Large Elastic Artery Stiffness Research Articles

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants

Although often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6–25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.

Dietary Nitrate and Nitric Oxide Metabolism: Mouth, Circulation, Skeletal Muscle, and Exercise Performance.

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in myriad physiological processes, including the regulation of vascular tone, neurotransmission, mitochondrial respiration, and skeletal muscle contractile function. NO may be produced via the canonical NO synthase-catalyzed oxidation of l-arginine and also by the sequential reduction of nitrate to nitrite and then NO. The body's nitrate stores can be augmented by the ingestion of nitrate-rich foods (primarily green leafy vegetables). NO bioavailability is greatly enhanced by the activity of bacteria residing in the mouth, which reduce nitrate to nitrite, thereby increasing the concentration of circulating nitrite, which can be reduced further to NO in regions of low oxygen availability. Recent investigations have focused on promoting this nitrate-nitrite-NO pathway to positively affect indices of cardiovascular health and exercise tolerance. It has been reported that dietary nitrate supplementation with beetroot juice lowers blood pressure in hypertensive patients, and sodium nitrite supplementation improves vascular endothelial function and reduces the stiffening of large elastic arteries in older humans. Nitrate supplementation has also been shown to enhance skeletal muscle function and to improve exercise performance in some circumstances. Recently, it has been established that nitrate concentration in skeletal muscle is much higher than that in blood and that muscle nitrate stores are exquisitely sensitive to dietary nitrate supplementation and deprivation. In this review, we consider the possibility that nitrate represents an essential storage form of NO and discuss the integrated function of the oral microbiome, circulation, and skeletal muscle in nitrate-nitrite-NO metabolism, as well as the practical relevance for health and performance.

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

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

The role of depressive symptoms on brain blood vessel pulsatility in humans

The prevalence of major depression continues to increase, particularly in young women. Depression is associated with increased risk for cardiovascular disease and cognitive impairment later in life. Peripheral vascular dysfunction, including stiffening of the large elastic arteries, is evident in adults with depression and may mediate the relation between depressive and neurocognitive symptoms by exposing the cerebral vasculature to damaging pulsatile pressure waves. We hypothesized that increased depression symptom severity would be associated with more pulsatile blood flow through the middle cerebral artery (MCA) as assessed by the pulsatility index (PI). Transcranial Doppler ultrasound was used to measure MCA cerebral blood velocity (CBV) in 40 young adults (25 F/15 M, mean age: 24±5 y) having a wide range of depressive symptom severity. MCA PI was calculated as the difference between maximum CBV and minimum CBV normalized to the mean CBV. Self‐reported depressive symptom severity was derived using the Patient Reported Outcome Measurement Information System (PROMIS; T‐score). The association between PI and depressive symptom severity was quantified using linear regression; sex differences were assessed using multiple linear regression. PI (mean±SE: 0.8±0.02; range: 0.6–1.0) was negatively correlated with depressive symptom severity (mean±SE: 51.3±1.6; range: 37.1–71.9) (r2=0.12, P=0.03). There was no difference in the relation between depressive symptom severity and PI between men and women (R2=0.09, P=0.39). Lower pulsatility of the cerebral arteries in adults with more severe depressive symptoms may indicate a possible compensatory role to protect the brain from damaging pressure waves. Future studies should examine the mechanisms by which depression contributes to decreased pulsatility of cerebral blood vessels and stiffening of large elastic arteries in young individuals, including the possible role of augmented cerebral autoregulation, and whether this mechanism changes with advancing age.Support or Funding InformationNIH Grant P20GM113125

Association Between Circulating Lipids and Vascular Function in Young and Postmenopausal Women

