Increase In Aortic Stiffness Research Articles

DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways.

Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs.

Arterial stiffening is a crucial factor for left ventricular diastolic dysfunction in a community-based normotensive population

BackgroundLeft ventricular (LV) diastolic dysfunction is an important underlying hemodynamic mechanism for heart failure. Hypertension reportedly increases aortic stiffness with histological changes in the aorta assessed using aortic pulse wave velocity (PWV) that is associated with LV diastolic dysfunction. The role of hypertension per se in the relationship between aortic stiffness and LV diastolic dysfunction has not been clarified; therefore, we investigated whether this relation works for normotensive subjects. MethodsOf the 502 subjects who underwent both echocardiography and PWV measurement in a medical check-up conducted in Arita, Japan, we enrolled 262 consecutive normotensive subjects (age 52 ± 13 years). LV diastolic dysfunction was defined as abnormal relaxation and pseudonormal or restrictive patterns determined with both transmitral flow velocity and mitral annular velocity. Aortic stiffness was assessed via non-invasive brachial-ankle PWV measurement. ResultsLV diastolic dysfunction was detected in 67 of the 262 (26%) normotensive subjects, and PWV was higher in subjects with LV diastolic dysfunction (15.4 ± 3.6 vs. 13.0 ± 2.7 m/s, p < 0.01). Multivariate logistic regression analyses revealed that PWV was independently associated with LV diastolic dysfunction (p = 0.02) after the adjustment for age; body mass index; blood pressure; eGFR; blood levels of BNP, glucose, and HDL cholesterol; LV mass index; and LA dimension. ConclusionsBoth aortic stiffness and LV diastolic function are mutually related even in normotensive subjects, independent of the potential confounding factors. The increase in aortic stiffness may be a risk factor for LV diastolic dysfunction, irrespective of blood pressure.

The relation between aortic stiffness and retinal microvascular flow pulsatility is attenuated by higher vascular resistance in healthy adults

Aortic stiffness is associated with increased risk of cerebrovascular disease and cognitive impairments with aging, although the mechanism that contribute to this link are not well‐defined. Increases in carotid artery flow pulsatility coincide with elevated aortic stiffness and may contribute to microvascular brain damage, but studies confirming augmented flow pulsatility in the downstream microvasculature have been limited. Given the ability to assess the retinal microvasculature non‐invasively in humans and evidence that disease‐ and age‐related alterations in the retinal microvasculature mirror changes in the cerebral microvasculature, we examined the hypothesis that age‐related increases in aortic stiffness would be correlated with higher retinal arteriole flow pulsatility (systolic flow – diastolic flow / mean flow). Among 33 healthy adults (age range: 25–60 years, 47% women), aortic stiffness was assessed by carotid‐femoral pulse wave velocity (CFPWV). Retinal arteriole flow pulsatility was quantified using laser speckle flowgraphy before and during a reduction in retinal vascular resistance via 30 s of diffuse luminance flicker. Multiple regression analysis including CFPWV, mean arterial pressure (MAP), and heart rate (HR) as independent variables demonstrated that lower MAP and HR, but not higher CFPWV, were significant determinants of greater flow pulsatility at baseline (CFPWV: β=0.10, P=0.548; MAP: β= −0.40, P=0.021; HR: β= −0.50, P=0.002; model R2=0.43, P=0.001). However, after reducing retinal vascular resistance (P&lt;0.001) via 30s of diffuse luminance flicker, multiple regression analysis demonstrated that higher CFPWV was a significant determinant of greater retinal arteriole flow pulsatility (β=0.35, P=0.026) in addition to lower MAP (β= −0.54, P=0.001) and HR (β= −0.43, P=0.005) (model R2=0.51, P&lt;0.001). In summary, no relation was observed between higher CFPWV and retinal arteriole flow pulsatility at rest, but a positive relation was observed during arteriole vasodilation. These findings suggest that greater vascular resistance may be an important compensatory mechanism to reduce transmission of flow pulsatility.Support or Funding InformationAHA 17POST33440101, T32 HL07121 NHLBI (P01HL014388), U54 TR001356 and AHA (13DG143400012).

