Age-related Aortic Stiffening Research Articles

Mechanistic insights on age-related changes in heart-aorta-brain hemodynamic coupling using a pulse wave model of the entire circulatory system.

Age-related changes in aortic biomechanics can impact the brain by reducing blood flow and increasing pulsatile energy transmission. Clinical studies have shown that impaired cardiac function in patients with heart failure is associated with cognitive impairment. Although previous studies have attempted to elucidate the complex relationship between age-associated aortic stiffening and pulsatility transmission to the cerebral network, they have not adequately addressed the effect of interactions between aortic stiffness and left ventricle (LV) contractility (neither on energy transmission nor on brain perfusion). In this study, we use a well-established and validated one-dimensional blood flow and pulse wave computational model of the circulatory system to address how age-related changes in cardiac function and vasculature affect the underlying mechanisms involved in the LV-aorta-brain hemodynamic coupling. Our results reveal how LV contractility affects pulsatile energy transmission to the brain, even with preserved cardiac output. Our model demonstrates the existence of an optimal heart rate (near the normal human heart rate) that minimizes pulsatile energy transmission to the brain at different contractility levels. Our findings further suggest that the reduction in cerebral blood flow at low levels of LV contractility is more prominent in the setting of age-related aortic stiffening. Maintaining optimal blood flow to the brain requires either an increase in contractility or an increase in heart rate. The former consistently leads to higher pulsatile power transmission, and the latter can either increase or decrease subsequent pulsatile power transmission to the brain.NEW & NOTEWORTHY We investigated the impact of major aging mechanisms of the arterial system and cardiac function on brain hemodynamics. Our findings suggest that aging has a significant impact on heart-aorta-brain coupling through changes in both arterial stiffening and left ventricle (LV) contractility. Understanding the underlying physical mechanisms involved here can potentially be a key step for developing more effective therapeutic strategies that can mitigate the contributions of abnormal LV-arterial coupling toward neurodegenerative diseases and dementia.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment.

Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction. We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263. In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s, P<0.05) to young levels (old-GCV vs. young-vehicle, P=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s, P<0.05). Aortic adventitial collagen was reduced by GCV (P<0.05) and ABT-263 (P=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%, P<0.05) to young levels (Old-GCV vs. young-vehicle, P=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%, P<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (P<0.05) and reduced oxidative stress (P<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance. Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.

Oral Supplementation with the Short-Chain Fatty Acid Acetate Ameliorates Age-Related Aortic Stiffening in Mice

Aging is the main risk factor for cardiovascular diseases (CVD) due in part to stiffening of large elastic arteries (e.g., aorta). High-fiber diets (H-FIB) are associated with reduced risk of CVD, but most people do not meet guidelines for adequate fiber intake. Short-chain fatty acids (SCFA), which are produced by gut microbiome-dependent fermentation of soluble fiber, are thought to mediate many of the benefits of a H-FIB. Acetate, the most prevalent SCFA in circulation, may be an adherable intervention as an oral supplement for improving age-related arterial stiffening and reducing the risk of CVD. PURPOSE: To determine if oral acetate supplementation can reduce age-related aortic stiffness comparably to a H-FIB. METHODS: Young (Y: 3mo; N=11-12/group) and old (O: 24mo; N=24-27/group) C57Bl/6N mice were split into 3 groups per age: 1) controls (YC/OC): standard chow (15% total, 2.5% soluble fiber) and normal drinking water; 2) acetate supplemented (YA/OA): standard chow and 100mM of calcium acetate in drinking water; and 3) H-FIB (YF/OF): chow supplemented with fiber (20% total, 8% soluble fiber) and normal drinking water. Aortic pulse wave velocity (aPWV; standard reference method of in vivo aortic stiffness) and blood pressure (BP; tail cuff) were measured before and after 8 weeks of intervention. Thoracic aortas were harvested to measure: elastic modulus (aEM) of aortic rings (structural measurement of stiffness dependent on engagement of collagen fibers); aortic wall thickness (structural contributor to arterial stiffening); and collagen abundance by immunofluorescence (pro-stiffening structural protein). RESULTS: Data are mean ± SE. aPWV was higher in old vs. young mice at baseline (O: 404±10 vs. Y: 335±4 cm/sec, p&lt;0.01), and was reduced comparably by both interventions in the old mice (OA: 379±5, p=0.04 vs. OC: 403±8 cm/sec; OF: 379±5 cm/sec, p=0.04 vs. OC). Post-intervention systolic blood pressure (OC: 83.1±3.2, OA: 87.5±4.7, OF: 85.4±5.9 mmHg, p=0.82) and aortic wall thickness (OC: 0.05±0.002, OA: 0.05±0.004, OF: 0.05±0.002 μM, p=0.77) were not different between groups, suggesting that neither factor explained the intervention effects on aPWV. Conversely, aortic collagen abundance (measured in a subset of mice, N=4/group), which was higher in old mice (OC: 964±118 vs. YC: 644±25 AU, p=0.02), was reduced to young levels by acetate supplementation (OA: 671±18 vs. YC: 644±25 A.U., p=0.41). Both acetate and H-FIB reduced aEM in old mice (OC: 3640±229 vs. OA: 2291±274 kPA, p=0.002; OF: 2600±321 kPA, p=0.06 vs. OC). There were no differences across groups in young mice. CONCLUSION: Oral acetate supplementation and H-FIB were similarly effective at mitigating age-related aortic stiffening; effects may be mediated in part by reduced collagen content in the arterial wall. Acetate supplementation may be a promising treatment for preventing age-related aortic stiffening and subsequent CVD risk. FUNDING: K99/R00 HL151818, CU Boulder BSI Scholarship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Greater aortic perivascular adipose tissue density is associated with aging, aortic stiffness, and central blood pressure in humans.

