Use of relaxation time as a marker for arterial distensibility

Antihypertensive drug therapy is a major modality of cardiovascular (CV) disease prevention, especially for stroke, congestive heart failure, and renal insufficiency. Coronary risk is also consistently prevented by antihypertensive treatment, but to a lesser extent.1–4 The Prime Study2 has shown that drug-induced blood pressure (BP) reduction in hypertensive subjects is associated with a significant decrease of coronary risk. However, when treated and untreated subjects are compared, at any given value of systolic BP (SBP), this risk remains higher in treated than in untreated subjects, suggesting the persistence of residual coronary complications. Results of therapeutic trials also indicate that coronary risk is associated with a particular hemodynamic pattern in treated hypertensive subjects.3 Although diastolic BP (DBP) is significantly lowered by drug treatment to <90 mm Hg (80% of the patients), SBP remains above 140 mm Hg in 60%, indicating an increase of pulse pressure (PP), which is the difference between SBP and DBP.4 It is widely accepted that SBP and PP rise sharply with age and that this increase is a major manifestation of vascular aging and stiffening, which are now considered major predictors of CV risk, independent of the mean BP (MBP) level.4 The purpose of this review is to analyze the mechanism(s) of SBP in untreated and chronically treated hypertensive subjects and to determine which pathophysiological factors are susceptible to attenuating consistently coronary and CV complications in hypertensive populations. Ventricular ejection in humans is associated with 2 principal events. First, the coronary circulation is transiently interrupted, as the principal consequence of cardiac contraction, and, second, an acute shock of stroke volume against the aortic wall is observed (Figure 1). Then, the BP curve may be considered as a wave, which travels along the arterial tree at a given speed, the pulse wave velocity (PWV). …

I n recent years, great emphasis has been placed on the role of arterial stiffness and wave reflection in the development of cardiovascular (CV) diseases.Arterial stiffness and wave reflections, which are now well accepted as the most important determinants of increasing systolic and pulse pressures in aging societies, are increasingly used in the clinical assessment of patients with hypertension and various CV risk factors. 1,2This review addresses recent advances in our understanding of the role played by arterial stiffness and wave reflection in the pathophysiology and treatment of human hypertension.According to the editorial rules for "Hypertension Highlights", and to better focus on recent research, apart from large clinical trials, only articles published during the last 2 years are quoted in this review. Determinants Of Arterial Stiffness: Role of Smooth Muscle Cells and InflammationResearch on the molecular determinants of arterial stiffness has focused for years on the structure and amount of the main load bearing proteins: elastin and collagens. 3Indeed, aging and blood pressure, the two major determinants of arterial stiffness, are associated with a number of molecular changes of the load-bearing media of elastic arteries: the orderly arrangement of elastic fibers and laminae is gradually lost over time, and thinning, splitting, fraying, and fragmentation are observed.The degeneration of elastic fibers is associated with an increase in collagenous material and in ground substance, often accompanied by calcium deposition in ground substance and in degenerate elastic fibers. 4owever, quantitative changes in elastin and collagen may not explain, by themselves, paradoxical observations.For instance, the changes in arterial wall material which accompany arterial hypertrophy in animal models of essential hypertension (SHRs and SHR-SPs) and in middle-age hypertensive patients are not necessarily associated with an increased isobaric stiffness. 5We suggested 5 that adaptive mechanisms may include a rearrangement of the arterial wall material through cell-matrix connections, with a major role of integrins. 6This remodeling may involve qualitative and quantitative changes in arterial wall components leading to redistribution of mechanical load toward elastic materials. 5In this respect, the dedifferentiation of smooth muscle cells (SMCs), leading to arterial wall hypertrophy, and the number of elastin/SMC connections, which influences the extent of elastin network anchorage to SMCs, may play an important role. 5,6he role of contractile proteins of SMCs was 7 illustrated by the discovery of an increased aortic stiffness in a genetic disease combining thoracic aortic aneurysm and/or aortic dissection and patent ductus arteriosus.In patients with MYH11 mutation, altering the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, an increased aortic stiffness was observed, in parallel with medial degeneration and very low SMC content of the aorta. 