Pulmonary hemodynamics and wave reflections in adults with atrial septal defects.

Using high-fidelity micromanometers and flow velocity sensors at right heart catheterization, we compared pulmonary hemodynamics and wave reflections in age-matched normal adults and those with atrial septal defects, separated into three subgroups based on levels of mean pulmonary artery pressure: low (<17 mmHg), intermediate (17-26 mmHg), high (>26 mmHg). We made baseline measurements in all groups and after intravenous sodium nitroprusside in the subgroups. All of the subgroups had higher than normal baseline pulmonary flows and corresponding power that did not differ among the subgroups. The pulmonary vascular resistance, input resistance, and characteristic impedance in the subgroups did not differ from normal. Aside from the elevated flow and power, the hemodynamics in the low subgroup did not differ from normal. The intermediate subgroup had significantly higher than normal right ventricular and pulmonary artery pressures, wave reflections, and shorter wave reflection time, which all reverted to normal after nitroprusside. The high subgroup had similar changes as the intermediate subgroup. Unlike that subgroup, however, the pressures, wave reflections, and reflection return time did not revert to normal after nitroprusside. Hence, elevated wave reflections, but not resistance or characteristic impedance, are the hallmark of pulmonary hypertension in adults with atrial septal defects. Our results demonstrate that detailed measurements of hemodynamics and assessment of responsiveness to vasodilators provide important information about the pulmonary circulation in atrial septal defect. Coupled with studies after defect closure, those results may be a better foundation than current ones for clinical decisions.

Arterial Hemodynamics in Prehypertensives.

Compared to age-matched normotensive adults, those with essential hypertension have been shown to have distinct arterial hemodynamic abnormalities consisting of increased peripheral resistance, pulse wave velocity, and wave reflection magnitude as well as decreased wave reflection time and aortic compliance. These abnormalities are further exacerbated by beta-adrenergic blockade. To see if there are similar hemodynamic abnormalities that antedate the onset of fixed hypertension, we compared age-matched normotensives with prehypertensives selected from patients undergoing diagnostic cardiac catheterization. Ascending aortic pressure and flow were measured with a micromanometer and flow velocity sensor in the baseline state and after beta-adrenergic blockade. In the baseline state the prehypertensive compared to the normotensive group had elevated blood pressure, resistance, left ventricular end-diastolic pressure (LVEDP), and wave reflections. Beta-adrenergic blockade increased resistance, LVEDP, and wave reflections in both groups. Some of these findings are the same as those we previously reported in young persons with established, essential hypertension. The differences in LVEDP and wave reflections, both in the baseline state and after beta-blockade, were still present in subgroups with no differences in blood pressure. Hence, the elevated wave reflections in prehypertensives do not appear to be directly related to the level of blood pressure. These results support the notion that the elevated blood pressure in hypertension may represent a later manifestation of an already abnormal vascular system rather than the vascular abnormalities resulting from hypertension. Consequently, even before blood pressure becomes elevated, early diagnosis and treatment of the vascular abnormalities in prehypertensives may be warranted.

Prognostic Utility of Morning Blood Pressure Surge for 20-Year All-Cause and Cardiovascular Mortalities: Results of a Community-Based Study.