Aging is the primary risk factor for cardiovascular disease (CVD), which remains the leading cause of death in the United States. The incidence of CVD increases in postmenopausal women (PMW) and is associated with a decline in vascular endothelial function and stiffening of the large elastic arteries, two important indicators of vascular aging; however, the underlying mechanisms are not completely understood. Traditional risk factors for CVD include a well‐established, causal relationship between low density lipoprotein (LDL) and total cholesterol (TC). In addition to these established markers, there has been increased attention to the added risk that elevated plasma triglycerides (TG) may have on CVD risk; however, whether TG contribute to the decline in vascular function with menopause is not known. Accordingly, we sought to examine the relation among common lipid markers and vascular function in young and postmenopausal women. We hypothesized that there would be an inverse relation between plasma TG and vascular function and that this relation would be stronger in PMW compared to young women (YW).METHODSNinety‐two women (53 PMW and 39 YW) completed a fasting blood draw and flow‐mediated dilation (FMD) was measured to assess vascular endothelial function. In a subset of women (29 PMW and 18 YW) large elastic artery stiffness was assessed by carotid‐femoral pulse wave velocity (PWV). All young women were tested during the early follicular phase of the menstrual cycle or the placebo phase of oral contraceptive use, and PMW were a minimum of one year since their last menstrual cycle. Group differences were analyzed using t‐test and associations tested with Pearson correlations.RESULTSPMW were older (59±6 vs.24±6 years; p<0.001), exhibited higher TC (207±31 vs 168±32 mg/dL; p<0.001) LDL (115±29 vs. 88±28 mg/dL; p<0.001) and HDL (76±17 vs. 64±14 mg/dL; p<0.01). BMI (24±4 vs. 23±3 kg/m2; p=0.053) and TG did not differ between the two groups (77±29 vs.77±38 mg/dL; p=0.920). As expected, PMW had lower FMD (4.89±2.54 vs. 7.15±3.25 %; p<0.001), and higher PWV (7.37±1.39 vs.5.63±0.93 m/s; p<0.001) compared to YW. Within each group there was no relation between TC, LDL, HDL or TG with FMD. PWV was inversely associated with HDL (r= −.499; p<0.001) and positively associated with TG (r = .595; p<0.001) in PMW. Interestingly, in YW, there was a positive association between PWV and HDL cholesterol (r = 0.509; p<0.05) whereas the negative association between PWV and TG was not significant (r = −0.448; p=0.06).CONCLUSIONAlthough we did not observe any relation between lipid markers and endothelial function in either age group, our findings suggest that plasma TG levels may contribute to stiffening of the large elastic arteries and that this effect is greater in PMW. Additional data are needed to determine the mechanisms by which increased TG may lead arterial stiffening in women across the menopausal transition and whether TG affect arterial stiffness similarly in men.Support or Funding InformationSupported by NIH R01 HL146558, P20 GM113125

Increased Large Elastic Artery Stiffening with The Anthracycline Chemotherapy Drug Doxorubicin: Potential Role of Excess Mitochondrial Superoxide

The highly effective, yet proteotoxic, chemotherapeutic agent Doxorubicin (DOXO) increases the risk of cardiovascular diseases (CVDs). A key antecedent to CVDs with DOXO is aortic stiffening (assessed in vivo via aortic pulse wave velocity [aPWV]), but the underlying mechanisms driving this increase in stiffness are currently unknown. Aortic stiffening can occur due to: 1) adverse changes in extracellular matrix (ECM) proteins; and 2) the formation of proteotoxic advanced glycation end products (AGEs) that form crosslinks between ECM proteins—both of these can be driven by inflammation and excess mitochondrial (mito) superoxide production.Purpose1) To investigate underlying molecular mechanisms of DOXO‐induced aortic stiffening. 2) To determine if increased arterial stiffness is partially attenuated by decreasing excess mito superoxide using the mito‐targeted antioxidant, MitoQ.MethodsC57BL6 young adult (4mo of age) male mice received one injection of either sham (PBS; n=4) or DOXO (10mg/ml in PBS; n=8). aPWV was assessed prior to and 4 weeks following sham/DOXO administration. To assess aortic stiffness independent of humoral factors and vasomotor tone, ex vivo aortic intrinsic mechanical stiffness (elastic modulus via wire myography) was measured following sacrifice. ECM proteins (elastin and collagen) and AGEs were measured via immunoblot. Lastly, aortic abundance of pro‐inflammatory proteins was assessed using a multiplex ELISA.ResultsDOXO increased aPWV from 330.2 ± 19.89 cm/sec (baseline) to 446.1 ± 32.62 at 4w (P < 0.05), whereas no difference was observed over time in the sham group. Aortic intrinsic mechanical stiffness was ~125% higher after DOXO vs. sham (6140 ± 507 vs. 2556 ± 417 kPa; P < 0.01). Elastin was 52% lower after DOXO vs. sham (0.61 ± 0.09 vs. 1.28 ± 0.24 A.U.; P < 0.05), whereas no difference was observed in collagen. Doxorubicin treatment did not affect AGE levels. Pro‐inflammatory Interferon‐γ (0.60 ± 0.09 vs. 0.34 ± 0.04 pg/ml; P < 0.05), Interleukin‐1β (0.16 ± 0.01 vs. 0.12 ± 0.01 pg/ml; P < 0.05), Interleukin‐6 (0.14 ± 0.01 vs. 0.11 ± 0.01 pg/ml; P < 0.05) and Tumor Necrosis Factor‐α (0.13 ± 0.05 vs. 0.04 ± 0.01 pg/ml; P < 0.05) were ~30–225% greater after DOXO vs. sham. Next, to determine that DOXO‐induced aortic stiffening is mediated by excess production of mito superoxide, we supplemented mice with MitoQ (250 μM in drinking water; n=5) for 4w following DOXO. The DOXO‐induced increase in aPWV was attenuated with MitoQ (374.4 ± 15.78 cm/sec [baseline] vs. 420.9 ± 17.52 [4w]; P = 0.18). Furthermore, MitoQ mitigated the greater aortic intrinsic mechanical stiffness observed in the DOXO only group (4239 ± 761 vs. 6140 ± 507 kPa; P < 0.05).ConclusionThese data suggest DOXO induces aortic stiffening, in part, by increasing aortic intrinsic wall stiffness, reducing elastin and increasing inflammation. Importantly, aortic stiffening was partially prevented by supplementation with the mito‐targeted antioxidant, MitoQ, suggesting an important role for the involvement of excessive mito superoxide in DOXO‐induced aortic stiffening.Support or Funding InformationSG‐089, Undergraduate Research Opportunities Program (D.A.H.)NIH T32 DK007135 (Z.S.C.)

