

Objectives One year of antihypertensive therapy may normalise left ventricular (LV) structure in 51% of hypertensive patients of European descent. Whether similar effects can be achieved in patients of African descent, who have a high prevalence of concentric LV hypertrophy (LVH) and remodelling, is unknown. Methods In 103 hypertensive patients in the Baragwanath Hypertension study we evaluated the prevalence of residual LV structural changes (echocardiography) after four and 13 months of stepwise antihypertensive therapy. Results After 13 months of therapy, 24-hour blood pressure control was achieved in 47% of patients. At baseline, 51.5% of patients had concentric LVH, 19% eccentric LVH and 12% concentric LV remodelling. Despite changes in LV mass index (p < 0.01) and relative wall thickness (p < 0.05) with treatment, the proportion of patients with a normal LV mass or geometry increased only from 17.5 to 25% (p > 0.05), while 26% remained with concentric LVH (p < 0.001 compared to baseline), 25% with eccentric LVH and 23% with concentric LV remodelling (p < 0.05 compared to baseline). Residual structural changes were associated with 24-hour pulse pressure (p = 0.02), but not with 24-hour systolic or diastolic blood pressure or clinic blood pressure. Conclusions Even after a year of antihypertensive therapy, a high proportion (74%) of hypertensives of African ancestry retained residual LV structural changes, an effect that was associated with 24-hour pulse pressure but not systolic or diastolic blood pressures or clinic blood pressure in this ethnic group.

In high-Na + , low-K + diets, which suppress renin release in salt-sensitive groups, the mechanisms maintaining increases in renin-angiotensin-aldosterone system activation downstream from renin and renin-angiotensin-aldosterone system–induced effects on blood pressure (BP) are uncertain. Whether circulating angiotensinogen concentrations (AGT) or its determinants may contribute to maintaining serum aldosterone concentrations (aldosterone) and increases in BP on high-Na + , low-K + diets was evaluated in 579 participants of a community sample of African ancestry. Plasma renin concentrations were inversely related to BP ( P + /K + , P + /K + was independently associated with aldosterone ( P P + /K + at or more than the median for the sample, AGT was positively associated with aldosterone ( P P + /K + less than the median for the sample. Standardized β-coefficients (slopes) of AGT-aldosterone and AGT-SBP relationships were greater in participants with urinary Na + /K + at or more than the median (AGT-aldosterone=0.30±0.06, AGT-SBP=0.16±0.05) compared with those with urinary Na + /K + less than the median (AGT-aldosterone=−0.04±0.06; AGT-SBP=−0.03±0.05; P + /K + at or more than the median for the sample was equivalent to the relationship between body mass index and BP. In conclusion, in participants of African ancestry, in the presence of high-Na + , low-K + diets, which suppress renin release, renin-angiotensin-aldosterone system activation and its impact on BP are maintained in part by AGT.

Objectives As the impact of mild smoking on blood pressure (BP) is uncertain, we assessed the relationship between predominantly mild current smoking and out-of-office BP and the effect of angiotensin-converting enzyme (ACE) genotype on this relationship in a community sample of black African ancestry. Methods In 689 participants randomly recruited from an urban, developing community of black African descent, we assessed smoking habits, out-of-office (24-h), and in-office conventional and central (applanation tonometry) BP, and ACE insertion (I)/deletion (D) variant genotype. Results A total of 14.5% (n = 100) were current smokers, the majority being mild (72%, 7.4 ± 4.6 cigarettes/day). Despite current smokers having only modest increases in in-office (P