7This is the first example that direct changes in a contractile protein produced specifically in SMC may alter arterial stiffness.Recent studies underlined the role of inflammation in the stiffening of large arteries.The inflammation process, either acute during Salmonella typhi vaccination, 8 or chronic during rheumatoid arthritis 9,10 or systemic lupus erythematosus, 10 has been reported to stiffen the large arteries.This may occur through various mechanisms including endothelial dysfunction, cell release of a number of inducible matrix metalloproteinases (including matrix metalloproteinase [MMP]-9), medial calcifications, changes in proteoglycan composition and state of hydration, and cellular infiltration around the vasa vasorum leading to vessel ischemia. 8 -10 Whether arterial stiffening was associated with inflammation in essential hypertension was only recently demonstrated through the relationships between arterial stiffness and either tumor necrosis factor-alpha (TNF-␣), interleukin-6 (IL-6), or high sensitive C-reactive protein (hs-CRP). 11,12The primary proinflammatory cytokines TNF-␣ and IL-6 are the main inducers for the hepatic synthesis of hs-CRP.Hs-CRP and IL-6 are independent predictors of increased risk of coronary artery disease.IL-6 and TNF-␣ are also independent risk factors for high BP in apparently healthy subjects.In untreated patients with essential hypertension, aortic stiffness, assessed through carotid-femoral pulse wave velocity, was significantly related with hs-CRP and IL-6. 11Baseline hs-CRP was not only an independent predictor of carotidfemoral pulse wave velocity and central augmentation in-

&lt;p&gt;Older age is a primary risk factor for the development of cardiovascular disease in part through the stiffening of the large cardiothoracic elastic arteries (e.g., aorta, carotid arteries). Aging is also associated with reduced cognitive function, cerebrovascular reactivity and brain white matter integrity, but whether these changes in brain structure and function are associated with age-related large artery stiffness remains unclear. In contrast, older adults who have high aerobic fitness demonstrate attenuated large artery stiffness and better cognitive performance compared to their sedentary counterparts, but the effects of aerobic fitness on white matter integrity and cerebrovascular reactivity with aging are conflicting and limited. Moreover, whether high aerobic fitness-associated lower large artery stiffness in older adults is associated with, and perhaps mediates, the beneficial changes in cognitive function and white matter structure remains unknown. The purpose of this study was to investigate the extent to which high aerobic fitness is associated with preserved white matter structure, cerebrovascular reactivity, and cognitive performance in aged individuals, and if these changes in brain structure and function are associated with attenuated large artery stiffness. In young (n=19, 23.6 ± 2.5 years) and old (n=22, 64.4 ± 4.2 years) healthy adults, large elastic artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV, aortic stiffness) via non-invasive applanation tonometry of carotid and femoral pulse waveforms and carotid artery beta-stiffness index (β-stiffness index) and compliance using high-resolution ultrasound and carotid blood pressure via applanation tonometry. Aerobic fitness was measured as maximal exercise oxygen uptake (VO2max) using respiratory gas analysis on an upright cycle ergometer. Older subjects were stratified as high or low fit based on gender and age VO2max classification. Letter, pattern and N-Back cognitive tests were used to assess processing speed and working memory respectively. Fractional anisotropy (FA) from diffusion tensor images and Blood Oxygenation Level Dependent (BOLD) imaging was used to assess cerebrovascular reactivity (CVR) response to a breath hold and brain activation during a working memory task. The association between large artery stiffness and FA was then assessed using a voxel-wise general linear model approach and a region-of-interest analysis.&lt;/p&gt; &lt;p&gt;Our results confirmed age-related increases in cfPWV, carotid β-stiffness index and central (carotid) but not brachial systolic blood pressure, and expected reductions in carotid compliance, VO2max, working memory and processing speed, and in white matter integrity in select brain regions (bilateral cingulate, frontal, occipital, temporal). In contrast, we found no age-associated differences in CVR to breath hold stimulus or change in BOLD response to the N-Back. In our cohort of health adults, we found that the age-related changes in large artery stiffness were not attenuated by high compared with low VO2max. Among older adults, large elastic artery stiffness was not associated with regional white matter integrity or cerebrovascular reactivity in any regions-of-interest. Greater carotid artery compliance and lower β-stiffness index was associated with higher processing speed, while compliance was related to higher d'Prime scores and lower