BACKGROUND: Morning blood pressure (BP) surge (MS), defined by the MS amplitude, is an independent prognostic factor of cardiovascular outcomes in some, but not all, populations. METHOD AND RESULTS: We enrolled 2020 participants (1029 men; aged 30-79 years) with 24-hour ambulatory BP data. During a median 19.7-year follow-up, 607 deaths (182 by cardiovascular causes) were confirmed from the National Death Registry. The amplitude of sleep-trough MS (STMS) was derived from the difference between morning systolic BP (SBP) and lowest nighttime SBP. The rate of STMS was derived as the slope of linear regression of sequential SBP measures on time intervals within the STMS period. Thresholds for high STMS amplitude and rate were determined by the 95th percentiles (43.7 mm Hg and 11.3 mm Hg/h, respectively). Multivariable Cox models, adjusting for age, sex, body mass index, smoking, alcohol, low-density lipoprotein cholesterol, 24-hour SBP, night:day SBP ratio, and antihypertensive treatment, revealed that a high STMS rate (hazard ratio, 1.666; 95% confidence interval, 1.185-2.341), but not STMS amplitude (hazard ratio, 1.245; 95% confidence interval, 0.984-1.843), was significantly associated with a greater mortality risk. Similarly, STMS rate (hazard ratio, 2.608; 95% confidence interval, 1.554-4.375), but not STMS amplitude, was significantly associated with the risk of cardiovascular mortality (hazard ratio, 0.966; 95% confidence interval, 0.535-1.747). Moreover, the prognostic values of STMS rate were comparable in subjects with or without morning and nocturnal hypertension (P>0.05 for interaction for all). In simulation studies, STMS rate was less susceptible to measurement errors of the sleep-trough SBP than STMS amplitude. CONCLUSIONS: STMS rate could independently help identify subjects with an increased cardiovascular risk.

Hemodynamic Determinants of the Short-Term Blood Pressure Variability: Differential Roles of Arterial Stiffness and Wave Reflection.

BACKGROUND: A high 24-hour ambulatory diastolic (DBP) but not systolic (SBP) blood pressure variability (BPV) is significantly predictive of long-term cardiovascular mortality in untreated hypertensive subjects, independent of office or 24-hour SBP. The present study was aimed to investigate hemodynamic factors that are independently associated with systolic and diastolic BPV from the 24-hour ambulatory blood pressure monitoring (ABPM). METHODS: A cohort of 624 normotensive and 633 untreated hypertensive participants with baseline ABPM was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour SBP and DBP (ARVs and ARVd, respectively). Hemodynamic variables including total peripheral resistance (TPR), carotid-femoral pulse wave velocity (cf-PWV), and amplitudes of the decomposed forward (Pf) and backward (Pb) carotid pressure waves were analyzed. RESULTS: In multivariable analyses, hemodynamic variables independently associated with 24-hour SBP were 24-hour heart rate (HR), TPR, cf-PWV, Pf, and Pb (model r2 = 0.535). Hemodynamic factors independently associated with ARV were 24-hour HR, Pf, and Pb for ARVs, and 24-hour HR, cf-PWV, Pf, and Pb for ARVd (model R2 = 0.345 and 0.220, respectively). Addition of 24-hour SBP to the ARV models only slightly improved variance explained by the models (R2 = 0.383 and 0.224, respectively). Pb accounted for >50% of total variance of ARVs and ARVd, whereas cf-PWV was a minor determinant of ARVd (<5% of total variance). CONCLUSIONS: ARVd was associated with fewer hemodynamic variables than to 24-hour SBP. Among those hemodynamic variables wave reflection but not arterial stiffness had the dominant independent association with ARV.

Prognostic significance of mechanical biomarkers derived from pulse wave analysis for predicting long-term cardiovascular mortality in two population-based cohorts.

BACKGROUND: Numerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts. METHODS: PWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI). RESULTS: In multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density- and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08-1.28, p<0.001; DC: 1.18 [1.09-1.28], p<0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI=0.049, p=0.0361), SC (NRI=0.043, p=0.0236) and DC (NRI=0.054, p=0.047). CONCLUSIONS: Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts.

High Short-Term Blood Pressure Variability Predicts Long-Term Cardiovascular Mortality in Untreated Hypertensives But Not in Normotensives.

