Frederic S. Michel

Contribution of Circulating Angiotensinogen Concentrations to Variations in Aldosterone and Blood Pressure in a Group of African Ancestry Depends on Salt Intake

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<0.0001) and an index of salt intake (24-hour urinary Na+/K+, P<0.0001). An interaction between AGT and urinary Na+/K+ was independently associated with aldosterone (P<0.001) and systolic BP (SBP; P<0.05). Independent of confounders, in participants with urinary Na+/K+ at or more than the median for the sample, AGT was positively associated with aldosterone (P<0.0001) and SBP (P<0.005). No independent AGT-aldosterone or AGT-SBP relationships were noted in participants with urinary Na+/K+ less than the median for the sample. Standardized &bgr;-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<0.01–0.0001 for comparison of slopes). The AGT-SBP relationship in participants with urinary Na+/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.

Urinary Angiotensinogen Excretion Is Associated With Blood Pressure Independent of the Circulating Renin–Angiotensin System in a Group of African Ancestry

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<0.0005) but not with indexes of salt intake. However, urinary angiotensinogen/creat was independently associated with office systolic BP (partial r=0.16; P<0.001), whereas plasma angiotensinogen (partial 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<0.05). The relationships between urinary angiotensinogen/creat and BP survived further adjustments for plasma angiotensinogen and serum aldosterone concentrations, plasma renin concentrations, estimated glomerular filtration rate, urinary Na+/K+, or 24-hour urinary Na+ excretion rates (P<0.005 for all). Participants with the highest compared with the lowest quartile of urinary angiotensinogen/creat showed an 8.2-mm Hg higher office (P<0.005) and 4.6-mm Hg higher 24-hour (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.

A Mismatch Between Aortic Pulse Pressure and Pulse Wave Velocity Predicts Advanced Peripheral Arterial Disease

OBJECTIVES To determine whether increases in central aortic pulse pressure (PPc), but decreases in carotid-femoral pulse wave velocity (PWV) predict the presence of advanced peripheral arterial disease (PAD). METHODS Applanation tonometry and vascular ultrasound were employed to assess carotid-femoral PWV, PPc, and carotid intima media thickness (IMT) in 136 patients of African ancestry with chronic critical lower limb ischaemia (CLI) and in 1,030 randomly selected healthy adults of African ancestry, 194 of whom were age- and sex matched (controls). RESULTS With adjustments for confounders, compared with age- and sex-matched controls, participants with CLI had an increased carotid IMT (p = .0001) and PPc (p < .0001), but a markedly reduced PWV (m/second) (CLI = 5.7 ± 3.7, controls = 8.6 ± 3.4, p < .0001). PWV was correlated with PPc in controls (r = .52, p < .0001), but not in CLI (r = -.06). A PPc/PWV mismatch index showed increased values in participants with CLI over the full adult age range assessed. With carotid IMT, PPc, or aortic augmentation index in the same regression model, an increase in the PPc/PWV mismatch index was independently associated with CLI (p < .0001) and a PPc/PWV value upper 95% confidence interval in the community sample predicted CLI (odds ratio = 32 [6-169], p < .0001). PPc/PWV predicted CLI with a similar level of performance and accuracy and a greater specificity (98%) than that of IMT (82%). CONCLUSION In CLI, while PPc increases, carotid-femoral PWV is markedly reduced. A PPc/PWV mismatch may be a new risk marker for advanced PAD.

Insulin Resistance and the Relationship Between Urinary Na+/K+ and Ambulatory Blood Pressure in a Community of African Ancestry