Effects of hemodialysis on blood volume, macro- and microvascular function

BackgroundVascular dysfunction is considered to spur the progression of cardiovascular disease in hemodialysis (HD) patients. Whether the HD procedure itself contributes to vascular dysfunction remains incompletely investigated. The present study sought to comprehensively assess the effects of HD on arterial and venous function along with concomitant changes in blood volume (BV). Methods and resultsWe determined BV with high-precision, automated carbon monoxide-rebreathing, arterial stiffness using applanation tonometry and intrinsic microvascular function via retinal vessel analysis prior to and after conventional 4-hour HD in fasting-controlled conditions in 10 patients. All HD patients were non-smokers and non-obese (body mass index = 22.8 ± 2.8 m·kg−2). Hypertension (70%), coronary artery disease (40%) and diabetes mellitus (20%) were the most prevalent comorbidities. Prior to HD, all patients presented with hypervolemia (+2208 ± 1213 ml). HD decreased body weight (−1.72 ± 1.25 kg, P = 0.002) and plasma volume (−689 ± 566 ml, P = 0.004), while hematocrit (Hct) was concomitantly increased (+4.8 ± 4.5%, P = 0.009). HD did not affect large elastic artery stiffness, as determined by carotid-femoral pulse wave velocity (P = 0.448) and carotid distensibility (P = 0.562). In contrast, flicker light-induced retinal venular dilation was reduced by three-fourths after HD (−2.4 ± 1.7%, P = 0.039), in parallel to increased retinal venular diameter (+11.2 ± 4.9 μm, P = 0.002). In regression analyses, a negative association was observed between HD-induced changes in Hct and retinal venular dilation (r ≥ −0.89, P ≤ 0.045). ConclusionConventional HD resulting in substantial plasma volume removal do not alter large artery elastic properties, whereas intrinsic microvascular venular dilator function is markedly impaired, an effect directly associated with the increase in hemoconcentration.

Aortic Augmentation Index is Dependent on Bodyside in Healthy Young Subjects

Aortic augmentation index (AIx) is a commonly used measure to evaluate the arterial stiffness of large elastic arteries. It has been used as an indicator for cardiovascular risk in clinical practice. To evaluate the difference in the aortic AIx assessed from the left and the right hand in a group of healthy young adults using SphygmoCor and Arteriograph devices. 32 subjects were enrolled in this study (27 ± 7years), 16 male and 16 female volunteers participated. Equally, half of the gender groups were left-handed and another half right-handed. It was found that the aortic AIx values assessed from the pressure waveforms of the right and the left hand are different and significantly higher in the left hand. Using a SphygmoCor device, the mean difference between the aortic AIx values from the right and the left hand among the whole study group was found - 4.78 ± 4.31% and using an Arteriograph the aortic AIx values were - 3.92 ± 3.90%. Aortic AIx values assessed from the right and the left hand were linearly related to each other for both devices. Moreover, it was found that the values of the aortic. AIx are independent of the subject's handedness. It has to be pointed out that subjects who cannot be subjected to assessment of the aortic AIx from one side of the body could have different AIx values estimated from the recorded pressure waveform from the other bodyside.