reaction time on the 2-Back task among the older adults. CVR to a breath hold stimulus was not related to any measure of cognitive performance. VO2max was not associated with any measures of vascular function, brain structure, function or cognition, indicating relations between large artery stiffness and cognition were independent of aerobic fitness capacity. Taken together, these data suggest that select measures of cognitive performance, but not white matter structure or CVR, may be susceptible to age-related changes in carotid stiffness/compliance and that are unaffected by aerobic fitness. More work is needed to understand the mechanisms by which age-related declines in carotid artery compliance and increased carotid stiffness are associated with reductions in cognitive function in older adults.&lt;/p&gt;

&lt;p&gt;Background: Women are more likely to develop age-related cognitive impairment compared with men of the same age. Pregnancy complications, such as preeclampsia (PE), and menopause may contribute to an elevated risk of cognitive decline with aging in women potentially through an adverse impact on vascular function. PE is associated with a heightened risk of hypertension and large elastic artery stiffness (i.e., aortic and carotid arteries) for several years postpartum. Persistent large artery stiffness may be further amplified in women with a history of PE during the menopause transition, which is marked by an accelerated rate of vascular aging. However, large artery stiffness has not been studied extensively in postmenopausal women with a history of PE. Age-related elevations in large artery stiffness are associated with cognitive decline in middle-aged and older adults however, this relation has not been investigated in young women with a history of PE. Moreover, the degree to which elevated large artery stiffness is amplified and associated with reduced cognitive function among postmenopausal women with a history of PE remains unknown. The purpose of this study was to examine the extent to which large elastic artery stiffness is associated with reductions in cognitive function in premenopausal and postmenopausal women with a history of PE.&lt;/p&gt;&lt;p&gt;Methods: Large elastic artery stiffness and domains of cognitive function were assessed in young women one year postpartum (n=18, ages 24-41 yrs.) and postmenopausal women (n=19, ages 52-77 yrs.) thirty-five years postpartum. Aortic stiffness was measured via non-invasive applanation tonometry at the carotid and femoral pulse sites and expressed as carotid-femoral pulse wave velocity (cfPWV). Carotid artery stiffness was quantified as beta-stiffness index (β-stiffness) was measured via ultrasonography and carotid tonometry. Cognitive tests were administered to assess cognitive function in immediate and delayed recall, working memory, processing speed, and executive function.&lt;/p&gt;&lt;p&gt;Results: Premenopausal women with a history of PE had higher systolic blood pressure (121 ± 4 vs. 101 ± 3 mmHg, p =0.01) one year postpartum but did not differ significantly from controls in cfPWV (6.2 ± 0.4 vs. 5.1 ± 0.2 m/s, p =0.08), β-stiffness (6.1 ± 0.5 vs. 6.1 ± 0.7 U, p =0.97), or cognitive domains of memory, executive function, or processing speed (all p&gt;0.05). Higher systolic blood pressure was associated with lower executive function (r = -0.53, p = 0.05) in young women one year postpartum. Postmenopausal women with a history of PE did not differ from controls in blood pressure, large artery stiffness, or age-adjusted cognitive domains of memory, executive function, or processing speed (all p&gt;0.05). Large artery stiffness was not associated with cognitive function in premenopausal or postmenopausal women.&lt;/p&gt;&lt;p&gt;Conclusions: Young women with a history of PE had elevated systolic pressure one year postpartum, which was associated with reductions in executive function. Large artery stiffness was not elevated or related to cognitive function in postmenopausal women with a history of PE. These preliminary findings suggest that young women with a history of PE are susceptible to reductions in selective cognitive domains related to higher blood pressure, but this effect does not appear to extend into the postmenopausal period.&lt;/p&gt;

This clinical advisory statement from the Coordinating Committee of the National High Blood Pressure Education Program is intended to advance and clarify the recommendations of the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI, 1997).1 The advisory addresses several interrelated issues about blood pressure (BP) that affect people approaching the later decades of life. On the basis of the wealth of currently available evidence, the committee now recommends a major paradigm shift in urging that systolic BP become the major criterion for diagnosis, staging, and therapeutic management of hypertension, particularly in middle-aged and older Americans. Several lines of strong evidence support the initiative to emphasize systolic BP. Pathophysiologically, there