BACKGROUND: The prognostic value of the short-term blood pressure variability (BPV) from the 24-hour ambulatory blood pressure monitoring (ABPM) remains controversial. The present study aimed to investigate the long-term prognostic value of a high BPV in normotensive and hypertensive subjects from a community-based population. METHODS: A cohort of 624 normotensive and 633 untreated hypertensive Taiwanese participants (overall 669 men, aged 30-79 years) with baseline ABPM and 20-year all-cause and cardiovascular mortality data was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour diastolic and systolic blood pressure (SBP) (ARVd and ARVs, respectively). RESULTS: In Cox proportional hazards analysis, ARVd predicted cardiovascular mortality independently of office SBP (hazard ratios (HRs) and 95% confidence intervals (CIs) per 1 SD: 1.31 (1.10-1.55), respectively, bivariate analysis), 24-hour SBP (HR: 1.19, 95% CI: 1.00-1.43), and conventional risk factors (age, sex, smoking, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose, HR: 1.40, 95% CI: 1.18-1.67). In subjects with hypertension, a high vs. low ARVd (median: 8.8mm Hg) significantly predicted cardiovascular mortality (HR: 2.11, 95% CI: 1.23-3.62 and HR: 2.04, 95% CI: 1.19-3.51, respectively), when the conventional risk factors plus office SBP or 24-hour SBP were accounted for, respectively. Similar but less significant results were obtained with ARVs. A high ARVd or ARVs did not significantly predict cardiovascular mortality in the normotensive subjects. CONCLUSIONS: A high short-term BPV is significantly predictive of long-term cardiovascular mortality in untreated hypertensive but not normotensive community-based subjects, independently of office or 24-hour SBP.

White coat hypertension is more risky than prehypertension: important role of arterial wave reflections.

Arterial aging may link cardiovascular risk to white coat hypertension (WCH). The aims of the present study were to investigate the role of arterial aging in the white coat effect, defined as the difference between office and 24-hour ambulatory systolic blood pressures, and to compare WCH with prehypertension (PH) with respect to target organ damage and long-term cardiovascular mortality. A total of 1257 never-been-treated volunteer subjects from a community-based survey were studied. WCH and PH were defined by office and 24-hour ambulatory blood pressures. Left ventricular mass index, carotid intima-media thickness, estimated glomerular filtration rate, carotid-femoral pulse wave velocity, carotid augmentation index, amplitude of the reflection pressure wave, and 15-year cardiovascular mortality were determined. Subjects with WCH were significantly older and had greater body mass index, blood pressure values, intima-media thickness, carotid-femoral pulse wave velocity, augmentation index, amplitude of the backward pressure wave, and a lower estimated glomerular filtration rate than PH. Amplitude of the backward pressure wave was the most important independent correlate of the white coat effect in multivariate analysis (model r(2)=0.451; partial r(2)/model r(2)=90.5%). WCH had significantly greater cardiovascular mortality than PH (hazard ratio, 2.94; 95% confidence interval, 1.09-7.91), after accounting for age, sex, body mass index, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein-cholesterol ratio. Further adjustment of the model for amplitude of the backward pressure wave eliminated the statistical significance of the WCH effect. In conclusion, the white coat effect is mainly caused by arterial aging. WCH carries higher risk for cardiovascular mortality than PH, probably via enhanced wave reflections that accompany arterial aging.

Associations of serum uric acid levels with arterial wave reflections and central systolic blood pressure.

BACKGROUND: Uric acid may be involved in the pathogenesis of hypertension. We investigated the roles of four major hemodynamic parameters of blood pressure, including arterial stiffness, wave reflections, cardiac output (CO), and total peripheral resistance (TPR), in the association between uric acid and central systolic blood pressure (SBP-c). METHODS: A sample of 1303 normotensive and untreated hypertensive Taiwanese participants (595 women, aged 30-79 years) was drawn from a community-based survey. Study subjects' baseline characteristics, biochemical parameters, carotid-femoral pulse wave velocity (cf-PWV), amplitude of the backward pressure wave decomposed from a calibrated tonometry-derived carotid pressure waveform (Pb), CO, TPR, and SBP-c were analyzed. RESULTS: In multi-variate analyses adjusted for age, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate, uric acid significantly correlated with Pb and cf-PWV in men, and Pb and TPR in women. The correlation between uric acid and Pb remained significant in men and women when cf-PWV was further adjusted. In the final multi-variate prediction model (model r(2)=0.839) for SBP-c, the significant independent variables included uric acid (partial r(2)=0.005), Pb (partial r(2)=0.651), cf-PWV (partial r(2)=0.005), CO (partial r(2)=0.062), TPR (partial r(2)=0.021), with adjustment for age, sex, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate. CONCLUSIONS: Uric acid was significantly independently associated with wave reflections, which is the dominant determinant of SBP-c. Uric acid was also significantly associated with SBP-c independently of the major hemodynamic parameters.