Aerobic exercise training and vascular function with ageing in healthy men and women.

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in both men and women in developed societies. Age is the greatest risk factor for CVD due largely to adverse changes to arteries that include stiffening of the large elastic arteries (aortic and carotid arteries) and endothelial dysfunction. Vascular ageing is driven by oxidative stress, which reduces nitric oxide (NO) bioavailability and stimulates changes in the extracellular matrix. In women, reductions in circulating oestrogens with menopause interact with ageing processes to induce vascular dysfunction. Regular aerobic exercise is the most evidence-based strategy for reducing CVD risk with ageing in both men and women. Much of this cardiovascular-protective effect of aerobic exercise is likely due to its vascular health-enhancing influence. Large elastic artery stiffening with advancing age is attenuated in healthy adults engaged in aerobic exercise training, and aerobic exercise interventions improve arterial stiffness in previously sedentary middle-aged and older men and postmenopausal women. Regular aerobic exercise also enhances endothelial function with ageing in men (by reducing oxidative stress and preserving NO bioavailability), but not consistently in oestrogen-deficient postmenopausal women. In postmenopausal women, treatment with oestradiol appears to restore the ability of aerobic exercise to improve NO-mediated endothelial function by reducing oxidative stress. Several research gaps exist in our understanding of potential sex differences in the vascular adaptations to regular aerobic exercise. More information is needed on the factors that are responsible for sex differences, including the role of circulating oestrogens in transducing the aerobic exercise training 'stimulus'.

Association between large elastic artery stiffness and brain mechanical properties

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 < 0.05, r2 = 0.7) while total brain stiffness significantly decreased with age (F = 6.1, p < 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.

Dietary Glycocalyx Precursor Supplementation Ameliorates Age‐Related Vascular Dysfunction

Large elastic artery stiffening and endothelial dysfunction, and associated reductions in nitric oxide (NO) bioavailability, are central features of vascular aging. We have recently demonstrated that the glycocalyx, a gel‐like structure that is bound to the luminal surface of the vascular endothelium, is dysfunctional in the aged vasculature. The glycocalyx has several functions that are critical for the maintenance of a healthy vasculature. We sought to determine if chronic dietary supplementation of glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) could restore glycocalyx function, while concomitantly ameliorating age‐related vascular dysfunction. Young (Y: 7 mo) and old (O: 30 mo) male B6D2F1 mice consumed a control (C) or glycocalyx precursor (GP: 37 mg/kg encapsulated chow provided courtesy of MicroVascular Health Solutions, LLC [U.S. Patent Serial No. 9,943,572]) diet ad libitum for 10 weeks. Glycocalyx barrier function (perfused boundary region [PBR]) was evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was ~13% higher in OC compared to YC, suggestive of an age‐related impairment in glycocalyx barrier function, and this was normalized in OGP mice (Both P<0.05; Figure 1). At baseline, aortic pulse wave velocity (PWV), a measure of large artery stiffness, was higher in OC and OGP compared with YC mice (Both P<0.05; Figure 2). However, after the dietary intervention, PWV decreased by ~13% in OGP (P<0.05), whereas, PWV was unchanged in OC and YC mice after the 10 week period (P>0.05). We assessed endothelial function by endothelium‐dependent dilation (EDD, maximal response to acetylcholine [ACh]) in the carotid artery. Carotid artery EDD was higher in YC and OGP compared to OC mice (92.5±2.4 and 90.7±2.3 vs. 69.0±4.9%, respectively, P<0.05). EDD of OGP was similar to YC mice (P>0.05). After incubation with the nitric oxide (NO) synthase inhibitor, L‐NAME, the dilatory response did not differ between groups (P>0.05). NO bioavailability (max ACh dilation ‐ max ACh+L‐NAME dilation) was ~10–14 fold higher in YC and OGP compared to OC mice (Both P<0.05; Figure 3). Endothelium‐independent dilation (vasodilation to sodium nitroprusside) was not different between groups (P>0.05). In young mice, GP diet did not affect any of the aforementioned measurements (P>0.05). In conclusion, 10 weeks of dietary GP supplementation in old mice restores glycocalyx barrier function that is accompanied by reduced aortic stiffness and augmented EDD and NO bioavailability, suggesting that the glycocalyx may be an effective therapeutic target for vascular dysfunction in older adults.Support or Funding InformationThis study was funded in part by grants from the National Institute of Health (R01 AG040297, R01 AG048366, K02 AG045339, K99 AT010017) and US Department of Veterans Affairs (1I01BX002151).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice.