are strong associations among aging, increased stiffness of large arteries, increased systolic BP, increased pulse pressure, and the prevalence of cardiac and vascular disease. Epidemiologically, isolated systolic hypertension is the most common form of hypertension and is present in approximately two thirds of hypertensive individuals >60 years of age. Diagnostically, classification and staging of hypertension are more precise when systolic rather than diastolic BP is used as the principal criterion. Risk stratification for major complications of hypertension (stroke, myocardial infarction, heart failure, and kidney failure) is actually confounded by the use of diastolic BP; in older people with systolic hypertension, diastolic BP is inversely related to cardiovascular risk. Clinical benefits of treatment of isolated systolic hypertension include reductions in stroke, myocardial infarction, heart failure, kidney failure, and overall cardiovascular disease morbidity and mortality. Currently, only 1 in 4 Americans with hypertension falls below JNC VI–recommended values of 140/90 mm Hg in uncomplicated hypertension or 130/85 mm Hg in individuals with kidney disease or diabetes. Hypertension control rates are poorest in older people, primarily as a result of inadequate …

That elevated heart rate (HR) is a risk factor for cardiovascular morbidity and mortality in healthy people as well as in patients with cardiac diseases is supported by numerous epidemiological association studies.1–4 Increased HR has been recognized as a negative prognostic factor independent of many other clinical parameters that can influence the HR, including physical activity scores, left ventricular function, or use of β-blockers. Thus, HR appears to satisfy all epidemiological criteria for being considered as a true risk factor, and its predictive value for cardiovascular disease appeared to be as strong as that of most important cardiovascular risk factors. This is particularly true for the results obtained in hypertensive patients. Elevated HR is a common feature among hypertensive individuals.1 Among the young hypertensive subjects participating in the HARVEST study, >15% had a baseline resting HR ≥85 bpm and 27% had a HR ≥80 bpm.5 According to the Tensiopulse study, which evaluated 38 145 patients cared for by 2000 general practitioners all across Italy, >30% of the hypertensive patients had a resting HR ≥80 bpm.6 In a large French population, untreated hypertensive subjects had approximately a 6-bpm faster HR than normotensive individuals.7 Elevated HR is frequently associated with high blood pressure (BP) and metabolic disturbances and increases the risk of new onset hypertension and diabetes.1 Many experimental data obtained both in animals and in human beings support the importance of HR as a true risk factor for atherosclerosis and cardiovascular disease, providing convincing evidence for this pathogenetic mechanism.1–3 The pathogenetic connection between HR and cardiovascular disease has been discussed in several reports1–3,8,9 and is beyond the scope of this review. ### High HR as a Precursor of Hypertension, Obesity, and Diabetes Numerous studies have demonstrated that tachycardia is frequently associated with hypertension in …

Although arterial stiffness is an independent cardiovascular risk factor associated with both aging and hypertension, relatively little is known regarding the structural changes in the vessel wall that occur with vessel stiffening. We determined if collagen type-I metabolism is related to arterial stiffening in both hypertensive and normotensive subjects. Arterial stiffness was assessed by aortic pulse wave velocity (PWV) and augmentation index (AIx) in 46 subjects (48.7 +/- 2 years, 32 hypertensives) and related to circulating markers of collagen type-I turnover. Collagen synthesis was assessed by the measurement of carboxy-terminal peptide of procollagen type-I (PIP) and collagen degradation by the measurement of carboxy-terminal telopeptide of collagen type-I (ICTP), by quantitative immunoassay. Matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase-1 (TIMP-1) were also quantified by immunoassay. The ratio of collagen type-I synthesis to degradation was negatively correlated with both PWV (P<0.05) and AIx (P<0.05), whereas plasma MMP-1 levels displayed a positive correlation with both PWV (P<0.01) and AIx (P<0.01), after adjustment for age and mean arterial pressure. The relationship between collagen type-I turnover and arterial stiffness was similar in both the normotensive and hypertensive subjects. Although circulating markers of collagen synthesis were increased in the hypertensive subjects, this was not related to arterial stiffness. Collagen type-I degradation is increased in relation to collagen type-I synthesis in subjects with stiffer arteries. Matrix metalloproteinase-1, the enzyme responsible for collagen type-I degradation, is positively related to both large elastic and muscular artery stiffness in normotensive and hypertensive subjects.