Similar Effects of Acute Resistance Exercise on Carotid Stiffness in Males and Females.

Sex differences exist in vascular responses to blood pressure perturbations, such as resistance exercise. Increases in aortic stiffness following acute resistance exercise appear different between sexes, with attenuated increases in females vs. males. Whether sex differences exist in carotid stiffness, following resistance exercise is unknown. This study sought to examine sex differences in carotid stiffness, aortic stiffness, and hemodynamics following acute resistance exercise. Thirty-five participants (18 male) completed 3 sets of 10 repetitions of maximal isokinetic knee extension/flexion. Aortic stiffness and hemodynamics were estimated using an automated oscillometric blood pressure monitor at baseline, 5- and 30-min post-exercise. Carotid stiffness was assessed by β-stiffness index, pressure-strain elastic modulus and arterial compliance using ultrasonography. Resistance exercise increased aortic stiffness, mean and systolic pressure at 5-min (p<0.01), and pressure-strain elastic modulus at 5-min in both sexes (p<0.05). Arterial compliance decreased at 5- and 30-min post exercise in both sexes (p<0.01). No interaction effects were detected in carotid stiffness, aortic stiffness, and hemodynamics, indicating similar vascular responses between sexes. Our findings indicate that the large arteries appear to stiffen similarly following resistance exercise in males and females when presented with similar blood pressure responses.

Arterial Hypertension and Unusual Ascending Aortic Dilatation in a Neonate With Acute Kidney Injury: Mechanistic Computer Modeling.

BackgroundNeonatal asphyxia caused kidney injury and severe hypertension in a newborn. An unusually dilatated ascending aorta developed. Dialysis and pharmacological treatment led to partial recovery of the ascending aortic diameters. It was hypothesized that the aortic dilatation may be associated with aortic stiffening, peripheral resistance, and cardiovascular changes. Mathematical modeling was used to better understand the potential causes of the hypertension, and to confirm our clinical treatment within the confines of the model’s capabilities.MethodsThe patient’s systolic arterial blood pressure showed hypertension. Echocardiographic exams showed ascending aorta dilatation during hypertension, which partially normalized upon antihypertensive treatment. To explore the underlying mechanisms of the aortic dilatation and hypertension, an existing lumped parameter hemodynamics model was deployed. Hypertension was simulated using realistic literature informed parameter values. It was also simulated using large parameter perturbations to demonstrate effects. Simulations were designed to permit examination of causal mechanisms. The hypertension inducing effects of aortic stiffnesses, vascular resistances, and cardiac hypertrophy on blood flow and pressure were simulated. Sensitivity analysis was used to stratify causes.ResultsIn agreement with our clinical diagnosis, the model showed that an increase of aortic stiffness followed by augmentation of peripheral resistance are the prime causes of realistic hypertension. Increased left ventricular elastance may also cause hypertension. Ascending aortic pressure and flow increased in the simultaneous presence of left ventricle hypertrophy and augmented small vessel resistance, which indicate a plausible condition for ascending aorta dilatation. In case of realistic hypertension, sensitivity analysis showed that the treatment of both the large vessel stiffness and small vessel resistance are more important in comparison to cardiac hypertrophy.Conclusion and DiscussionLarge vessel stiffness was found to be the prime factor in arterial hypertension, which confirmed the clinical treatment. Treatment of cardiac hypertrophy appears to provide significant benefit but may be secondary to treatment of large vessel stiffness. The quantitative grading of pathophysiological mechanisms provided by the modeling may contribute to treatment recommendations. The model was limited due to a lack of data suitable to permit model identification.

