Role of atrial natriuretic peptide in the dissociation between flow relations with ventricular mass and function in a community with volume-dependent hypertension.

Background: Whether differential effects of volume load on left ventricular mass (LVM) and function occur in sustained volume-dependent primary hypertension, and the impact of atrial natriuretic peptide (ANP) on these effects, is unknown. Methods: From aortic pressure, velocity and diameter measurements and echocardiography, we determined in an African community (n = 772), the impact of systemic flow-induced increases in central pulse pressure (PPc) and circulating ANP (ELISA) on LVM and indexes of function. Results: Stroke volume (SV), but not aortic flow (Q), was associated with LVM and mean wall thickness (MWT) beyond stroke work and confounders (p < 0.0001). Adjustments for SV markedly decreased the relationships between PPc and LVMI or MWT. However, neither SV, nor Q were independently associated with either myocardial s', e', or E/e' (p > 0.14) and adjustments for neither SV nor Q modified relationships between PPc and s', e' or E/e' (p < 0.005 to <0.0001). SV was nevertheless strongly and independently associated with ANP (p < 0.0001) and ANP was similarly strikingly associated with s' (p < 0.0001) and e' (p < 0.0005), but not E/e', independent of confounders and several determinants of afterload. Importantly, ANP concentrations were inversely rather than positively associated with LV diastolic dysfunction (DD) (p < 0.005) and lower rather than higher ANP concentrations contributed markedly to the ability to detect DD in those with, but not without LV hypertrophy. Conclusion: In populations with sustained volume-dependent hypertension, flow (SV)-related increases in PP have a major impact on LV structure, but not on function, an effect attributed to parallel striking beneficial actions of ANP on myocardial function.

Attenuated Relationships Between Indexes of Volume Overload and Atrial Natriuretic Peptide in Uncontrolled, Sustained Volume-Dependent Primary Hypertension.

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<0.005) despite higher stroke volume and cardiac output (P<0.0001) and renal differences consistent with enhanced fluid retention. In those with a controlled SBP, fractional Na+ excretion (FeNa+; P<0.0005) and creatinine clearance (glomerular filtration rate; P<0.005) were inversely associated with ANP concentrations independent of confounders. Moreover, in those with a controlled SBP, stroke volume and cardiac output (P<0.0001) were independently and positively associated with ANP concentrations. In addition, in those with a controlled SBP, ANP concentrations were independently and inversely associated with systemic vascular resistance (SVR; P<0.0001) and aortic characteristic impedance (Zc; P<0.005). By contrast, in those with uncontrolled SBP, no relationships between either stroke volume (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.

Marked intrafamilial aggregation and heritability of aortic flow in a community with prevalent volume-dependent hypertension in Africa.

AIMS: 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. METHODS: 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. RESULTS: 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 ±â€Š0.07, P < 0.0001) than Zc (h2 = 0.44 ±â€Š0.10, P < 0.0001)(P < 0.005 for comparisons) and TAC (h2 = 0.47 ±â€Š0.08, P < 0.0001)(P < 0.005 for comparisons). Importantly, the heritability of Q was also greater than that for PP (h2 = 0.12 ±â€Š0.09, P = 0.11) (P < 0.0001 for comparisons), or SBP (h2 = 0.13 ±â€Š0.10, P = 0.08) (P < 0.0001 for comparisons). CONCLUSION: 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.

Contribution of systemic blood flow to untreated or inadequately controlled systolic--diastolic or isolated systolic hypertension in a community sample of African ancestry.

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 < 0.05--P < 0.0001). In multivariate regression models, uncontrolled Syst--diast HT was as strongly associated with Q, SV or CO as with SVR (P = 0.04--P = 0.20), Zc (P = 0.74--P < 0.0005) and TAC (P = 0.43--P < 0.005). Independent of confounders, compared with normotensive individuals those with uncontrolled ISH had increases in SV, CO, Q and Zc but not SVR, and decreases in TAC (P < 0.05-P < 0.0001), and those with IDH only had increases in SVR (P < 0.0001). Uncontrolled ISH was more strongly associated with Q, SV and CO than with SVR (P < 0.0005), but less than with TAC (P < 0.05--P < 0.0005). CONCLUSION: In groups of African ancestry living in Africa, hypertension because of increases in either SBP or DBP is as strongly associated with increases in systemic flow (SV, Q) as with arterial and arteriolar effects (Zc, TAC, SVR).