Stiffness of large elastic arteries is elevated in subjects with hypertension, an effect that could potentially be explained by increased distending pressure. We examined effects of an acute change in blood pressure on carotid-femoral pulse wave velocity and carotid artery distensibility (inversely related to stiffness) in normotensive control subjects (n=20, mean age 42) with mean arterial pressure (MAP) 84+/-1.7 mm Hg (mean+/-SE) and subjects with essential hypertension (n=20, mean age 45, MAP 104+/-2.0 mm Hg). Normotensive subjects received intravenous nitroglycerin (NTG) and angiotensin II to lower/increase blood pressure. Hypertensive subjects received NTG to lower blood pressure. Pulse wave velocity was 24% (95% CI: 12% to 35%) higher and carotid distensibility 47% (95% CI: 32% to 63%) lower in hypertensive subjects compared with controls. In normotensive subjects, acute changes in blood pressure produced expected changes in stiffness. However, in hypertensive subjects, despite reducing MAP by 22 mm Hg to the same level as in normotensive subjects, there was no detectable reduction in arterial stiffness: pulse wave velocity remained 24% (95% CI: 10% to 38%) higher and carotid distensibility 48% (95% CI: 31% to 63%) lower in hypertensive compared with normotensive subjects. Because blood pressure-independent effects of NTG are, if anything, to reduce stiffness, these results indicate that elevated carotid and aortic stiffness in hypertensive subjects is not explained by elevated blood pressure but relates to structural change in the arterial wall.

The association between arterial stiffening and aging is well described and can be observed in almost all populations worldwide. A number of other cardiovascular risk factors including diabetes and cigarette smoking are also associated with increased large artery stiffness, often referred to as “premature arterial stiffening.” It is now apparent that the aortic pulse wave velocity (PWV), a measure of arterial distensibility, predicts outcome in a variety of different populations, including hypertensives,1 diabetics,2 individuals with end-stage renal disease (ESRD),3 and even in older adults.4 Indeed, in some populations, aortic PWV is a better predictor of future events than peripheral blood pressure.4 Moreover, arterial stiffening may be more than just a marker of cardiovascular risk; stiffening may also play a more direct role in the development of atherosclerotic plaques. Thus, arterial stiffness would appear to be a novel therapeutic target for the prevention of excess cardiovascular morbidity and mortality. To exploit such an exciting prospect fully, it is necessary to understand the factors regulating arterial stiffness. Traditionally, the stiffness of a vessel was viewed as simply a function of the structural elements of the vessel wall and distending (mean arterial) pressure. However, the large arteries also have a generous coat of smooth muscle, which can alter the distribution of stresses between the elastic and collagenous fibers of the vessel wall and thus alter arterial stiffness. Because smooth muscle tone is influenced by a number of circulating and local vasoactive mediators, arterial stiffness may be actively regulated, and indeed modifiable, at least in the short-term. The muscular arteries have a rich sympathetic innervation, and catecholamines are known to alter smooth muscle tone. Moreover, removal of the vascular endothelium in animals alters large artery stiffness,5,6 suggesting that endothelial-derived substances regulate arterial stiffness in vivo. However, the endothelium …