α-actinin1 and 4 tyrosine phosphorylation is critical for stress fiber establishment, maintenance and focal adhesion maturation.

In polarized, migrating cells, stress fibers are a highly dynamic network of contractile acto-myosin structures composed of bundles of actin filaments held together by actin cross-linking proteins such as α-actinins. As such, α-actinins influence actin cytoskeleton organization and dynamics and focal adhesion maturation. In response to environmental signals, α-actinins are tyrosine phosphorylated and this affects their binding to actin stress fibers; however, the cellular role of α-actinin tyrosine phosphorylation remains largely unknown. We found that non-muscle α-actinin1/4 are critical for the establishment of dorsal stress fibers and maintenance of transverse arc stress fibers. Analysis of cells genetically depleted of α-actinin1 and 4 reveals two distinct modes for focal adhesion maturation. An α-actinin1 or 4 dependent mode that uses dorsal stress fiber precursors as a template for establishing focal adhesions and their maturation, and an α-actinin-independent manner that uses transverse arc precursors to establish focal adhesions at both ends. Focal adhesions formed in the absence of α-actinins are delayed in their maturation, exhibit altered morphology, have decreased amounts of Zyxin and VASP, and reduced adhesiveness to extracellular matrix. Further rescue experiments demonstrate that the tyrosine phosphorylation of α-actinin1 at Y12 and α-actinin4 at Y265 is critical for dorsal stress fiber establishment, transverse arc maintenance and focal adhesion maturation.

Central versus ambulatory blood pressure in the prediction of all-cause and cardiovascular mortalities.

OBJECTIVES: Central systolic (SBP-C) and/or pulse pressure (PP-C) better predicts cardiovascular events than does peripheral blood pressure. The present study compared the prognostic significance of office central blood pressure with multiple measurements of out-of-office ambulatory peripheral blood pressure, with reference to office peripheral systolic (SBP-B) or pulse pressure (PP-B). METHODS: In a community-based population of 1014 healthy participants, SBP-C and PP-C were estimated using carotid tonometry, and 24-h systolic (SBP-24 h) and pulse pressure (PP-24 h) were obtained from 24-h ambulatory blood pressure monitoring. Associations of SBP-B, PP-B, SBP-C, PP-C, SBP-24 h, and PP-24 h with all-cause and cardiovascular mortalities over a median follow-up of 15 years were examined by Cox regression analysis. RESULTS: In multivariate analyses accounting for age, sex, BMI, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein cholesterol ratio, only PP-C (hazard ratio 1.16, 95% confidence interval 1.01-1.32, per one standard deviation increment) was significantly predictive of all-cause mortality, whereas all but PP-B were significantly predictive of cardiovascular mortality. When SBP-B was simultaneously included in the models, SBP-24 h (2.01, 1.42-2.85) and SBP-C (1.71, 1.21-2.40) remained significantly predictive of cardiovascular mortality. When SBP-C was simultaneously included in the models, SBP-24 h (1.71, 1.16-2.52) remained significantly predictive of cardiovascular mortality. CONCLUSION: Office central blood pressure is more valuable than office peripheral blood pressure in the prediction of all-cause and cardiovascular mortalities. Out-of-office ambulatory peripheral blood pressure (SBP-24 h) may be superior to central blood pressure in the prediction of cardiovascular mortality, but PP-C may better predict all-cause mortality than SBP-24 h or PP-24 h.

Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study.