Abstract 149: Postpartum Cognitive Function in Young Women With a History of Preeclampsia: Association With Blood Pressure but Not Large Artery Stiffness

Introduction: Women with a history of preeclampsia (PE) have elevated large artery stiffness and blood pressure (BP) several years postpartum. Age-related increases in aortic stiffness are deleterious to brain structure and cognitive function; however, the relationship between large artery stiffness and cognitive function has not been assessed in women with a history of PE. The purpose of this study was to determine the extent to which large artery stiffness and BP are associated with cognitive function in women with a history of PE. Methods: Women with a history of PE (n=12; age 33±1 yrs; BMI 28.5±3.1 kg/m 2 ) and healthy pregnancy controls (n=7; age 34±2 yrs; BMI 26.5±4.0 kg/m 2 ) were assessed one year postpartum. Brachial BP was collected in triplicate using an automated cuff. Aortic stiffness was measured via applanation tonometry and quantified as carotid-femoral pulse wave velocity (cfPWV). Carotid stiffness (β-stiffness) was obtained via ultrasonography and carotid tonometry. Cognitive function was assessed in domains of memory, processing speed, and executive function. Results: Women with a history of PE had higher systolic BP (121±4 vs. 104±3 mmHg, p&lt;0.01) and cfPWV (6.2±0.4 vs. 5.1±0.2 m/s, p=0.06), though the latter did not reach statistical significance. There was no difference between groups in β-stiffness (6.1±0.4 vs. 6.1±0.6 U, p=0.97). Cognitive domains of executive function, memory, and processing speed did not differ between groups (all p&gt;0.05). Systolic BP was associated with reductions in executive function (r = -0.52, p=0.04) independent of education level, but was not related to reductions in memory or processing speed. Arterial stiffness was not associated with cognition. Conclusions: Women with a history of PE had elevated systolic BP and aortic stiffness, but only BP was associated with reductions in executive function. These preliminary findings suggest that young women with a history of PE may be vulnerable to reductions in cognitive function related to persistent elevated systolic BP.

Increased aortic stiffness in adults with chronic indeterminate Chagas disease.

An ever-increasing number of patients with chronic indeterminate Chagas disease are diagnosed with early vascular and cardiac abnormalities, as cardiovascular imaging becomes more sensitive. However, the currently available information on aortic stiffness (a prognostic marker for adverse cardiovascular outcomes) in these patients is scarce. In this study, we consecutively recruited 21 asymptomatic Bolivian adult patients with chronic indeterminate Chagas disease and 14 Bolivian adults, who were seronegative for Trypanosoma cruzi infection. No participants had a prior history of heart disease, hypertension, diabetes, chronic kidney disease or atrial fibrillation. Carotid-femoral pulse wave velocity (cf-PWV), carotid-radial PWV (cr-PWV), carotid intima-media thickness and conventional echocardiographic measurements were recorded in all participants. Patients with chronic indeterminate Chagas disease had significantly higher cf-PWV (7.9±1.3 vs. 6.4±1.1 m/s, p = 0.003) and greater HOMA-estimated insulin resistance than subjects without Chagas disease. The two groups did not significantly differ in terms of age, sex, smoking, adiposity measures, blood pressure, plasma lipids, fasting glucose levels as well as cr-PWV, carotid intima-media thickness measurements, left ventricular mass and function. Presence of chronic indeterminate Chagas disease was significantly associated with increasing cf-PWV values (β coefficient: 1.31, 95% coefficient interval 0.44 to 2.18, p = 0.005), even after adjustment for age, sex, heart rate, systolic blood pressure and insulin resistance. In conclusion, asymptomatic Bolivian adult patients with chronic indeterminate Chagas disease have an early and marked increase in aortic stiffness, as measured by cf-PWV, when compared to Bolivian adults who were seronegative for Trypanosoma cruzi infection.

Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening

Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs) and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice. The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice. Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.

Arterial Stiffness in the Heart Disease of CKD.

CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Aortic Stiffness Increases More in the Abdominal Than the Thoracic Aorta in Aging Female Monkeys