Our population is aging; in the United States today there are 35 million people 65 years of age or older. That number will double by the year 2030 (Figure 1). Although epidemiological studies have discovered that lipid levels, diabetes, sedentary lifestyle, and genetic factors are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, the quintessential cardiovascular diseases within our society, advancing age unequivocally confers the major risk. The incidence and prevalence of these diseases increase steeply with advancing age (Figure 2). Not only does clinically overt cardiovascular disease increase dramatically with aging, but so do subclinical or occult diseases, such as silent coronary atherosclerosis. Figure 3 (top) shows that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease (Figure 3, bottom). Figure 1. The demographic imperative. Numbers of persons 65 years of age or older (light bars) and 85 years of age or older in the United States from 1900 through 2030. Data taken from the US Census Bureau data with projections for 2030. Figure 2. A, Prevalence of hypertension, defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or current use of medication for purposes of treating high blood pressure. Data are based on National Health and Nutrition Examination Survey III (1988–1991) (Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension . 1995;25:305–313). B, Incidence of atherothrombotic stroke (per 1000 subjects per year) by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Wolf PA. Lewis A. Conner lecture: contributions of epidemiology to the …

Elevated large elastic artery (i.e. aorta and common carotid) stiffness has emerged as a risk factor of cognitive impairment in older adults. Stiffening of these arteries leads to increased pulsatile energy transmission into the brain, which may result in structural damage to neuronal tissue, and potentially precipitate cognitive decline. In this regard, changes to microstructural integrity of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of age‐related increases in arterial stiffness and pulsatile blood flow through the middle cerebral artery (MCA). Therefore, the purpose of this study was to determine whether large elastic artery stiffness and associated pulsatile hemodynamics are related with HC integrity in healthy adults across the lifespan. We included 25 participants (16M/9F, age: 44±16 y; age range: 22‐69 y; BMI: 27±5 kg/m2; BP: 115±11/71±10 mmHg) in this study. Aortic stiffness was assessed as carotid‐femoral pulse wave velocity (PWV) using applanation tonometry (AtCor Medical, Sydney, Australia). Common carotid artery (CCA) stiffness was measured using duplex ultrasound (Logiq e, GE Healthcare, Chicago, IL) and analyzed with an offline wall‐tracking software (Cardiovascular Suite, Pisa, Italy). CCA blood pressures were acquired from applanation tonometry. Transcranial Doppler ultrasound was used to measure basal mean blood flow velocity of the MCA (MCAv) from which Gosling’s pulsatility index (PI) was calculated as the difference between peak systolic MCAv and end‐diastolic MCAv over mean MCAv. HC tissue integrity was measured using magnetic resonance elastography (MRE), which was acquired using a Siemens 3T Prisma MRI scanner coupled with shear waves generated via a pneumatic actuator (Resoundant, Rochester, MN) at 50 Hz. Bilateral HC stiffness (µ) and HC damping ratio (ξ) were estimated from MRE displacement data using a nonlinear inversion algorithm. A correlation matrix was used to determine if arterial stiffness, vascular hemodynamics, and other lifestyle factors (e.g., age, sex, BMI) were related with HC integrity. BMI (r=‐0.40, p=0.048), CCA pulse pressure (PP) (r=‐0.61, p=0.001), and MCAv PI (r=‐0.48, p=0.01) were associated with HC µ while age (r=0.66, p=0.0004), BMI (r=0.45, p=0.02), SBP (r=0.52, p= 0.008), aortic PWV (r=0.65, p=0.0004), and CCA stiffness (r=0.60, p=0.002) were associated with HC ξ. Next, multiple linear regressions were performed to determine the independent associations among arterial stiffness, vascular hemodynamics of interest, and HC integrity while correcting for age and BMI. HC µ remained significantly associated with CCA PP (β=‐0.52, p=0.03) and was trending towards negative association with MCAv PI (β=‐0.37, p=0.06). There were no significant independent associations among the variables of interest and HC ξ, however, together these variables significantly explained variance in HC ξ (R2=0.37, p=0.03). Our results suggest increased pulsatile pressure through the carotid artery along with elevated cerebral pulsatility negatively impacts HC tissue integrity. Future studies should consider how our current findings affect functional outcomes like memory and age‐related neurological conditions.

