Contribution of backward and forward wave pressures to age-related increases in aortic pressure in a community sample not receiving antihypertensive therapy.

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 aged <50 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 aged >50 years, adjustments for Pf (ß-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 aged <50 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.

Impact of aortic rather than brachial pulsatile haemodynamics on variations in end-organ measures across the full adult blood pressure range.

AIMS: To determine the extent to which the adverse effects of blood pressure (BP) are mediated by pulsatile haemodynamic changes across the normotensive as compared with the hypertensive adult brachial BP range, and whether aortic rather than brachial pulsatile changes best index these effects. METHODS: In 1307 community participants, the contribution of pulsatile haemodynamics (applanation tonometry and SphygmoCor software) to variations in left ventricular mass index (LVMI) (echocardiography) (n = 920), carotid intima-media thickness (IMT) (n = 712) and estimated glomerular filtration rate (eGFR) (n = 1164) were assessed. RESULTS: In normotensive participants (50.5%) independent of steady-state pressure (mean arterial pressure), significant relations between aortic backward wave pressure and LVMI (partial r = 0.16, P < 0.001) or IMT (partial r = 0.15, P < 0.005) and between aortic pulse wave velocity and eGFR (partial r = -0.18, P < 0.0001) were noted, effects which in hypertensive participants were observed for LVMI and eGFR, but not IMT. With adjustments for brachial pulse pressure (PP) or SBP and confounders, aortic backward wave pressure and aortic pulse wave velocity showed independent relations with LVMI, IMT or eGFR in normotensive participants, but only with LVMI or eGFR in hypertensive participants. In normotensive participants, as compared with brachial PP or SBP, aortic backward wave pressure showed a greater slope (ß-coefficient) of the relation with LVMI (0.99 ±â€Š0.24 versus 0.47 ±â€Š0.10 and 0.41 ±â€Š0.09 mmHg, P < 0.05) and IMT (0.0045 ±â€Š0.0013 versus 0.0013 ±â€Š0.0006 and 0.0013 ±â€Š0.0005 mmHg, P < 0.05) and a stronger association with left ventricular hypertrophy [odds ratios (95% confidence interval), 1.125 (1.059-1.195) versus 1.054 (1.027-1.082) and 1.042 (1.020-1.066), P < 0.05]. However, in hypertensive participants, only the slope of the aortic backward wave pressure-LVMI relationship was greater than that of PP-LVMI and SBP-LVMI relations. CONCLUSION: Beyond brachial BP, pulsatile haemodynamics rather than steady-state pressures account for end-organ effects more consistently across the normotensive than the hypertensive BP range. Hence, targeting aortic pulsatile haemodynamic changes may best limit BP-related cardiovascular risk within the normotensive BP range.

Brachial Pressure Control Fails to Account for Most Distending Pressure-Independent, Age-Related Aortic Hemodynamic Changes in Adults.

BACKGROUND: 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 BP < 140/90 mm Hg) accounts for age-related aortic hemodynamic changes across the adult lifespan. METHODS: 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 (age >16 years; 36.4% uncontrolled BP). RESULTS: 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, P < 0.02, 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 (P < 0.0001). CONCLUSION: 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.

Intrafamilial Aggregation and Heritability of Aortic Reflected (Backward) Waves Derived From Wave Separation Analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: With appropriate adjustments, significant correlations were noted between parent-child pairs for Pb and Pa (P < 0.05 for all), but not for RI (P = 0.50) or AIx (P = 0.90) and between sib-sib pairs for Pb and Pa (P < 0.05), 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 (P > 0.57). After adjustments, Pb (h2 = 0.24±0.07) and Pa (h2 = 0.23±0.07) (P < 0.001 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. CONCLUSIONS: 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.

Indexes of aortic pressure augmentation markedly underestimate the contribution of reflected waves toward variations in aortic pressure and left ventricular mass.

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<0.0001 for comparison of partial r values). In those <50 years of age, while backward wave pressures (partial r=0.28, P<0.0001) contributed more than forward wave pressures (partial r=0.15, P<0.001; P<0.05 for comparison of r values), Pa (partial r=0.13, P<0.005) contributed to a similar extent as incident wave pressure (partial r=0.22, P<0.0001) to variations in LVMI. Furthermore, in those ≥50 years of age, backward wave pressures (partial r=0.21, P<0.0001), but not forward wave pressures (P=0.98), while incident wave pressure (partial r=0.23, P<0.0001), but not Pa (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.

Gender-specific contribution of aortic augmentation index to variations in left ventricular mass index in a community sample of African ancestry.