The value of increased arterial wave reflection, usually assessed by the transit time-dependent augmentation index and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit time-independent measures of reflected wave magnitude predict cardiovascular outcomes independent of arterial stiffness indexed by carotid-femoral pulse wave velocity. A total of 1272 participants (47% women; mean age: 52+/-13 years; range: 30 to 79 years) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed into their forward wave amplitudes, backward wave amplitudes (Pb), and a reflection index (=[Pb/(forward wave amplitude+Pb)]), in addition to augmentation index, Pa, and reflected wave transit time. During a median follow-up of 15 years, 225 deaths occurred (17.6%), including 64 cardiovascular origins (5%). In univariate Cox proportional hazard regression analysis, pulse wave velocity, Pa, and Pb predicted all-cause and cardiovascular mortality in both men and women, whereas augmentation index, reflected wave transit time, and reflection index were predictive only in men. In multivariate analysis accounting for age, height, and heart rate, Pb predicted cardiovascular mortality in both men and women, whereas Pa was predictive only in men. Per 1-SD increment (6 mm Hg), Pb predicted 15-year cardiovascular mortality independent of brachial but not central pressure, pulse wave velocity, augmentation index, Pa, and conventional cardiovascular risk factors with hazard ratios of approximately 1.60 (all P<0.05). In conclusion, Pb, a transit time-independent measure of reflected wave magnitude, predicted long-term cardiovascular mortality in men and women independent of arterial stiffness.

Effect of focal adhesion proteins on endothelial cell adhesion, motility and orientation response to cyclic strain.

Focal adhesion proteins link cell surface integrins and intracellular actin stress fibers and therefore play an important role in mechanotransduction and cell motility. When endothelial cells are subjected to cyclic mechanical strain, time-lapse imaging revealed that cells underwent significant morphological changes with their resultant long axes aligned away from the strain direction. To explore how this response is regulated by focal adhesion-associated proteins the expression levels of paxillin, focal adhesion kinase (FAK), and zyxin were knocked down using gene silencing techniques. In addition, rescue of endogenous and two mutant zyxins were used to investigate the specific role of zyxin interactions. Cells with decreased zyxin expression levels and rescue with the mutant lacking zyxin/alpha-actinin binding exhibited lower orientation angles after comparable times of stretching as compared to normal and control cells. However, knockdown of the expression levels of paxillin and FAK and rescue with the mutant lacking zyxin/VASP (vasodilator-stimulated phosphoprotein) binding did not significantly affect the degree of cell orientation. In addition, wound closure speed and cell-substratum adhesive strength were observed to be significantly reduced only for cells with zyxin depletion and the mutation lacking zyxin/alpha-actinin binding. These results suggest that zyxin and its interaction with alpha-actinin are important in the regulation of endothelial cell adhesive strength, motility and orientation response to mechanical stretching.

A hyperelastic constitutive law for aortic valve tissue.

The objective of the present study was to perform biaxial testing and apply constitutive modeling to develop a strain energy function that accurately predicts the material behavior of the aortic valve leaflets. Ten leaflets from seven normal porcine aortic valves were biaxially stretched in a variety of protocols and the data combined to develop and fit a strain energy function to describe the material behavior. The results showed that the nonlinear anisotropic behavior of the aortic valve is well described by a strain energy function of two strain invariants, which uses only three coefficients to accurately predict the stress-strain behavior over a wide range of deformations. This structurally-motivated constitutive law has many applications, including computational modeling for clinical and engineering valve treatments.

Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality?

OBJECTIVE: To examine the relationship between brachial and central carotid pressures and target organ indices at baseline and their association with future mortality. METHODS: We examined, cross-sectionally and longitudinally, the relations of baseline systolic and pulse pressures in central (calibrated tonometric carotid pulse) and peripheral (brachial, mercury sphygmomanometer) arteries to baseline left ventricular mass, carotid intima-media thickness, estimated glomerular filtration rate, and 10-year all-cause and cardiovascular mortality in 1272 participants (47% women aged 30-79 years) from a community of homogeneous Chinese. RESULTS: Left ventricular mass was more strongly related to central and peripheral systolic pressures than pulse pressures. Intima-media thickness and glomerular filtration rate were more strongly related to central pressures than peripheral pressures. A total of 130 participants died, 37 from cardiovascular causes. In univariate analysis, all four blood pressure variables significantly predicted all-cause and cardiovascular mortality. Each blood pressure variable was entered into the multivariate models, both individually and jointly with another blood pressure variable. After adjustment for age, sex, heart rate, BMI, current smoking, glucose, ratio of total cholesterol to high-density lipoprotein cholesterol, carotid-femoral pulse wave velocity, left ventricular mass, intima-media thickness, and glomerular filtration rate, only central systolic pressure consistently and independently predicted cardiovascular mortality (hazards ratio, 1.30 per 10 mmHg). No significant sex interactions were observed in all analyses. CONCLUSION: Systolic and pulse pressures relate differently to different target organs. Central systolic pressure is more valuable than other blood pressure variables in predicting cardiovascular mortality.