AIM To determine whether high-quality nurse-recorded auscultatory blood pressure (BP) values obtained at a single visit predict cardiovascular target organ changes as closely as ambulatory BP measurements. METHODS In a randomly selected population sample (n = 458, 21% receiving antihypertensive treatment; approximately 40% hypertensive), we compared high-quality single visit nurse-recorded auscultatory BP values to same-day 24-h ambulatory BP in their ability to predict multiple target organ changes [left ventricular mass index (LVMI), left ventricle (LV) mean wall thickness (MWT), early-to-late transmitral velocity ratios (E/A), (echocardiography); log of urinary albumin-to-creatinine ratios (log ACR) (24-h urine samples); large artery dysfunction [carotid-femoral pulse wave velocity (PWV) and central augmentation index (Alc) (applanation tonometry)]. RESULTS Nurse-recorded systolic BP (SBP) measurements obtained at a single visit were as closely associated with LVMI (r = 0.44), LV MWT (r = 0.44), E/A (r = -0.55), log ACR (r = 0.20), PWV (r = 0.62) and AIc (r = 0.41) (P < 0.0001 for all relations) as was 24-h SBP (LVMI; r = 0.33, LV MWT; r = 0.37, E/A; r = -0.35, log ACR; r = 0.24, PWV; r = 0.41, and AIc; r = 0.18, P < 0.001 for all relations) and either day or night SBP. On multivariate regression analysis with both nurse-recorded SBP and 24-h SBP in the same model, nurse-recorded SBP was independently associated with LVMI (P = 0.006), LV MWT (P = 0.03), E/A (P < 0.02), PWV (P < 0.0001) and AIc (P = 0.0002), and 24-h SBP was independently and positively associated with log ACR (P < 0.005), and PWV (P = 0.01). CONCLUSION One or more, high-quality single visit nurse-recorded auscultatory BP measurements may be equally as effective as ambulatory BP in predicting target organ damage in a population sample of African ancestry.

AIM: The relationship between waist circumference (WC) and conventional blood pressure (BP) is independent of other clinical indices of adiposity. As ambulatory BP may offer more prognostic information than conventional BP, we aimed to identify whether indices of central adiposity are associated with ambulatory BP independent of other indices of adiposity. METHODS: The relationship between indices of adiposity [WC, waist-to-hip ratio, body mass index (BMI) or skin-fold thickness] and ambulatory or conventional BP was determined in 300 randomly selected individuals of African descent living in an urban developing community in South Africa. Relationships were determined with multiple indices of adiposity in the same regression model and after adjusting for age, gender, alcohol and tobacco intake, the presence or absence of diabetes mellitus or inappropriate blood glucose control [haemoglobin A1c (HbA1c)], antihypertensive therapy and menopausal status. RESULTS: Sixty-five per cent of participants were overweight or obese. With respect to the relationships between indices of adiposity, BMI and WC showed the strongest correlation (r=0.84, P

Although several indexes of left ventricular (LV) diastolic function show heritability, the genetic influence on the tissue Doppler index, E/e' (early transmitral velocity/velocity of myocardial tissue lengthening), an index of LV filling pressures in those of black African descent is currently unknown. Furthermore, whether any genetic influences on E/e' are through an impact of LV remodeling or aortic function is unknown. Intrafamilial aggregation and heritability (SAGE software) of E/e' (echocardiography) were assessed in 129 nuclear families (29 spouse pairs, 216 parent-child pairs, and 113 sibling-sibling pairs) from an urban developing community of black Africans, independent of LV mass index (LVMI), LV relative wall thickness (RWT), central aortic systolic pressure (SBPc), and backward wave pressures (Pb) (applanation tonometry, SphygmoCor software). Independent of confounders including LVMI and RWT, E/e' was correlated in parent-child (r = 0.23; P

BACKGROUND Although aortic-to-brachial pulse pressure amplification (PPamp) may offer prognostic information beyond brachial blood pressure (BP), this approach is limited in resource-limited settings. We aimed to derive an equation to impute central aortic PP (PPc) from simple clinical measures and assess whether imputed PPamp adds to the ability of brachial BP to predict mortality. METHODS An imputation equation for PPc, incorporating brachial PP, age, mean arterial pressure, and pulse rate, was identified from multivariate modeling of the factors associated with radial applanation tonometry-derived (measured) PPc in 1,179 community participants and validated in a clinical sample of 351 patients. We applied the equation to ambulatory awake BP and pulse rate values in a separate group of 4,796 patients referred for ambulatory monitoring and evaluated the impact on all-cause mortality. RESULTS Imputed PPc values closely approximated measured PPc (r (2) = 0.96, mean difference ± (2 × SD) = 1.4±6.2mm Hg). In adjusted Cox proportional models including adjustments for awake brachial PP during 47,111 person-years of follow-up, where 648 patients died, hazards ratio for all-cause mortality per SD of awake PPamp was 0.79 (95% confidence interval (CI): 0.68-0.93, P < 0.005). The hazards ratio for brachial PP with (1.49, CI = 1.36-1.64, P < 0.0001) or without (1.46, CI = 1.35-1.59, P < 0.0001) PPamp in the model was similar. Awake PPamp also predicted survival independent of awake brachial systolic BP (P < 0.0001). CONCLUSIONS PPc imputed from simple clinical assessments closely approximates measured PPc. PPamp derived from imputed PPc adds to the ability of brachial BP to predict survival. In resource-limited settings, an imputation equation may be employed to approximate aortic BP and enhance risk prediction.