Most experimental studies on vascular stiffness in aging females have been conducted in rodents. However, the lifespan of rodents is only 2–3 years, limiting clinical relevance to humans, and they do not go through menopause, making it difficult to translate the data to aging women. The hypothesis of this investigation was that this topic would be more relevant in aging non‐human primates, as their lifespan is over 30 years and they do go through menopause. Accordingly, the goal of this investigation was to compare aortic stiffness in young adult (6±1 years old) and old (24±1 years old) female macaques. An additional unique feature was chronically implanting aortic pressure and diameter transducers to permit the study of direct and continuous measurements of aortic stiffness in conscious monkeys after full recovery from surgery. Another unique feature was to examine aortic stiffness in both the thoracic aorta (TA) and the abdominal aorta (AA). Aortic stiffness (β) was calculated as systolic pressure/diastolic pressure)/aortic strain. Aortic stiffness increased more, p&lt;0.05, in both the TA (49%) and AA (71%) in old vs young female monkeys. The greatest increases in aortic stiffness in the old female monkeys was in the AA, as reflected by a 42% greater increase in the AA than the TA. These differences were confirmed histologically measuring collagen and elastin density and disarray. Whereas collagen density increased and elastin density decreased more in old vs young monkeys, the greatest differences were observed in collagen and elastin disarray. For example, elastin disarray increased more in the AA than the TA, and more in old vs young monkeys, e.g., there was a 48% greater increase, p&lt;0.05, in the TA elastin disarray in old vs young monkeys. Thus, aortic stiffness increases more in old vs young females, with larger increases in the abdominal vs the thoracic aorta, with the mechanism involving changes in collagen and elastin density, but more importantly, increases in collagen and elastin disarray.Support or Funding InformationFunding information: NIH R01 HL102472This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated Aortic Stiffness is Associated with Lower Brain pH and Executive Function Performance in Middle‐aged and Older Adults

IntroductionElevated aortic stiffness and pulse pressure (PP) are risk factors for development of mild cognitive impairment (MCI) and Alzheimer's disease (AD) mediated in part by the development of cerebrovascular dysfunction. Cerebrovascular dysfunction uncouples cerebral blood flow (CBF) supply from metabolic demand, contributing in part to cerebral hypoperfusion, acidosis and cognitive decline in AD. Brain T1rho is a novel pH‐sensitive magnetic resonance imaging (MRI) biomarker that is increased in patients with MCI and AD compared with healthy controls (HC). T1rho measures the change in T1 relaxation time in the rotating frame with greater T1rho values (i.e., longer relaxation time) associated with a more acidic pH. However, the degree to which higher T1rho signal (i.e., lower brain pH = more acidic) is associated with 1) lower cognitive performance; 2) higher brachial PP and 3) elevated aortic stiffness in middle‐aged/older (MA/O) adults is unknown.Methods/ResultsTwenty‐seven MA/O adults (mean ± SE: 71.8 ± 2.1 years, range: 50–90 years) were recruited to undergo clinic blood pressure (BP), neuropsychological, MRI (structural and T1rho) testing and vascular testing (subset only). Executive function and delayed memory performance were measured using the Trailmaking test (TMT) A &amp; B and Rey Auditory Verbal Learning Test, respectively. In agreement with prior studies, global T1rho signal was elevated in individuals with cognitive impairment (MCI or early AD, n=10) compared with HC (90.7 ± 3.1 vs. 81.8 ± 1.2 ms, p= 0.004). Consistent with our hypothesis, higher T1rho signal was associated with greater time to completion on the TMT B (r = 0.44, p = 0.026), TMT B‐A (r = 0.39, p = 0.047) and lower delayed memory performance (r = −0.48, p = 0.012, all adjusted for age) in the entire cohort. However, T1rho was not related to PP (r = 0.38, p= 0.069) and remained unassociated after adjusting for age (p=0.80). In the subset of MA/O adults with T1rho (n = 15; 70.0 ± 2.0 years, HC, n= 21, MCI, n=2), greater aortic stiffness (carotid‐femoral pulse wave velocity, cfPWV) was associated with higher T1rho signal (r= 0.58, p= 0.039, adjusted for mean arterial pressure). Furthermore, cfPWV was associated with slower TMT B (r = 0.45, p = 0.034) but not TMT B‐A (r = 0.46, p = 0.066) or delayed memory performance (p= 0.77, all adjusted for mean arterial pressure). Additional adjustment for age abolished (p &gt; 0.05) the relation between cfPWV and TMT performance and T1rho signal in the present cohort.ConclusionThese preliminary data indicate that the age‐related increase in aortic stiffness is associated with lower executive function performance on the TMT task and higher T1rho signal, consistent with lower brain pH, in MA/O adults. More studies are needed to determine the mechanism by which elevated aortic stiffness contributes in part to decreased brain pH and how brain pH may potentially modulate reduced executive function with aging.Support or Funding InformationBiological Sciences Funding Program, Office of Vice President for Research, University of Iowa and NIH 1R03AG047306This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Supplementation with the Gut Microbiome‐Derived Metabolite Trimethylamine N‐Oxide Induces Aortic Stiffening in Young Mice