Mechanical properties of actin stress fibers in living cells.

Actin stress fibers (SFs) play an important role in many cellular functions, including morphological stability, adhesion, and motility. Because of their central role in force transmission, it is important to characterize the mechanical properties of SFs. However, most of the existing studies focus on properties of whole cells or of actin filaments isolated outside cells. In this study, we explored the mechanical properties of individual SFs in living endothelial cells by nanoindentation using an atomic force microscope. Our results demonstrate the pivotal role of SF actomyosin contractile level on mechanical properties. In the same SF, decreasing contractile level with 10 microM blebbistatin decreased stiffness, whereas increasing contractile level with 2 nM calyculin A increased stiffness. Incrementally stretching and indenting SFs made it possible to determine stiffness as a function of strain level and demonstrated that SFs have nearly linear stress-stain properties in the baseline state but nonlinear properties at a lower contractile level. The stiffnesses of peripheral and central portions of the same SF, which were nearly the same in the baseline state, became markedly different after contractile level was increased with calyculin A. Because these results pertain to effects of interventions in the same SF in a living cell, they provide important new understanding about cell mechanics.

Strain-induced orientation response of endothelial cells: effect of substratum adhesiveness and actin-myosin contractile level.

Endothelial cells subjected to cyclic stretching change orientation so as to be aligned perpendicular to the direction of applied strain in a magnitude and time-dependent manner. Although this type of response is not the same as motility, it could be governed by motility-related factors such as substratum adhesiveness and actin-myosin contractile level. To examine this possibility, human aortic endothelial cells (HAEC) were uniaxially, cyclically stretched on silicone rubber membranes coated with various concentrations of fibronectin, collagen type IV and laminin to produce differing amounts of adhesiveness (measured using a radial flow detachment assay). Cells were subjected to 10% pure cyclic uniaxial stretching for three hours at a rate of 10%/sec. Time-lapse images revealed that cells underwent large morphological changes without moving. For each type of protein there was a parabolic dependence on initial adhesiveness with optimal cell orientation occurring at very similar adhesive strengths. The effect of actin-myosin contractile level was examined by stretching cells treated with different doses of 2,3-butanedione monoxime (BDM) and Blebbistatin. Each drug induced a dose-dependent decrease in orientation angles after three hours of cyclic stretching. Furthermore, cell and stress fiber orientations were tightly coupled for untreated and Blebbistatin-treated cells but were uncoupled for BDM-treated cells. Even though orientation response to cyclic stretching is not a spontaneous motile response, it is determined, in large part, by the same factors that affect spontaneous motility--the cell-substratum adhesiveness and actin-myosin contractile level.

Do hypertensive individuals have enlarged aortic root diameters? Insights from studying the various subtypes of hypertension.