Cerebrovascular reactivity: a new frontier for measuring cognitive health in models of accelerated ageing?

Stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) occurs with aging and may play a key role in memory impairment via a diminished pressure‐dampening effect, ultimately leading to loss of neuronal tissue integrity. In this regard, changes in brain tissue viscoelastic mechanical properties, an indirect measure of neuronal tissue integrity, may reflect the impact of elastic artery stiffening on brain health. Therefore, the purpose of this pilot study was to determine whether large elastic artery stiffness is associated with total brain viscoelasticity in healthy adults across the lifespan. All measures were performed in 13 healthy participants (6 females, mean age: 38 ± 15 y; age range: 22–69 y; mean BMI: 26 ± 5 kg/m2; mean BP: 111 ± 9/68 ± 10 mmHg). Carotid artery stiffness, beta‐stiffness index and compliance were assessed using B‐mode ultrasound (Logiq e, GE) coupled with applanation tonometry (SphygmoCor, AtCor Medical Inc.) and analyzed using commercial wall‐tracking software (Cardiovascular Suite, Quipu). Aortic stiffness was assessed as carotid‐to‐femoral pulse wave velocity (PWV) using applanation tonometry. Brain tissue viscoelastic mechanical properties (shear stiffness and damping ratio) were measured using magnetic resonance elastography (MRE). MRE data were acquired using 3T magnetic resonance imaging (Magnetom Prisma, Siemens, Inc.) while the brain viscoelastic property maps were generated using a nonlinear inversion algorithm. Associations between measures of age, large elastic artery stiffness and brain viscoelastic properties were determined using linear regression. PWV significantly increased with age (F = 25.6, p &lt; 0.05, r2 = 0.7) while total brain stiffness significantly decreased with age (F = 6.1, p &lt; 0.05, r2 = 0.36). Carotid artery stiffness (F = 4.3, p = 0.06, r2 = 0.28) and beta‐stiffness index (F = 2.9, p = 0.11, r2 = 0.21) tended to be inversely associated with total brain stiffness, whereas carotid artery compliance tended to be positively associated with total brain stiffness (F = 2.5, p = 0.14, r2 = 0.18). No relation was observed between PWV and total brain stiffness (F = 0.9, p = 0.37, r2 = 0.08). There were no associations between any measures of arterial stiffness and damping ratio. These preliminary data confirm that aging is associated with increase in arterial stiffness and loss of brain tissue integrity. They also indicate a possible association between large artery stiffening with brain tissue integrity and suggest that preserving elasticity of the carotid artery in particular may be important for protecting brain health with aging. Future work should assess the relation between carotid artery stiffness and brain mechanical properties in a larger group of individuals.Support or Funding InformationSupported by Center for Biomedical and Brain Imaging (CBBI) Pilot Grant P20GM103653 and Center of Biomedical Research Excellence (COBRE) Pilot Grant P20GM113125.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Older age is associated with elevated large elastic artery stiffness, a strong predictor of cardiovascular (CVD) risk in middle-age/older (MA/O) adults independent of blood pressure (BP). Greater 24-hour systolic BP variability (BPV) is also an independent risk factor for CVD and is linked to large artery stiffness in MA/O adults with hypertension and diabetes. However, its relation to age-related arterial stiffness in adults with low risk factor burden is unclear. We hypothesized that higher systolic BPV would be: 1) associated with advancing age, and 2) related to elevated aortic and carotid artery stiffness among healthy MA/O adults. To determine