BACKGROUND Although groups of African descent are particularly sensitive to blood pressure (BP) effects of salt intake, the role of obesity and insulin resistance in mediating this effect is uncertain. We determined whether obesity or insulin resistance is independently associated with urinary Na(+)/K(+)-BP relationships in a community sample of African ancestry. METHODS We measured 24-hour urinary Na(+)/K(+), homeostasis model assessment of insulin resistance (HOMA-IR), and nurse-derived conventional and 24-hour ambulatory BP in 331 participants from a South African community sample of black African descent not receiving treatment for hypertension. RESULTS With adjustments for diabetes mellitus and the individual terms, an interaction between waist circumference and urinary Na(+)/K(+) was associated with day diastolic BP (P < 0.05) and an interaction between log HOMA-IR and urinary Na(+)/K(+) was associated with 24-hour and day systolic (P < 0.05) and 24-hour, day, and night diastolic (P < 0.002; P < 0.001) BP. The multivariable-adjusted relationship between urinary Na(+)/K(+) and night diastolic BP increased across tertiles of HOMA-IR (tertile 1: β-coefficient = -0.79 ± 0.47; tertile 2: β-coefficient = 0.65 ± 0.35; tertile 3: β-coefficient = 1.03 ± 0.46; P < 0.05 tertiles 3 and 2 vs. 1). The partial correlation coefficients for relationships between urinary Na(+)/K(+) and 24-hour (partial r = 0.19; P < 0.02), day (partial r = 0.17; P < 0.05), and night (partial r = 0.18; P < 0.02) diastolic BP in participants with log HOMA-IR greater than or equal to the median were greater than those for relationships between urinary Na(+)/K(+) and 24-hour (partial r = -0.08; P = 0.29), day (partial r = -0.10; P < 0.22), and night (partial r = -0.06; P = 0.40) diastolic BP in participants with log HOMA-IR less than the median (comparisons of r values: P < 0.05). CONCLUSIONS Insulin resistance may modify the relationship between salt intake, indexed by urinary Na(+)/K(+), and ambulatory BP in groups of African descent.

Large vessel adventitial vasculitis characterizes patients with critical lower limb ischemia with as compared to without human immunodeficiency virus infection.

Objectives Whether a human immunodeficiency virus (HIV)-associated vasculitis in-part accounts for occlusive large artery disease remains uncertain. We aimed to identify the histopathological features that characterize large vessel changes in HIV sero-positive as compared to sero-negative patients with critical lower limb ischemia (CLI). Materials and Methods Femoral arteries obtained from 10 HIV positive and 10 HIV negative black African male patients admitted to a single vascular unit with CLI requiring above knee amputation were subjected to histopathological assessment. None of the HIV positive patients were receiving antiretroviral therapy. Results As compared to HIV negative patients with CLI, HIV positive patients were younger (p<0.01) and had a lower prevalence of hypertension (10 vs 90%, p<0.005) and diabetes mellitus (0 vs 50%, p<0.05), but a similar proportion of patients previously or currently smoked (80 vs 60%). 90% of HIV positive patients, but no HIV negative patient had evidence of adventitial leukocytoclastic vasculitis of the vasa vasorum (p<0.0001). In addition, 70% of HIV positive, but no HIV negative patient had evidence of adventitial slit-like vessels. Whilst T-lymphocytes were noted in the adventitia in 80% of HIV positive patients, T-lymphocytes were noted only in the intima in HIV negative patients. The presence of femoral artery calcified multilayered fibro-atheroma was noted in 40% of HIV positive and 90% of HIV negative patients with CLI. Conclusions An adventitial vasculitis which characterizes large artery changes in CLI in HIV-infected as compared to non-infected patients, may contribute toward HIV-associated occlusive large artery disease.

Relationship between inappropriate left ventricular hypertrophy and ejection fraction independent of absolute or indexed mass in a community sample of black African ancestry.

Aim: We determined whether left ventricular hypertrophy (LVH) which exceeds that predicted from workload [inappropriate LV mass (LVMinappr)] is associated with reduced left ventricle (LV) systolic chamber function independent of and more closely than absolute or indexed left ventricular mass (LVM). Methods: In 626 randomly selected adult participants from a community sample of black Africans, using echocardiography we assessed absolute LVM, LVM indexed to height2.7 (LVMI), LVMinappr, LV wall stress, ejection fraction, and midwall fractional shortening (FSmid). LVMinappr was determined as percentage of observed/predicted LVM. Predicted LVM was calculated from a previously validated formula that incorporates stroke work. LVMIinappr more than 150% was considered to be inappropriate LVH. This threshold was identified from the upper 95% confidence interval for LVMIinappr determined in 140 healthy participants. Results: A total of 21.7% of participants had LVH (LVMI > 51 g/m2.7) and 18.5% had inappropriate LVH. With adjustments for LV stress and other confounders there was a strong inverse relationship between LVMinappr and ejection fraction (partial r = −0.41, P < 0.0001), whereas only modest inverse relations between LVM or LVMI and ejection fraction were noted (partial r = −0.07 to −0.09, P < 0.05–0.09) (P < 0.0001, comparison of partial r values). The independent relationship between LVMinappr and ejection fraction persisted with further adjustments for LVM or LVMI (partial r = −0.52, P < 0.0001). LVMinappr and FSmid were similarly inversely related (P < 0.0001) and these relations were also stronger and independent of LVM or LVMI. Conclusion: Inappropriate LVH is strongly and inversely related to variations in ejection fraction independent of and more closely than LVM or LVMI in a community sample of black African ancestry. These data suggest that LVH is a compensatory response to workload, but when exceeding that predicted by workload, is associated with LV systolic chamber decompensation.