BACKGROUND: Aortic root diameter (AoD) increases with aging and is related to body size. AoD is also presumed to increase in hypertension. In prior studies, however, after adjusting for age and body size, AoD did not differ between hypertensive and normotensive (NT) individuals. Hypertension is a heterogeneous condition with various subtypes that differ in pathophysiology and age distribution. We assessed whether AoD differs among subjects with the various subtypes of hypertension and nonhypertensive individuals. METHODS: In 1,256 volunteers aged 30-79 years (48% women, 48% hypertensive; all untreated), AoD was measured at the sinuses of Valsalva with transthoracic echocardiography. Using cutoff values based on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, subjects were identified as NT (23%), or prehypertensive (PH, 29%), or as having isolated diastolic (IDH, 6%), isolated systolic (ISH, 12%), or systolic-diastolic (SDH, 30%) hypertension. Groups were compared using analysis of variance with Bonferroni's correction. RESULTS: AoD increased with age and body surface area (BSA) in both men (r = 0.25 and 0.19, respectively) and women (r = 0.30 and 0.22, respectively) (all P < 0.0001). In men, those identified as having IDH, ISH, and SDH each had a 6% larger AoD than NT individuals (all P < 0.05). In women, those identified with ISH and SDH had a 10 and 8% larger AoD than NT individuals, respectively (all P < 0.05). In both sexes, after indexing to BSA, only ISH individuals exhibited larger AoD compared with NT individuals (both P < 0.05). But, with further adjustment for age, these differences were no longer observed. CONCLUSIONS: Even when the subtypes of hypertension are examined separately, age and BSA, not hypertension status, account for the AoD differences between NT and hypertensive subjects.

Actin stress fiber pre-extension in human aortic endothelial cells.

Actin stress fibers (SFs) enable cells to sense and respond to mechanical stimuli and affect adhesion, motility and apoptosis. We and others have demonstrated that cultured human aortic endothelial cells (HAECs) are internally stressed so that SFs are pre-extended beyond their unloaded lengths. The present study explores factors affecting SF pre-extension. In HAECs cultured overnight the baseline pre-extension was 1.10 and independent of the amount of cell shortening. Decreasing contractility with 30 mM BDM or 10 microM blebbistatin decreased pre-extension to 1.05 whereas increasing contractility with 2 nM calyculin A increased pre-extension to 1.26. Knockdown of alpha-actinin-1 with an interfering RNA increased pre-extension to 1.28. None of these affected the wavelength of the buckled SFs. Pre-extension was the same in unperturbed cells as in those in which the actin cytoskeleton was disrupted by both chemical and mechanical means and then allowed to reassemble. Finally, disrupting MTs or IFs did not affect pre-extension but increased the wavelength. Taken together, these results suggest that pre-extension of SFs is determined primarily by intrinsic factors, i.e. the level of actin-myosin interaction. This intrinsic control of pre-extension is sufficiently robust that pre-extension is the same even after the actin cytoskeleton has been disrupted and reorganized. Unlike pre-extension, the morphology of the compressed SFs is partially determined by MTs and IFs which appear to support the SFs along their lengths.

Pulse pressure is inversely related to aortic root diameter implications for the pathogenesis of systolic hypertension.

Hypertension accelerates the age-associated increase in aortic root diameter (AoD), likely because of chronically elevated distending pressures. However, the pulsatile component of blood pressure may have a different relationship with AoD. We sought to assess the relationship between AoD and pulse pressure (PP) while accounting for left ventricular and central arterial structural and functional properties, which are known to influence PP. The study population was composed of 1256 individuals, aged 30 to 79 years (48% women and 48% hypertensive), none of whom were on antihypertensive medications. Blood pressure was measured in the sitting position with conventional sphygmomanometry. PP was calculated as the difference between systolic and diastolic blood pressures. AoD was measured at end diastole at the level of the sinuses of Valsalva with echocardiography. The relationship between AoD and PP was evaluated with multiple regression analyses. PP was 50+/-14 mm Hg in men and 54+/-18 mm Hg in women, and AoD was 31.9+/-3.5 mm in men and 28.9+/-3.5 mm in women. After adjusting for age, age(2), height, weight, and mean arterial pressure, AoD was independently and inversely associated with PP in both sexes. After further adjustments for central arterial stiffness and wall thickness, reflected waves, and left ventricular geometry, AoD remained inversely associated with PP in both men (coefficient=-0.48; P=0.0003; model R(2)=0.51) and women (coefficient=-0.40; P=0.01; model R(2)=0.61). Thus, AoD is inversely associated with PP, suggesting that a small AoD may contribute to the pathogenesis of systolic hypertension. Longitudinal studies are needed to examine this possibility.