Impact of stroke work on the ability of left ventricular mass to account for pressure effects on function in a community with prevalent systemic flow-dependent hypertension.

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 < 0.0001 for comparisons). In contrast, although SBPc, Pb, and 24-h SBP were inversely associated with myocardial tissue shortening (s') and lengthening (e') velocity, stroke work was not. With adjustments for stroke work, positive relationships between SBPc, Pb, or 24-h SBP and LVMI were eliminated (P = 0.20 to P = 0.89), but strong relations between BP and s', e' or E/e' (P = 0.009 to P < 0.0001) remained. In mediation analysis, stroke work fully accounted for BP effects on LVMI, but explained none of the effects of BP on LV function. Hence LVMI accounted for little of the impact of BP load on LV function. Although LVMI beyond stroke work (inappropriate LVM) improved on relations between LVMI and s', it failed to improve on relations with e' or E/e' and contributed little beyond LVMI to the impact of BP on LV function. CONCLUSION: In systemic flow-dependent hypertension, the impact of stroke work markedly limits the ability of LVM to account for adverse effects of hypertension on LV function.

Hemodynamic and Functional Correlates of Concentric vs. Eccentric LVH in a Community-Based Sample With Prevalent Volume-Dependent Hypertension.

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 <0.0001). However, neither LVMI nor RWT were positively and independently associated with systemic vascular resistance (SVR), or aortic characteristic impedance (Zc) or inversely associated with total arterial compliance (TAC). Consequently, both concentric (P < 0.0001) and eccentric (P < 0.0001) LVH were associated with similar increases in EDV, SV, and either office brachial, central arterial, or 24-hour blood pressures (BP), but neither increases in SVR or Zc nor decreases in TAC. LV RWT, but not LVMI was nevertheless independently and inversely associated with myocardial systolic function (midwall shortening and s') (P < 0.05 to <0.005) and decreases in LV systolic function were noted in concentric (P < 0.05), but not eccentric LVH. 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.

Independent relationships between renal mechanisms and systemic flow, but not resistance to flow in primary hypertension in Africa.

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 < 0.0001) and Q (P < 0.01), but not SVR, Zc or TAC (P = 0.09-0.20) were independently associated with decreases in both GFR (index of nephron number) and FeNa+. Through an interactive effect (P < 0.0001), the impact of GFR on SV or Q was strongly determined by FeNa+ and vice versa. The relationship between the GFR-FeNa+ interaction and either SV or Q was noted in those above or below 50 years of age, although neither GFR, FeNa+ nor the interaction were independently associated with SVR, Zc or TAC at any age. CONCLUSION: Across the full adult lifespan, in groups of African ancestry, renal mechanisms of hypertension translate into increases in systemic flow rather than into resistance or impedance to flow.

Relations of aortic stiffness with arterial damage beyond brachial pressure are both dependent and independent of central arterial pulsatile load.

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 < 0.0001), these relations were not independent of confounders (P = 0.90). Both Zc and hence central arterial pressures generated by the product of Zc and aortic flow (Q) (PQxZc), as well as PWV were independently associated with carotid intima-media thickness, estimated glomerular filtration rate (eGFR), endothelial activation markers [vascular cell adhesion molecule-1 (V-CAM-1)] and events. With further adjustments for brachial pulse pressure (PP) or SBP, PWV and PQxZc were both associated with eGFR and V-CAM-1. Relationships between PWV and eGFR or V-CAM-1 were independent of PQxZc (P < 0.05) and relationships between PQxZc and eGFR and V-CAM-1 were independent of PWV (P < 0.005). Similarly, with adjustments for confounders and brachial PP or SBP, across the full adult lifespan, both aortic PWV and PQxZc were increased in those with arterial events (P < 0.005). Relationships between PWV and events were again independent of PQxZc (P < 0.005) and between PQxZc and events were independent of PWV (P < 0.0001). CONCLUSION: Beyond brachial blood pressure, the impact of aortic stiffness on arterial damage involves effects that are both dependent (proximal aortic Zc and hence PQxZc) and independent (full aortic length indexed by PWV) of central arterial pulsatile load. Hence, PWV and brachial PP may be insufficient to account for all of the damage mediated by increases in aortic stiffness.