Sex-Specific Effects of Adrenergic-Induced Left Ventricular Remodeling in Spontaneously Hypertensive Rats

OBJECTIVE The aim of this work was to determine whether adrenergic-induced left ventricular (LV) dilation and eccentric remodeling in pressure-overload hypertrophy is sex specific. METHODS AND RESULTS Chronic β-adrenoreceptor activation was produced in male and female spontaneously hypertensive rats (SHRs) by means of daily administration of isoproterenol (ISO; 0.04 mg/kg daily) from 9 to 15 months of age. LV chamber dimensions were determined in vivo by means of echocardiography and ex vivo in isolated perfused heart preparations. The acute hemodynamic response to ISO, the degree of myocardial necrosis and apoptosis, and collagen distribution were also assessed. Female SHRs demonstrated inotropic and chronotropic responses to ISO similarly to male SHRs. Compared with control subjects (saline solution vehicle), following chronic ISO administration, LV end-diastolic diameter (mm) was increased in male (ISO 7.8 ± 0.3 vs control 6.6 ± 0.2; P < .001) but not in female (ISO 6.3 ± 0.2 vs control 6.2 ± 0.2; P = .23) SHRs. Similarly, compared with control, ISO administration increased the volume intercept of the LV end-diastolic pressure-volume relation (mL) in male (ISO 0.31 ± 0.02 vs control 0.22 ± 0.01; P < .0001) but not in female (ISO 0.17 ± 0.01 vs control 0.17 ± 0.01; P = 1.00) SHRs. Relative wall thickness was also decreased in male SHRs receiving ISO but not in female SHRs receiving ISO. Chronic ISO administration increased the percentage of area covered by interstitial collagen in male but not in female SHRs. Finally, chronic adrenergic stimulation failed to influence LV chamber or myocardial systolic function in either male or female SHRs. CONCLUSIONS Male SHRs are more susceptible to adrenergic-induced LV dilation and eccentric LV remodeling than female SHRs. These effects are associated with increased collagen deposition. In pressure-overload hypertrophy, LV dilation and eccentric LV remodeling occur before LV dysfunction in male rats.

Independent associations between resistin and left ventricular mass and myocardial dysfunction in a community sample with prevalent obesity

BACKGROUND 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. METHODS 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). RESULTS Resistin concentrations were not independently associated with blood pressure (BP). However, resistin concentrations were associated with LVMI (partial r=0.12, p<0.0005), LVMinappr (partial r=0.18, p<0.0001) and LV hypertrophy (partial r=0.13, p<0.001) 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, p<0.002 in all and partial r=-0.15, p<0.0005 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. CONCLUSIONS Resistin in-part explains variations in LVM, hypertrophy and myocardial systolic dysfunction, and these effects are independent of insulin resistance and general inflammatory changes.

7A.07: LIMITED CONTRIBUTION OF OBESITY TO VARIATIONS IN OFFICE, AMBULATORY AND AORTIC BLOOD PRESSURES IN A BLACK AFRICAN COMMUNITY WITH PREVALENT OBESITY AND HYPERTENSION.