AIMS To determine whether brachial blood pressure (BP)-independent relations between aortic pressure and cardiovascular damage are better explained by reflected (backward) (Pb) or forward (Pf) wave pressure effects. METHODS In 1174 participants from a community of African ancestry, we assessed central aortic pulse pressure (PPc), Pb, and Pf (radial applanation tonometry, SphygmoCor) as well as left ventricular mass index (LVMI) (n = 786), aortic pulse wave velocity (PWV) (n = 1019), carotid intima-media thickness (IMT) (n = 578), transmitral early-to-late left ventricular diastolic velocity (E/A) (n = 779) and estimated glomerular filtration rate (eGFR) (n = 1174). RESULTS Independent of mean arterial pressure and confounders, PPc, and both Pb and Pf were associated with end-organ measures or damage (P

Although several characteristics of aortic function, which are largely determined by age, predict outcomes beyond brachial blood pressure (BP), the extent to which brachial BP control accounts for age-related variations in aortic function is uncertain. We aimed to determine the extent to which brachial BP control in the general population (systolic/diastolic BP140/90 mm Hg) accounts for age-related aortic hemodynamic changes across the adult lifespan.Central aortic pulse pressure (PPc), backward wave pressure (Pb), pulse wave velocity (PWV), and PP amplification (PPamp) (applanation tonometry and SphygmoCor software) were determined in 1,185 participants from a community sample (age16 years; 36.4% uncontrolled BP).With adjustments for distending pressure (mean arterial pressure, MAP), no increases in PPc, Pb, or PWV and decreases in PPamp were noted in those with an uncontrolled brachial BP younger than 50 years. In those older than 50 years with an uncontrolled brachial BP, MAP-adjusted aortic hemodynamic variables were only modestly different to those with a controlled brachial BP (PPc, 46±14 vs. 42±15 mm Hg, P0.02, Pb, 23±8 vs. 21±8 mm Hg, PWV, 8.42±3.21 vs. 8.19±3.37 m/second, PPamp, 1.21±0.17 vs. 1.21±0.14). Nonetheless, with adjustments for MAP, marked age-related increases in PPc, Pb, and PWV and decreases in PPamp were noted in those with uncontrolled and controlled brachial BP across the adult lifespan (P0.0001).Brachial BP control in the general population fails to account for most distending pressure-independent, age-related changes in aortic hemodynamics across the adult lifespan.

Although the profibrotic inflammatory substance galectin-3 predicts outcomes in the general population, the mechanisms responsible for this effect are uncertain. We aimed to determine whether circulating galectin-3 concentrations are associated with carotid femoral (aortic) pulse wave velocity and aortic reflective wave index (applanation tonometry and SphygmoCor software) in 966 randomly selected participants from a community sample. Galectin-3 concentrations were not independently associated with office (n=966) or 24-hour (n=661) systolic ( P =0.88–0.92) or diastolic ( P =0.65–0.94) blood pressure. In contrast, with adjustments for age, sex (in all participants), office or 24-hour mean arterial pressure (or systolic blood pressure and pulse pressure), pulse rate, body mass index, regular smoking, regular alcohol intake, total cholesterol concentrations, diabetes mellitus or an glycohemoglobin >6.1%, treatment for hypertension, and estimated glomerular filtration rate, galectin-3 was independently associated with aortic pulse wave velocity in all participants (partial r =0.15, P r =0.13, P P r =0.15, P r =0.14, P r =0.12, P

Background The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. Methods We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, −20A→C), and aldosterone synthase ( CYP11B2 )(−344C→T) genes. Results The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the −344C allele (n = 75), patients who were homozygous for the −344T allele (n = 156) had both higher ambulatory SBP (150 ± 1 v 144 ± 1 mm Hg, P = .002 before and P = .01 after adjusting for multiple genotyping) and office SBP (163 ± 2 v 156 ± 2 mm Hg, P = .01 before and P = .05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. Conclusion A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