Age-related arterial dysfunction, characterized by oxidative stress- and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age-related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad-spectrum, poorly-absorbed antibiotics in drinking water for 3-4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age-related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide. The results of the present study provide the first proof-of-concept evidence that the gut microbiome is an important mediator of age-related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345±16AU vs. old control (OC): 220±34 AU, P<0.01; vs. old antibiotic-treated (OA): 334±15AU; P<0.01vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62±0.15m s-1 vs. OC: 4.43±0.38m s-1 ; vs. OA: 3.52±0.35m s-1 ; P=0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6±0.4μmol L-1 vs. OC: 7.2±2.0μmol L-1 ; P<0.0001) and suppressed by antibiotic treatment (OA: 1.2±0.2μmol L-1 ; P<0.0001vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness.

What is the central question of this study? Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater risk of Alzheimer's disease. However, it is unknown whether stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance? In a mouse model with greater large artery stiffness (Eln+/- ), we find an exacerbated vasoconstrictor response to angiotensinII in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensinII responsiveness in the poor brain outcomes associated with greater large artery stiffness. Greater stiffness of the large elastic arteries is associated with end-organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown whether large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/- ) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wild-type (Eln+/+ ) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response to angiotensinII (AngII) was ∼40% greater in Eln+/- compared with Eln+/+ mice (P=0.02), and this group difference was ameliorated by losartan, indicating a role for AngII type1 receptors (AT1Rs). In gastrocnemius feed arteries, Eln+/- and Eln+/+ mice did not differ in the response to AngII. In addition, the vasoconstrictor responses to noradrenaline, endothelin-1 and potassium chloride were not different between Eln+/- and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas AngII type2 receptor gene expression was ∼50% lower in MCAs from Eln+/- versus Eln+/+ mice (P=0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to AngII in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.

CT-measured lung air-trapping is associated with higher carotid artery stiffness in individuals with chronic obstructive pulmonary disease.

Early stages of chronic obstructive pulmonary disease (COPD) are characterized by the loss and narrowing of terminal bronchioles in the lung, resulting in "air-trapping," often occurring before overt emphysema manifests. Individuals with an airway-predominant phenotype of COPD display extensive lung air-trapping and are at greater cardiovascular disease (CVD) risk than COPD patients with an emphysema-predominant phenotype. We hypothesized that the degree of computed tomography (CT)-quantified lung air-trapping would be associated with greater aortic and carotid artery stiffness and lower endothelial function, known biomarkers of CVD risk. Lung air-trapping was associated with greater aortic stiffness (carotid femoral pulse wave velocity, CFPWV) (r = 0.60, P = 0.007) and carotid β-stiffness (r = 0.75, P = 0.0001) among adults with (n = 10) and without (n = 9) a clinical diagnosis of COPD and remained significant after adjusting for blood pressure (BP) and smoking history (pack-years) (carotid β-stiffness: r = 0.68, P < 0.01; CFPWV r = 0.53, P = 0.03). The association between lung air-trapping and carotid β-stiffness remained significant after additionally adjusting for age and forced expiratory volume 1(FEV1) (r = 0.64, P = 0.01). In the COPD group only (n = 10), lung air-trapping remained associated with carotid β-stiffness (r = 0.82, P = 0.05) after adjustment for age, pack-years, and FEV1. In contrast, no association was observed between CFPWV and lung air-trapping after adjustment for BP, pack-years, age, and FEV1 (r = 0.12, P = 0.83). Lung air-trapping was not associated with endothelial function (brachial artery flow-mediated dilation) in the entire cohort (P = 0.80) or in patients with COPD only (P = 0.71). These data suggest that carotid artery stiffness may be a mechanism explaining the link between airway-predominant phenotypes of COPD and high CVD risk.NEW & NOTEWORTHY Previous cross-sectional studies have demonstrated greater large elastic artery stiffness and lower endothelium-dependent dilation in chronic obstructive pulmonary disease (COPD) patients compared with controls. Furthermore, COPD patients with emphysema have greater aortic stiffness than non-COPD controls, and the degree of stiffness is associated with emphysema severity. The present study is the first to demonstrate that even before overt emphysema manifests, lung air-trapping is associated with carotid artery stiffness in COPD patients independent of blood pressure, age, or smoking history.

Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease.

Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations. Two major age-related arterial phenotypes, large elastic artery stiffening and endothelial dysfunction, are independent predictors of future CVD diagnosis and likely are responsible for the development of CVD in older adults. Not limited to traditional CVD, these age-related changes in the vasculature also contribute to other age-related diseases that influence mammalian health span and potential life span. This review explores mechanisms that influence age-related large elastic artery stiffening and endothelial dysfunction at the tissue level via inflammation and oxidative stress and at the cellular level via Klotho and energy-sensing pathways (AMPK [AMP-activated protein kinase], SIRT [sirtuins], and mTOR [mammalian target of rapamycin]). We also discuss how long-term calorie restriction-a health span- and life span-extending intervention-can prevent many of these age-related vascular phenotypes through the prevention of deleterious alterations in these mechanisms. Lastly, we discuss emerging novel mechanisms of vascular aging, including senescence and genomic instability within cells of the vasculature. As the population of older adults steadily expands, elucidating the cellular and molecular mechanisms of vascular dysfunction with age is critical to better direct appropriate and measured strategies that use pharmacological and lifestyle interventions to reduce risk of CVD within this population.

Effects of testosterone and progressive resistance exercise on vascular function in older men.

The cardiovascular effects of testosterone (T) are controversial. Low T has been associated with accelerated vascular aging, characterized by large elastic artery stiffening (decreased compliance), intimal-medial thickening (IMT), and endothelial dysfunction. Endurance exercise improves vascular function, but resistance training may increase arterial stiffness. We sought to determine whether T supplementation improved markers of vascular aging in men with low-normal T and whether T supplementation prevented arterial stiffness with resistance exercise. We studied 160 community-dwelling older men (66 ± 5 yr) with low-normal baseline total T levels (200-350 ng/dl). Participants were randomized to transdermal T gel targeting either a lower (400-550 ng/dl) or higher (600-1,000 ng/dl) T range or to placebo gel and to either progressive resistance training (PRT) or to no exercise for 12 mo. Carotid artery stiffness (arterial compliance) and carotid IMT were measured at baseline, 6 mo, and 12 mo. Endothelial function (brachial artery flow-mediated dilation) was measured in a subset (n = 86). Changes in carotid artery compliance, IMT, and endothelial function with either the lower or higher range of T supplementation were not different from placebo at 6 or 12 mo. There were no differences between PRT and no PRT groups, alone or with T supplementation, in changes in any of the vascular measures at either time point. Supplementation of T and PRT in older men with low-normal levels do not appear to improve or harm vascular function.NEW & NOTEWORTHY Increased promotion and prescription of testosterone (T) to aging men has raised concerns about potential adverse cardiovascular effects. We show that in older men with T levels in the low-normal range, 12 mo of T supplementation with or without resistance exercise did not improve or harm vascular function.

Keynote lecture: strategies for optimal cardiovascular aging.

This review summarizes the opening keynote presentation overview of the American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends held in Westminster, CO, in August 2017. Age is the primary risk factor for cardiovascular diseases (CVDs). Without effective intervention, future increases in the number of older adults will translate to a greater prevalence of CVDs and related disorders. Advancing age increases the risk of CVDs partly via direct effects on the heart and through increases in blood pressure; however, much of the risk is mediated by vascular dysfunction, including large elastic artery stiffening and both macro- and microvascular endothelial dysfunction. Although excessive superoxide-related oxidative stress and chronic low-grade inflammation are the major processes driving cardiovascular aging, the upstream mechanisms involved represent new frontiers of investigation and potential therapeutic targets. Lifestyle practices, including aerobic exercise, energy intake (caloric) restriction, and healthy diet composition, are the most evidence-based strategies (old friends) for optimal cardiovascular aging, but adherence is poor in some groups. Healthy lifestyle "mimicking" approaches, including novel forms of physical training, intermittent fasting paradigms, exercise/healthy diet-inspired nutraceuticals (functional foods and natural supplements), as well as controlled environmental stress exposure (e.g., heat therapy), may hold promise but are unproven. Mitigating the adverse effects of aging on cardiovascular function and health is a high biomedical priority.