Although indices of aortic augmentation derived from radial applanation tonometry are independently associated with adverse cardiovascular effects, whether these relationships are influenced by gender is uncertain. We compared the brachial blood pressure-independent contribution of augmentation index (AIx) to variations in left ventricular mass index (LVMI) in a community sample of 808 participants, 283 of whom were men. Aortic haemodynamics were determined using radial applanation tonometry and SphygmoCor software and LVMI from echocardiography. In men, both AIx derived from aortic augmentation pressure/central aortic pulse pressure (AP/PPc; partial r = 0.17, ß-coefficient ± s.e.m. = 0.55 ± 0.20, P < 0.01) and AIx derived from the second peak/first peak (P2/P1) of the aortic pulse wave (partial r = 0.21, ß-coefficient ± s.e.m. = 0.42 ± 0.12, P<0.0005) were associated with LVM indexed to body surface area (LVMI-BSA). In contrast, in women, neither AIx derived from AP/PPc (partial r = -0.08, ß-coefficient ± s.e.m.=-0.20 ± 0.11, P = 0.08) nor AIx derived from P2/P1 (partial r = -0.06, ß-coefficient ± s.e.m. = -0.07 ± 0.05, P = 0.17) were associated with LVMI-BSA. Both the strength of the correlations (P<0.001 and P<0.0005 with z-statistics) and the slope of the AIx-LVMI relationships (P=0.001 and P<0.0005) were greater in men as compared with women. The lack of relationship between AIx and LVMI was noted in both premenopausal (n=285; AP/PPc vs. LVMI-BSA, partial r = 0.01, P = 0.95, P2/P1 vs. LVMI-BSA, partial r = 0.02, P = 0.77), and postmenopausal (n = 240; AP/PPc vs. LVMI-BSA, partial r = -0.06, P = 0.37, P2/P1 vs. LVMI-BSA, partial r = -0.03, P = 0.64) women. Similar differences were noted in the relationships between AIx and LVM indexed to height(2.7) in men and women. In conclusion, radial applanation tonometry-derived AIx may account for less of the variation in end-organ changes in women as compared with men.

Impact of castration on changes in left ventricular diastolic pressure-volume relations induced by chronic adrenergic stimulation in rats.

A reduced testosterone concentration characterizes heart failure and independently predicts outcomes. Although testosterone replacement therapy may have non cardiac-related therapeutic benefits in heart failure, whether reduced testosterone concentrations protect against adverse left ventricular remodeling (LV dilatation) is uncertain. We therefore evaluated whether surgical castration modifies LV dilatation after 6 months of daily injections of the ß-adrenergic receptor (AR) agonist, isoproterenol (ISO) (0.015 mg·kg(-1)·d(-1)), to rats. The extent of LV dilatation and LV systolic chamber dysfunction were determined using both echocardiography and isolated perfused heart procedures. The extent of LV dilatation was determined from LV diastolic pressure-volume (P-V) relationships. As compared with the saline vehicle-treated group, after 6 months of ß-AR activation in sham-castrated rats, a marked right shift in the LV diastolic P-V relationship was noted with an increased LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (ISO = 0.38 ± 0.02, saline vehicle = 0.30 ± 0.02, P < 0.05). However, chronic ß-AR activation did not alter LV systolic chamber function either in vivo (LV endocardial fractional shortening, echocardiography) or ex vivo (LV end systolic elastance). Although castration decreased body weight, castration failed to modify the impact of ISO on the LV diastolic P-V relationships or the LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (castration ISO = 0.35 ± 0.02, castration saline vehicle = 0.27 ± 0.03, P < 0.05). In conclusion, castration does not influence the extent of LV dilatation induced by chronic adrenergic activation in an animal model, where adverse LV remodeling precedes LV systolic chamber dysfunction.

Telomere length and adrenergic-induced left ventricular dilatation and systolic chamber dysfunction in rats.

PURPOSE: The mechanisms responsible for telomere shortening in heart failure are uncertain. We evaluated whether left ventricular (LV) dilatation and systolic chamber dysfunction produced by chronic ß-adrenergic receptor (ß-AR) activation is associated with leukocyte or cardiac telomere shortening. METHODS: Following 6 months of daily injections of the ß-AR agonist, isoproterenol (0.02 mg/kg/day) or the saline vehicle to rats, the extent of LV dilatation and LV systolic chamber dysfunction were determined using echocardiography and isolated perfused heart procedures, and relative telomere length of leukocyte (LTL) and cardiac (CTL) deoxyribonucleic acid were determined using a quantitative real-time polymerase chain reaction assay. RESULTS: ß-AR activation resulted in LV dilatation as indexed by increased LV diastolic diameters (9.2 ± 0.6 vs. 8.4 ± 0.9 mm, P = 0.01) and increased diastolic volume intercepts at zero pressure of the LV diastolic pressure-volume relationship (isolated, perfused heart preparation) (0.40 ± 0.06 vs. 0.37 ± 0.08 ml, P = 0.03). Moreover, ß-AR activation resulted in LV systolic chamber dysfunction as indexed by reductions in LV endocardial fractional shortening (0.40 ± 0.05 vs. 0.45 ± 0.06, P = 0.01) and the slope of the LV systolic pressure-volume relation (609 ± 176 vs. 901 ± 230, P = 0.01). Although LTL decreased with age in rats receiving either the ß-AR agonist or the saline vehicle (P < 0.05), neither CTL (-0.10 ± 0.14 vs. -0.15 ± 0.12, P = 0.3) nor LTL (-0.11 ± 0.19 vs. -0.15 ± 0.18, P = 0.5) were modified by ß-AR activation. CONCLUSION: In conclusion, chronic ß-AR activation sufficient to produce LV dilatation and systolic chamber dysfunction is not associated with alterations in leukocyte or cardiac telomere length. Telomere shortening in chronic heart failure is unlikely to be attributed to chronic ß-AR activation.