Elevated plasma levels of the gut‐derived metabolite trimethylamine N‐oxide (TMAO) cause atherosclerosis in mice and predict cardiovascular (CV) risk in humans. Stiffening of the large elastic arteries is a major risk factor and antecedent to atherosclerosis and other CV diseases (CVD), but it is unknown if TMAO contributes to arterial stiffening.PurposeTo determine if increased circulating TMAO induces arterial stiffness in young mice.MethodsYoung C57BL/6 mice (6 mo.) were fed a defined‐choline (0.07%) diet supplemented either without (Control; n=11) or with 0.12% TMAO (n=11) for 6 months. Arterial stiffness was measured in vivo by aortic pulse wave velocity (aPWV). After sacrifice, intrinsic mechanical stiffness of the aorta was measured using wire myography. A stress‐strain curve was constructed, and the elastic moduli (EM) were calculated as the slopes of the high‐force collagen‐dominant (collagen EM) and low‐force elastin‐dominant (elastin EM) regions of the curve. Abundance of arterial structural proteins was measured in aortic lysates via Western blotting.ResultsTMAO supplementation increased plasma TMAO levels vs. Control (TMAO: 31.5±4.1 μM, Control: 2.9±0.6 μM, p= 0.01), with no effect on body weight (TMAO: 41.5±1.6 g, Control: 39.7±1.6 g, p = 0.43). aPWV was higher in the TMAO group vs. Control (483±32 vs. 392±20 cm.s−1, p= 0.04). This greater aPWV in the TMAO‐supplemented group was associated with a higher collagen EM in the TMAO‐supplemented group (TMAO: 8642±437 kPa, Control: 7056±625 kPa, p= 0.05), which was accompanied by strong trends toward higher protein abundance of type 1 collagen (TMAO: 1.62±0.33 A.U., Control: 0.99±0.08 A.U., p= 0.08) and advanced glycation end products (TMAO: 1.69±0.36 A.U., Control: 1.00±0.07 A.U., p= 0.08). There were no group differences in the elastin EM (TMAO: 642±40 kPa, Control: 620±54 kPa, p= 0.75) or elastin protein expression (TMAO: 1.09±0.04 A.U., Control: 1.00±0.04 A.U., p= 0.83).ConclusionTMAO supplementation induced a marked increase in circulating TMAO concentration and aortic stiffness in young mice. The increase in aortic stiffness appeared to be mediated by increased deposition of collagen (fibrosis) and abundance of advanced glycation end products, which form crosslinks between arterial structural proteins. These preliminary results introduce a novel mechanistic link between elevated plasma TMAO levels and CV risk, suggesting that TMAO may be a promising target to prevent arterial dysfunction and reduce consequent risk of CVD.Support or Funding InformationR01 HL134887, F32 HL140875This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic Kidney Disease and Pulse Wave Velocity: A Narrative Review.