Suppression of the Gut Microbiome‐Derived Metabolite Trimethylamine N‐oxide Prevents Western Diet‐Induced Arterial Dysfunction

Consumption of a Western‐style diet (WD; high fat, high sugar) is associated with impaired arterial function and increased risk of cardiovascular diseases (CVD). One possible link between WD and impaired arterial function may be the gut microbiome. WD induces adverse changes to the gut microbiome, and consequently, increased production of the gut‐derived metabolite trimethylamine N‐oxide (TMAO). TMAO is causally atherogenic in mice and predicts incident risk of major CV events in humans, but it is unknown whether TMAO mediates arterial dysfunction that precedes clinical CVD.PURPOSETo determine if inhibition of TMAO with 3,3‐dimethyl‐1‐butanol (DMB; inhibitor of microbial TMA lyase) prevents WD‐induced large elastic artery stiffening and endothelial dysfunction.METHODSTwenty‐four young (3 mo) male C57BL/6 mice were fed WD (40% fat, 25% sugar) for 5 months and were supplemented without (WD‐Control, WD‐C; N=11) or with 1% DMB (N=13) in drinking water for the last 8 weeks. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV) following 3 mo of WD (intervention baseline, BL) and following 4 and 8 weeks on the intervention. Endothelial function and its suppression by oxidative stress were evaluated ex vivo as carotid artery endothelium‐dependent dilation (EDD) to increasing doses of acetylcholine (10−9 to 10−4M) alone and following pre‐incubation with the superoxide dismutase mimetic TEMPOL. Total whole‐cell superoxide production was assessed in aortic rings via electron paramagnetic resonance spectroscopy. The same assessments were made in a reference group of age‐matched C57BL/6 male mice fed standard rodent chow (Normal Chow, NC; N=10). Data are mean±S.E.RESULTSWD induced progressive increases in aPWV (BL: 346±15, 4wks: 363±14, 8wks: 420±23 cm/sec, p=0.01), which were prevented by DMB (BL: 347±10, 4wks: 349±20, 8wks: 355±16cm/sec, p=0.98; DMB vs. WD‐C at 8wks: p=0.02). WD impaired EDD (peak dilation: 83.0±1.1% vs. NC: 92.5±2.0%, p&lt;0.01), which was prevented by DMB (93.4±1.5%, p&lt;0.0001 vs. WD‐C, p=0.71 vs. NC). Group differences in EDD were no longer significant after inhibition of oxidative stress with TEMPOL (peak EDD: p=0.22). Aortic superoxide production tended to be lower in DMB (2.2±0.3 AU) vs. WD‐C mice (3.9±1.1 AU, p=0.12) and was not different from NC (2.5±0.6 AU, p=0.52).CONCLUSIONSDMB supplementation prevented WD‐induced arterial stiffening and endothelial dysfunction, possibly through attenuation of oxidative stress. These data establish a role of the gut microbiome and TMAO in mediating WD‐induced arterial dysfunction and provide initial evidence of a novel strategy for preventing arterial dysfunction and reducing CVD risk.Support or Funding InformationSupported by R01 HL134887 &amp; T32 HL007822This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Long‐Acting Beta‐Agonist Use is Associated with Lower Carotid Artery Stiffness and Greater Carotid Artery Compliance in Individuals with Chronic Obstructive Pulmonary Disease