Background The T594M variant of the β-subunit of the sodium epithelial channel (ENaC) gene may contribute to hypertension in individuals of African origin. Methods A case-control study was performed to assess the role of the ENaC gene variant as an independent risk factor for hypertension in subjects of African ancestry. The effects of the ENaC gene variant on ambulatory blood pressure (BP) in hypertensive individuals and on office BP in hypertensive individuals and control subjects were also assessed. A total of 519 hypertensive patients with 24-h ambulatory BP (ABP) values determined while off medication, and 514 normotensive South African individuals of African ancestry were genotyped for the T594M polymorphism of the ENaC gene. Results A total of 22 (4.2%) hypertensive participants compared with 23 (4.5%) normotensive participants possessed the T594M variant (odds ratio = 1.06, confidence interval = 0.58 to 1.92, not significant). A similar genotype frequency distribution was noted in subjects representing the two predominant chiefdoms (Nguni and Sotho) in both case and control groups. No differences in frequency distribution of the T594M variant were noted with respect to either body mass index or gender. There were no differences in clinic or ambulatory mean, day, or night BP between hypertensive patients with or without the variant. Similarly, no differences were noted in clinic BP between control subjects with or without the variant. Other phenotypic parameters (including age and hypertension duration and severity) were also similar among hypertensive patients with or without the variant. Conclusion These results do not support an important role for the T594M variant of the ENaC gene contributing to either the development or severity of hypertension in subjects of African ancestry.

Background— The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size–BP relations. Methods and Results— Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT –6G→A, –532C→T, –20A→C, and 704T→C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The –6A and –532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the –20A→C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the –20A allele (n=399, r =0.23, P r =0.01, P =0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the –20A→C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP–age relation. Conclusion— An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.

We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and beta blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor-alpha (TNF-alpha) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-alpha, on clinical status, left ventricular function, and circulating plasma levels of TNF-alpha, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF-alpha determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P = 0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P = 0.03). Treatment with pentoxifylline (P = 0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Although indexes of wave reflection enhance risk prediction, the extent to which measures of aortic systolic pressure augmentation (augmented pressures [Pa] or augmentation index) underestimate the effects of reflected waves on cardiovascular risk is uncertain. In participants from a community sample (age >16), we compared the relative contribution of reflected (backward wave pressures and the reflected wave index [RI]) versus augmented (Pa and augmentation index) pressure wave indexes to variations in central aortic pulse pressure (PPc; n=1185), and left ventricular mass index (LVMI; n=793). Aortic hemodynamics and LVMI were determined using radial applanation tonometry (SphygmoCor) and echocardiography. Independent of confounders, RI and backward wave pressures contributed more than forward wave pressures, whereas Pa and augmentation index contributed less than incident wave pressure to variations in PPc ( P r values). In those r =0.28, P r =0.15, P P r values), Pa (partial r =0.13, P r =0.22, P r =0.21, P P =0.98), while incident wave pressure (partial r =0.23, P P =0.80) were associated with LVMI. Pa and augmentation index underestimated the effect of wave reflection on PPc and LVMI in both men and women. Thus, as compared with relations between indexes of aortic pressure augmentation and PPc or LVMI, strikingly better relations are noted between aortic wave reflection and PPc or LVMI.

Although the circulating renin–angiotensin system (RAS) is suppressed in salt-sensitive populations, the role of the intrarenal RAS in blood pressure (BP) control in these groups independent of the circulating RAS is uncertain. We evaluated the relationship between 24-hour urinary angiotensinogen excretion and either office (mean of 5 measurements; n=425) or 24-hour ambulatory (n=340) BP independent of the circulating RAS in a community-based sample of African descent that had never received antihypertensive drug therapy. Circulating RAS activity was determined from plasma renin and angiotensinogen and serum aldosterone concentrations. Urinary angiotensinogen to creatinine ratio (angiotensinogen/creat) was correlated with plasma angiotensinogen concentrations ( P r =0.16; P r =0.07; P =0.14) was not independently associated with office systolic BP. Urinary angiotensinogen/creat was also associated with 24-hour systolic BP (partial r =0.11; P + /K + , or 24-hour urinary Na + excretion rates ( P P P =0.01) systolic BP. In conclusion, independent of the systemic RAS, including plasma angiotensinogen concentrations, urinary angiotensinogen excretion is associated with BP in a salt-sensitive, low-renin group of African descent. These data lend further support for a role of the RAS in BP control in salt-sensitive groups of African ancestry.