Chronic kidney disease (CKD) is associated with excess cardiovascular mortality, resulting from both traditional and nontraditional, CKD-specific, cardiovascular risk factors. Nontraditional risk factors include the entity Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) which is characterised by disorders of bone and mineral metabolism, including biochemical abnormalities of hyperphosphatemia and hyperparathyroidism, renal osteodystrophy, and vascular calcification. Increased arterial stiffness in the CKD population can be attributed amongst other influences to progression of vascular calcification, with significant resultant contribution to the cardiovascular disease burden. Pulse wave velocity (PWV) measured over the carotid-femoral arterial segments is the noninvasive gold-standard technique for measurement of aortic stiffness and has been suggested as a surrogate cardiovascular end-point. A PWV value of 10 m/s or greater has been recommended as a suitable cut-off for an increased risk of cardiovascular mortality. CKD is a risk factor for an excessive rate of increase in aortic stiffness, reflected by increases in PWV, and increased aortic PWV in CKD shows faster progression than for individuals with normal kidney function. Patients with varying stages of CKD, as well as those on dialysis or with a kidney transplant, have different biological milieu which influence aortic stiffness and associated changes in PWV. This review discusses the pathophysiology of arterial stiffness with CKD and outlines the literature on PWV across the spectrum of CKD, highlighting that determination of arterial stiffness using aortic PWV can be a useful diagnostic and prognostic tool for assessing cardiovascular disease in the CKD population.

Vascular smooth muscle cell contraction and relaxation in the isolated aorta: a critical regulator of large artery compliance.

Over the past few decades, isometric contraction studies of isolated thoracic aorta segments have significantly contributed to our overall understanding of the active, contractile properties of aortic vascular smooth muscle cells (VSMCs) and their cross‐talk with endothelial cells. However, the physiological role of VSMC contraction or relaxation in the healthy aorta and its contribution to the pulse‐smoothening capacity of the aorta is currently unclear. Therefore, we investigated the acute effects of VSMC contraction and relaxation on the isobaric biomechanical properties of healthy mouse aorta. An in‐house developed set‐up was used to measure isobaric stiffness parameters of periodically stretched (10 Hz) aortic segments at an extended pressure range, while pharmacologically modulating VSMC tone and endothelial cell function. We found that the effects of α1‐adrenergic stimulation with phenylephrine on the pressure‐stiffness relationship varied in sensitivity, magnitude and direction, with the basal, unstimulated NO production by the endothelium playing a pivotal role. We also investigated how arterial disease affected this system by using the angiotensin‐II‐treated mouse. Our results show that isobaric stiffness was increased and that the aortic segments demonstrated a reduced capacity for modulating the pressure‐stiffness relationship. This suggests that not only increased isobaric stiffness at normal pressure, but also a reduced capacity of the VSMCs to limit the pressure‐associated increase in aortic stiffness, may contribute to the pathogenesis of this mouse model. Overall, this study provides more insight in how aortic VSMC tone affects the pressure‐dependency of aortic biomechanics at different physiological and pathological conditions.

Nicotine Regulates Segmental Aortic Stiffening

Introduction: Vascular stiffness and aortic stiffness in particular contributes to the development of AAA. Differential segment-specific stiffness development, quantified via the “segmental aortic stiffness (SAS)”- gradient, in adjacent segments may be a major contributor. Nicotine is the major risk factor for AAA development. This study investigates how nicotine influences stiffness development in the abdominal (AS) and thoracic (TS) segment. Methods: Wildtype-mice (C57BL/6) were infused with nicotine for 40 days using osmotic mini pumps (20mg/KG/day). Segmental aortic stiffness was analyzed using M-mode and pulse-wave velocity (PWV) ultrasound measurements. Thereafter, explanted aortae were used for myograph measurements and stiffness-related gene expression (Matrix-Metalloproteinase (MMP)-2, MMP-9, Col1A1, Col3A1) was analyzed. Results: Aortic PWV increased with nicotine (p<.05). In particular, stiffening for the AS occurred after 10 days (p<.05), while increase in aortic stiffness for the TS was only found after 40 days (p<.05). SAS was enhanced with nicotine vs. PBS for both time points. Stiffness-related genes were up-regulated after 40 days in both segments (p<.05). Discussion: Aortic stiffening is different for the TS and AS over a 40-day time course. SAS is enhanced with nicotine infusion based on stiffness-related gene expression. The TS has a higher capacity to withstand aortic stiffening, although the reason remains uncertain. Differences in stiffness development for the TS and AS may in part explain nicotine’s role in promoting AAA.

Exercise stress echocardiogram for the evaluation of change in the ventricular-arterial interaction after thoracic endovascular aortic repair.