BackgroundCardiovascular disease (CVD) is the most prevalent comorbidity in individuals with chronic obstructive pulmonary disease (COPD). Elevated large elastic artery stiffness (i.e. carotid and aorta) is a robust predictor of CVD events and mortality and is associated with airway obstruction in COPD patients, suggesting that large artery stiffness may contribute, at least in part, to the high CVD risk in COPD. Previous studies demonstrate that in COPD patients, bronchodilator therapy improves respiratory symptoms, lowers the risk of exacerbations and reduces aortic stiffness, as measured by carotid‐femoral pulse wave velocity (CFPWV), in COPD patients with a very high CFPWV (≥ 11 m/s). However, the long‐term benefits of bronchodilator therapy on cardiovascular risk remain controversial. We hypothesized that individuals with COPD who reported using a long‐acting beta‐agonist (LABA) or an inhaled corticosteroid (ICS) would have lower carotid artery stiffness/greater compliance compared with COPD patients not on LABAs or ICSs.MethodsSixty‐three adults with COPD (age 70 ± 7 yrs; 23M/40F; GOLD stage 1–4; 6% stage 1, 47% stage 2, 24% stage 3, 23% stage 4) completed measurements of common carotid artery stiffness and compliance (carotid artery ultrasound and tonometry) and were retrospectively stratified by self‐report of LABA and ICS use.ResultsThirty‐two (49%) participants reported using a LABA/ICS combination bronchodilator. Seven (11%) of patients reported using a LABA alone and 7 (11%) of patients reported using an ICS alone. COPD patients using a LABA/ICS combination bronchodilator had significantly lower carotid β‐stiffness (8.7 ± 0.5 vs. 10.9 ± 0.9 U, P=0.04) and greater carotid compliance (0.11 ± 0.01 vs. 0.08 ± 0.01 mm/mmHg, P=0.01) compared with patients not using a LABA/ICS. This difference remained significant after adjusting for age, gender, BMI, oxygen use and smoking pack‐years (carotid β‐stiffness P=0.04; carotid compliance P=0.05). BP, heart rate and oxygen saturation did not differ between COPD patients using vs. not using a LABA/ICS. Furthermore, patients that reported using a LABA alone, and not in combination with an ICS, had significantly lower carotid β‐stiffness (6.9 ± 0.6 vs. 10.1 ± 0.6 U, P&lt;0.01), but not greater carotid compliance (0.11 ± 0.01 vs. 0.09 ± 0.01 mm/mmHg, P=0.2) compared with those not using a LABA. In contrast, there was no difference in carotid β‐stiffness (9.0 ± 1.2 vs. 9.9 ± 0.6 U, P=0.60) or carotid compliance (0.10 ± 0.01 vs. 0.10 ± 0.01 mm/mmHg, P=0.93) between COPD patients that reported using vs. not using an ICS.ConclusionThese data indicate that COPD patients who are taking a LABA, either in combination with an ICS or alone, have lower carotid artery stiffness than those not taking a LABA. This finding raises the possibility that LABAs may be beneficial in reducing the CVD risk observed in COPD, however randomized, controlled clinical trials are needed to test whether LABAs impact CVD risk.Support or Funding InformationNIH K23 HL095658, R01 HL089897, NIH/NCATS CTSI UL1 TR001082This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The gut-derived metabolite trimethylamine N-oxide induces large elastic artery stiffening and endothelial dysfunction in young mice

The gut microbiome, an emerging mediator of host physiological function, is adversely altered by aging and many diseases, termed “gut dysbiosis.” One consequence of gut dysbiosis is elevated circulating levels of the gut-derived metabolite trimethylamine N-oxide (TMAO), which has been directly linked to cardiovascular (CV) risk, including the development of atherosclerosis. However, it is unknown whether TMAO mediates arterial dysfunction that precedes the onset of clinical disease, and if so, the underlying mechanisms.PurposeTo determine whether TMAO independently induces large elastic artery stiffening and endothelial dysfunction via increased superoxide-related oxidative stress.MethodTwenty young (6 mo) male C57BL/6 mice were fed a chemically-defined choline (0.08–0.09%) diet supplemented without (Control; N = 9) or with (N = 11) 0.12% TMAO for 6 months. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV). Endothelial function was evaluated ex vivo as carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine (10−9 to 10−4M) in the absence or presence of the superoxide dismutase mimetic TEMPOL.ResultsTMAO increased aPWV (Control: 392 ± 20 vs. TMAO: 483 ± 32 cm/ sec, p = 0.04) and impaired EDD (peak dilation, Control: 93.7 ± 3.2 vs. TMAO: 79.9 ± 3.4%, p = 0.01).Suppression of oxidative stress with TEMPOL restored EDD in TMAO-treated animals (peak dilation: 92.1 ± 4.7%, p = 0.46 vs. Control).ConclusionsTMAO independently induces large elastic artery stiffening and endothelial dysfunction in mice. Dysfunction appears to occur through increases in oxidative stress. These data may explain, at least in part, why TMAO increases CV risk and provide a potential target for prevention/treatment of arterial dysfunction.Supported by R01 HL134887 & T32 HL007822.