Increased Aortic Characteristic Impedance Explains Relations Between Urinary Na+/K+ and Pulse or Systolic Blood Pressure.

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<0.005) but not peak aortic Q (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 [PQxZc]) 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 PQxZc. 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.

Hemodynamic Determinants of Age Versus Left Ventricular Diastolic Function Relations Across the Full Adult Age Range.

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], [PQ×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<0.0001). Before 50 years of age, before when PQ×Zc positively correlates with age, Pb, but not systemic vascular resistance was independently associated with LV mass index (P<0.002), E/e' (P<0.002), and e' (P<0.05). Moreover, in those over 50 years of age, when PQ×Zc positively correlates with age, again Pb, but neither PQxZc nor systemic vascular resistance was independently associated with LV mass index (P<0.01), E/e' (P<0.001), and e' (P<0.001). The contribution of Pb to age-related decreases in LV diastolic function was as strong in those younger as compared with older than 50 years of age and poorly indexed by brachial BP. In conclusion, a striking age-related deterioration in LV diastolic function begins at an early adult age and Pb is the dominant hemodynamic factor that accounts for this relationship. Age-related increases in Pb in young adults contribute as much to functional abnormalities ultimately responsible for LV diastolic dysfunction in hypertension as at an older age, effects poorly indexed by brachial BP.

Distinct Contribution of Systemic Blood Flow to Hypertension in an African Population Across the Adult Lifespan.

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<0.0001), effects associated with ventricular end diastolic volume and aldosterone-to-renin ratios. Age-related increases in mean arterial pressure were associated with stroke volume and not systemic vascular resistance. Although age-Q relations began from early adulthood, initially an inverse association between age and aortic Zc (P<0.0001) driven by increments in aortic root diameter (P<0.0001) prevented an enhanced systolic blood pressure and pulse pressure. When Zc began to positively relate to age (P<0.0001), age-Q relations translated into increases in forward wave pressures and hence systolic blood pressure and pulse pressure. Age relations with pulse pressure were as strongly determined by Q as by Zc or total arterial compliance (0.027±0.001 versus 0.028±0.001 and 0.032±0.003 mm Hg per yearly increase in pulse pressure produced by Q, Zc, and total arterial compliance; P<0.0001). Uncontrolled hypertension (confirmed with 24-hour blood pressure) was determined more by Q, Zc, and total arterial compliance than by increases in systemic vascular resistance (P<0.0005 for comparison). In conclusion, relationships between age and systemic blood flow contribute markedly to hypertension in groups of African origins.

Ongoing initiatives to improve the use of antibiotics in Botswana: University of Botswana symposium meeting report.

BACKGROUND AND OBJECTIVE: There are ongoing initiatives in Botswana to enhance appropriate antibiotic use. The objective of this meeting was to discuss ongoing initiatives in Botswana since February 2016 to improve antibiotic use. Subsequently, use the findings to refine national and local action plans. METHOD: Presentation and review of ongoing initiatives. RESULTS: There was a high rate of antibiotic prescribing among ambulatory care patients in the public sector (42.7%) as well as for patients with upper respiratory tract infections in the private sector (72.9%). Prophylactic antibiotics were given to 73.3% of surgical patients to reduce surgical site infections (SSIs) in a leading tertiary hospital in Botswana; however, SSIs at 9% of patients can be reduced further with better timing of antibiotic prophylaxis. To date, 711 patients have been enrolled into the national point prevalence study. Highlighted concerns included limited ordering and use of sensitivity tests despite functional laboratories, as well as concerns with missed doses of antibiotics across most hospitals. CONCLUSION: A number of issues and concerns regarding antibiotic use were highlighted. Activities are ongoing across sectors to address identified concerns.