The aim of this study was to explore, with exercise echocardiography, the potential impact of thoracic endovascular aortic repair (TEVAR) on the ventricle-aorta coupling, based on the hypothesis that the interaction between the ventricle and aorta may be influenced by an increase in aortic stiffness due to the stent graft. Of the patients who underwent isolated TEVAR for thoracic aortic diseases between April 2016 and December 2016, changes found in haemodynamic and echocardiographic parameters between the control (n = 17) and TEVAR (n = 30) groups were analysed by a stress echocardiogram. The end-systolic elastance significantly increased with stress in both groups [from 3.0 (2.5-4.5) mmHg/ml to 4.8 (3.7-6.5) mmHg/ml, P < 0.001, in the control group and from 2.9 (2.0-3.5) mmHg/ml to 3.4 (2.6-4.2) mmHg/ml, P < 0.001, in the TEVAR group]. The arterial elastance significantly elevated only in the TEVAR group [from 1.6 (1.3-1.8) mmHg/ml to 1.7 (1.5-2.0) mmHg/ml, P = 0.007] and arterial elastance/end-systolic elastance (ventricular-arterial coupling) significantly decreased only in the control group [from 0.5 (0.4-0.7) to 0.4 (0.3-0.5), P = 0.002, in the control group and from 0.6 (0.4-0.8) to 0.5 (0.4-0.6), P = 0.10, in the TEVAR group]. In the control group, the change in end-systolic elastance and ventricular-arterial coupling tended to be greater (P = 0.002 and 0.07). An exercise echocardiogram showed the underlying influences of TEVAR on the interaction between the heart and aorta. TEVAR may have the potential to suppress left ventricular contractile capacity and increase cardiac afterload during exercise. A201770-01.

Abstract 109: Association Between Aortic Stiffness and Lower Retinal Microvascular Blood Flow Revealed by Laser Speckle Flowgraphy: Surrogate Measures of Cerebral Microcirculation in Humans

The age-related increase in aortic stiffness increases systolic blood pressure (BP) and flow pulsatility and is associated with target organ damage such as ischemic cerebrovascular disease. However, the mechanistic link between aortic stiffness and cerebrovascular disease remains unclear because techniques available to non-invasively assess dynamic changes in the human brain microcirculation with high spatial and temporal resolution are limited. Given the evidence that disease- and age- related alterations in the retinal microvasculature may mirror changes in the cerebral microvasculature, we assessed resting and dynamic changes in the retinal microcirculation using high resolution laser speckle flowgraphy. We tested the hypothesis that retinal microvascular blood flow at rest and during acute increases in BP would be associated with age-related increases in aortic stiffness (carotid-femoral pulse wave velocity, CFPWV). In 40 healthy subjects (35 ± 2 years; 25-60 years; 18 M/22 F; systolic BP: 123 ± 2 mmHg; diastolic BP: 77 ± 2 mmHg), retinal arterial blood flow was assessed at baseline (following dilation of the left pupil with 0.5% topicamide), and during a sympatho-excitatory stimulus (2-min cold pressor test). At baseline, lower retinal blood flow was significantly correlated with higher CFPWV (R=-0.35, P=0.03) and older age (R=-0.38, P=0.02) independent of mean BP (partial correlation). In response to the CPT, significant increases were observed in mean BP (BL: 92 ± 2 vs. CPT: 106 ± 2 mmHg, P&lt;0.001) and retinal blood flow (BL: 215 ± 6 vs. CPT: 230 ± 8 AU, P&lt;0.001). The relation between higher CFPWV and lower retinal blood flow observed at baseline was maintained during the CPT independent of mean BP (R=-0.37, P=0.03). However, no association was noted between CFPWV and % change in retinal blood flow. These preliminary data suggest that higher aortic stiffness is associated with lower retinal microvascular blood flow at rest and during sympatho-excitation independent of BP. These findings have important implications for age-related ocular degeneration, and lend support for future studies aiming to identify retinal microvascular abnormalities as markers of age-related cerebrovascular pathology.

Effects of acute aerobic exercise on arterial stiffness and cerebrovascular pulsatility in adults with and without hypertension.