AIMS To determine whether SBP or DBP is best associated with different components of left ventricular diastolic dysfunction. METHODS In 241 randomly selected participants, echocardiographic left ventricular diastolic function was assessed from early-to-atrial (E/A) transmitral velocity and E/e' where e' represents myocardial tissue lengthening velocity in early diastole as measured at the mitral annulus. Relationships between diastolic function and blood pressure (BP) were assessed from brachial and central aortic (radial applanation tonometry and SphygmoCor software) measurements. RESULTS Independent of confounders, brachial DBP (partial r = -0.21, P

Background —We previously reported beneficial effects of pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-α, in patients with idiopathic dilated cardiomyopathy treated with diuretics, digoxin, and ACE inhibitors. Since then, 3 large clinical trials showed important clinical benefits of β-blockers in this population. Therefore, we designed the present study to establish whether in patients with heart failure already receiving treatment with ACE inhibitors and β-blockers, the addition of pentoxifylline would have an additive beneficial effect. Methods and Results —In a single-center, prospective, double-blind, randomized, placebo-controlled study, 39 patients with idiopathic dilated cardiomyopathy were randomized to pentoxifylline 400 mg TID (n=20) or placebo (n=19) if they had a left ventricular ejection fraction P =0.01), with an increment in exercise time from 9.5±5 to 12.3±6 minutes ( P =0.1). Left ventricular ejection fraction improved from 24±9% to 31±13%, P =0.03, in the treatment group. Conclusions —In patients with idiopathic dilated cardiomyopathy, the addition of pentoxifylline to treatment with digoxin, ACE inhibitors, and carvedilol is associated with a significant improvement in symptoms and left ventricular function.

A single-center, prospective double-blind randomized trial was conducted to compare the efficacy and safety of the calcium channel blocker nisoldipine in a sustained release coat-core formulation (CC), titrated from 10 mg to 40 mg daily, with the angiotensin converting enzyme inhibitor enalapril, titrated from 10 to 40 mg daily, in the treatment of black South African patients with severe hypertension (sitting diastolic blood pressure [DBP] between 115 and 140 mm Hg, confirmed by 24-h ambulatory blood pressure monitoring). Treatment target was a sitting DBP < 95 mm Hg by the 9th week of treatment. This was followed by a 4-month open phase using nisoldipine CC 10 to 60 mg daily. Ninety-six patients had complete data at baseline, and at the end of the double-blind and open phases, and were included in this analysis. In both groups, all patients required titration up to the maximal dose of double-blind medication. Monotherapy with nisoldipine CC, but not enalapril, significantly reduced both sitting and 24-h ambulatory blood pressure (BP). Twenty-four-hour BP in the nisoldipine CC group decreased from 179+/-14 / 118+/-7 to 144+/-16 / 94+/-10 mm Hg (P < .0001) versus 181+/-13 / 117+/-5 to 171+/-17 / 110+/-11 mm Hg in the enalapril group (P = ns). The profound decrease in blood pressure achieved with nisoldipine CC was accompanied by a significant reduction in left ventricular [LV] mass index, observed after only 2 months of treatment (from 146+/-40 to 129+/-35 g/m2, P = .05). In contrast, enalapril had no effect on LV mass (from 139+/-36 to 142+/-50 g/m2, P = NS). The antihypertensive effect of nisoldipine CC was further demonstrated in the open phase, during which 24-h BP decreased from 180+/-14 / 118+/-6 mm Hg (at baseline) to 142+/-16 / 92+/-10 mm Hg at the end of the 16-week open phase (P < .0001). This effect was sustained with trough-to-peak ratio of 74% for systolic and 67% for diastolic BP, with further regression in LV mass. Reduction in 24-h systolic BP to < 135 mm Hg was associated with a greater degree of regression of LV mass index in patients treated with nisoldipine CC. The incidence of adverse events in both groups was low and both nisoldipine CC and enalapril were well tolerated. The incidence of significant ventricular arrhythmia was also low and did not change with treatment. In conclusion, our findings suggest that nisoldipine CC administered once daily could be considered as a suitable first-line antihypertensive agent in black patients with severe hypertension, based on its profound and sustained blood-pressure-lowering effect, associated with significant regression of left ventricular mass and its low side effect profile.