Objective: Obesity causes an increased blood pressure (BP). This effect may be diminished in communities of African descent. However, the impact of obesity on ambulatory or aortic BP, which are enhanced in groups of African ancestry, has not been assessed. We aimed to determine the extent to which obesity is related to variations in office, ambulatory and aortic BP in a community sample of African ancestry with a high prevalence of obesity. Design and method: In 1167 randomly selected participants of black South African ancestry >16 years of age (42.5% obese and 45.1% with abdominal obesity), we determined the impact of adiposity indexes on age-related increases in office, ambulatory (n = 767) and aortic (n = 1141) BP. Aortic BP was determined using radial applanation tonometry and SphygmoCor software. Results: Age was strongly related to all BP values and indexes of metabolic abnormalities (p < 0.0001). Independent of age, adiposity indexes were associated with insulin resistance, HDL cholesterol, glucose and triglyceride concentrations (p < 0.0001 for all). However, across the adult lifespan neither office, 24-hour, day, night, nor aortic BP were increased in participants with an increased waist circumference (WC), or body mass index (BMI)(> = 30 kg/m2) as compared to participants with a normal WC or BMI. Independent of age, WC accounted for only 0 to 1.02% of the variation in office, 24-hour or aortic BP and translated into only a 0.38 to 1.40 mm Hg increase in office or 24-hour systolic or diastolic BP for every 15.9 to 16.6 cm (1 SD) increase in WC. Neither WC (Odds ratio = 1.12, CI = 0.78 to 1.61, p = 0.54) nor BMI (Odds ratio = 1.11, CI = 0.78 to 1.58. p = 0.55) were associated with hypertension (38.5%) diagnosed according to 24-hour BP thresholds or the presence of treatment. Independent of age, adiposity indexes were not positively associated with factors that account for age-related increases in BP (aortic pulse wave velocity, and aortic forward and backward wave pressures). Conclusions: Although obesity and hypertension are prevalent in black African communities and obesity independently associates with metabolic abnormalities, obesity plays little role in the pathogenesis of hypertension in these communities.

SAT0124 Aortic stiffness and time to wave reflection are associated with left ventricular diastolic dysfunction measures in rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) experience an increased frequency of heart failure with a preserved ejection fraction (HFpEF) (1). The treatment of HFpEF is currently suboptimal. Elucidation of the underlying pathophysiological mechanisms of HFpEF may provide potential targets for its management. Diastolic dysfunction often precedes the progression to HFpEF (2). Abnormalities in aortic function contribute to diastolic dysfunction in non-RA populations (3,4). Objectives The aim of this study was to determine whether impaired aortic function is associated with left ventricular diastolic dysfunction in RA. Methods Arterial function was determined by applanation tonometry using SphygmoCor software and left ventricular diastolic function was assessed by echocardiography in 176 patients with RA. Markers of arterial function included carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification and the magnitude and timing of the forward and reflected waves. Markers of diastolic function included the ratio of early-to-late transmitral blood flow velocity (E/A), the ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (e’)(E/e’) and the septal and lateral e’. Relationships of comprehensively evaluated arterial function with markers of LV diastolic function were determined in confounder adjusted multivariate regression models. Results The timing of the forward (Ft) and reflected (Rt) waves were each associated with E/A (Ft: partial r=0.20, p=0.02; Rt: partial r=0.30, p=0.001) and Rt was further associated with lateral e’ (partial r=0.36, p<0.0001) and septal e’ (partial r=0.36, p<0.0001); PWV was associated with E/e’ (partial r=0.18; p=0.03). Reflected wave timing was associated with two indices of impaired relaxation (E/A<0.8: OR (95% CI)=0.51 (0.29-0.91), p=0.01; lateral e’<10: OR (95% CI)=0.43 (0.26-0.71), p=0.001); PWV was associated with an increased left ventricular filling pressure (E/e’>12: OR (95% CI)=1.58 (1.04-2.38), p=0.03). Conclusions Aortic stiffness and time to wave reflection are associated with increased filling pressure and impaired relaxation of the left ventricle, respectively. The development of diastolic dysfunction in RA may be partly mediated by changes in large artery function. References: [1] Davis JM, Roger VL, Crowson CS, et al. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheumatol 2008;58:2603-11. [2] Aurigemma GP, Gottdiener JS, Shemanski L, et al. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042-8. [3] Peterson VR, Woodiwiss AJ, Libhaber CD, et al. Cardiac diastolic dysfunction is associated with aortic wave reflection, but not stiffness in a predominantly young-to-middle-aged community sample. Am J Hypertens 2016;29:1148-57. [4] Cauwenberghs N, Knez J, Tikhonoff V, et al. Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population. J Hypertens 2016;34:762-71. Disclosure of Interest: None declared