Stiffer central arteries, as seen in hypertension (HTN), foster transmission of pulsatile hemodynamics into fragile cerebral vessels. Aerobic exercise is recommended for adults with HTN, but its effects on arterial stiffness and pulsatility in this group are unclear. This study sought to investigate the effect of acute aerobic exercise on arterial stiffness and cerebrovascular pulsatility in 30 adults with treated HTN and 30 age, sex, and BMI-matched adults without HTN (56 ± 6 years, BMI 28.2 ± 2.9 kg/m; 28 women). Patients underwent hemodynamic measures before/after 30-min cycling (≈55% peak oxygen consumption). Aortic stiffness was measured using carotid-femoral pulse wave velocity, and carotid artery stiffness was assessed with β-stiffness via ultrasound. Aortic/carotid pulse pressure (aortic via radial generalized transfer function) was measured by tonometry and calibrated to brachial mean pressure and diastolic pressure. Carotid/middle cerebral artery (MCA) blood velocity pulsatility indices were measured using Doppler. Carotid wave intensity analysis was used to derive forward wave intensity (W1). Exercise impacted hemodynamics similarly in HTN compared to no-HTN. Carotid-femoral pulse wave velocity, MCA pulsatility index, carotid pulsatility index, and W1 increased similarly after exercise in both groups (P < 0.05). Carotid pulse pressure and β-stiffness were unaltered after exercise. Postexercise changes in W1 were positively associated with carotid pulsatility index, which was further associated with MCA pulsatility index. These data suggest adults with treated HTN experience similar increases in aortic stiffness and cerebrovascular hemodynamic pulsatility during early recovery from acute aerobic exercise as their counterparts without HTN.

Aortic stiffness, central pulse pressure and cognitive function following acute resistance exercise.

While resistance exercise (RE) is known to be beneficial for overall health, one bout of RE acutely increases aortic stiffness and pulse pressure (PP). Increases in aortic stiffness and PP in a setting of aging has been shown to detrimentally impact cognitive function. This study examined whether increased aortic stiffness and PP from an acute bout of RE is associated with cognitive function. Thirty-five participants (21 ± 2years) underwent cognitive testing before and after either an acute bout of RE or a non-exercise time-control condition. Cognitive function was assessed as reaction time and accuracy during memory recognition, attention (Flanker) and working memory (N-back) tasks. Aortic stiffness and PP were measured via pulse wave velocity (PWV) and pulse wave analysis, respectively, using a brachial oscillometric device. There were significant increases in aortic PWV and aortic PP following RE (p < 0.05) with no change in PWV or PP following the non-exercise control condition (p > 0.05). There was no change in accuracy metrics (% hits) across conditions for any cognitive task (p > 0.05). There was a condition-by-time interaction for reaction time for the memory task (p < 0.05) driven by a significant decrease in reaction times following RE (p < 0.05) with no change in reaction time following the non-exercise control (p > 0.05). Functional increases in aortic stiffness and pulse pressure following acute RE occur in the absence of detrimental changes in cognitive function in young, healthy adults.

New insights into arterial stiffening: does sex matter?

This review discusses sexual dimorphism in arterial stiffening, disease pathology interactions, and the influence of sex on mechanisms and pathways. Arterial stiffness predicts cardiovascular mortality independent of blood pressure. Patients with increased arterial stiffness have a 48% higher risk for developing cardiovascular disease. Like other cardiovascular pathologies, arterial stiffness is sexually dimorphic. Young women have lower stiffness than aged-matched men, but this sex difference reverses during normal aging. Estrogen therapy does not attenuate progressive stiffening in postmenopausal women, indicating that currently prescribed drugs do not confer protection. Although remodeling of large arteries is a protective adaptation to higher wall stress, arterial stiffening increases afterload to the left ventricle and transmits higher pulsatile pressure to smaller arteries and target organs. Moreover, an increase in aortic stiffness may precede or exacerbate hypertension, particularly during aging. Additional studies are needed to elucidate the mechanisms by which females are protected from arterial stiffness to provide insight into its mechanisms and, ultimately, therapeutic targets for treating this pathology.