this, 98 healthy adults (ages 19-70 yrs) with measurements of systolic BPV (standard deviation of 24 hr systolic BP) via ambulatory BP monitoring, aortic stiffness (carotid-femoral pulse wave velocity, cfPWV), carotid artery stiffness (β-stiffness via carotid tonometry/B mode ultrasound) and circulating metabolic factors were included. In the entire cohort, greater systolic BPV was not associated with age, cfPWV, carotid β stiffness or circulating lipids/glucose (all P&gt;0.05), but was correlated (age-adjusted) with 24 hr systolic BP (r= 0.41, P&lt;0.001) and BMI (r= 0.21, P&lt;0.05). In stepwise linear regression analyses that included age, sex, BMI, only 24 hr systolic BP was associated with systolic BPV (β= 0.14 ± 0.03, Model R 2 = 0.20, P&lt; 0.001). Interestingly, there was no difference in 24 hr systolic BPV (11.4 ± 0.4 vs 11.4 ± 0.5 SD mmHg, P=0.99) in young (n=55; 29.0 ± 0.7 yrs) vs. MA/O (n= 43; 53.0 ± 1.2 yrs) adults despite higher cfPWV (594 ± 12 vs 913 ± 39 cm/sec, P&lt;0.001), carotid β-stiffness (6.8 ± 0.6 vs 9.3 ±0.9 U, P=0.001) and 24 hr systolic BP (121 ± 1 vs 125 ± 2 mmHg, P&lt;0.05). Systolic BPV was associated with BMI (r= 0.42, p&lt; 0.01) and fasting blood glucose (r= 0.54, P= 0.001) in MA/O but not young adults. In a stepwise linear regression model among MA/O, 24 hr systolic BP (β= 0.18 ± 0.04, R 2 = 0.36, P&lt;0.001) and fasting glucose (β= 0.10 ± 0.05, R 2 change= 0.07, P&lt;0.001) were the only significant correlates of systolic BPV (Model R 2 = 0.43, P&lt;0.001). In conclusion, 24 hr systolic BP and fasting blood glucose, but not age or large elastic artery stiffness, were the strongest determinants of higher systolic BPV in normotensive MA/O adults.

### CONTRIBUTION OF THE AREA POSTREMA TO THE INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN OVINE HEART FAILURE Abukar Y, Ramchandra R, May CN The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Background : Heart failure (HF) is associated with an increase in cardiac sympathetic nerve activity (CSNA), which is directly linked to mortality in HF patients. The mechanisms responsible for the elevated CSNA remain unclear. Previous studies indicate that the area postrema (AP), a circumventricular organ in the brainstem, plays a role in the control of sympathetic nerve activity. We hypothesized that the elevated CSNA in HF is mediated by the AP and lesioning this region would reduce the increased CSNA in sheep with HF. Aims : To determine the effect of sham lesion or lesion of the AP on CSNA and hemodynamics in conscious sheep with HF. Methods : Studies were conducted in 2 groups of sheep with pacing-induced HF: sham (n=6) and AP lesion (n=6) sheep. Mean arterial blood pressure (MAP), heart rate (HR) and CSNA were recorded simultaneously in conscious sheep at least 4 days after surgery. Results : Heart failure was associated with a significant decrease in ejection fraction (from 74±2 % to 38±1 %; P<0.001), which was similar in both groups. There was a significant reduction in CSNA burst incidence in the AP lesion group compared with the sham group (45±10 and 89±3 bursts/100 heartbeats, respectively; P<0.01). Conclusions : In sheep with HF, the group with lesion of the AP had a significantly lower CSNA compared with the sham group. These data suggest that the AP plays a role in setting the detrimental high levels of CSNA in HF. ### G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING IMPROVES STROKE OUTCOME IN FEMALE MICE Broughton BRS, Jansen GL, Sobey CG Department of Pharmacology, Monash University, Clayton, Victoria, Australia Background: Estrogen has been assumed to provide neuroprotection following stroke entirely via classical estrogen receptors. Interestingly, there is recent evidence that activation of a novel G …