Aging results in aortic perivascular adipose tissue (aPVAT)-mediated aortic stiffening in preclinical animal models to promote cardiovascular dysfunction. We hypothesized that greater human aPVAT density will be associated with aging, higher aortic stiffness, and blood pressure (BP). Fourteen apparently healthy adults (6 M/8 F, age range 20-79 yr) were recruited for this study. Aortic stiffness, assessed by carotid-femoral pulse wave velocity (cfPWV), resting aortic BP via pulse wave analysis, and aPVAT and abdominal visceral adipose tissue (VAT) density by computed tomography attenuation were acquired. aPVAT and epididymal (visceral) fat from young (4-6 mo) and old (27-29 mo) mice were used for ex vivo-conditioned media intrinsic mechanical stiffness experiments. Compared with younger adults, older adults had higher cfPWV (8.6 ± 0.4 vs. 6.2 ± 0.6 m/s, P < 0.05) and greater aPVAT attenuation (-80.2 ± 2.0 vs. -95.9 ± 1.5 HU, P < 0.05), but not VAT attenuation (P > 0.05). aPVAT-conditioned media from old mice compared with young mice increased intrinsic mechanical stiffness of the aorta (4,519 ± 510 vs. 2,325 ± 563 kPa, P < 0.05), which was not observed with epididymal fat-conditioned media from old mice (P > 0.05). aPVAT, but not VAT density, was positively associated with age (r = 0.89), cfPWV (r = 0.56), resting augmentation index normalized to heart rate 75 (AIxHR75; r = 0.67), aortic systolic BP (r = 0.58), and aortic pulse pressure (PP; r = 0.59; P < 0.05, all) and were independent of VAT density (P < 0.05, all). These data herein provide evidence for aPVAT as a novel fat depot and therapeutic target to lower aortic stiffness and future cardiovascular disease risk with aging in humans.NEW & NOTEWORTHY Aortic perivascular adipose tissue (aPVAT) promotes age-related aortic stiffening in preclinical animal models, but the relation between aPVAT density and cardiovascular function in adults is unknown. We demonstrate that aPVAT, but not abdominal visceral adipose tissue density, is positively associated with aging, aortic stiffness, and higher resting aortic blood pressure in apparently healthy adults. These findings provide novel evidence for aPVAT as a viable therapeutic target for improving cardiovascular function in humans.

Impact Of Age On Aortic Pressure And Pressure Waves Responses To Metaboreflex Activation In Women

INTRODUCTION: Aging and hypertension are related to exaggerated peripheral blood pressure (BP) responses to exercise and metaboreflex activation (post-exercise muscle ischemia, PEMI). Postmenopausal (POST) women have greater risk of heart failure with preserved ejection fraction due to increased aortic pulsatile load on the left ventricle induced by increased systolic BP (SBP) and decreased diastolic BP (DBP) at rest. Age-related aortic stiffening augments pressures of the forward (Pf) and the reflected wave (Pb) traveling from peripheral arteries to the aorta. Increases in Pf and Pb contribute to elevated aortic SBP and pulse pressure (PP) responses to exercise, increasing the risk for cardiovascular events. However, the influence of Pf and Pb on aortic pulsatile load during isometric handgrip (IHG) and PEMI in normotensive premenopausal (PRE) and POST women have not been examined. PURPOSE: To investigate the effect of age on aortic BP, Pf, and Pb during IHG and PEMI in normotensive PRE and POST women. METHODS: Fifteen PRE (age: 24 ± 1 years) and 16 POST women (age: 59 ± 1 years) participated in this study. Brachial BP was obtained using an automated device and radial arterial tonometry was used to capture aortic waveforms to estimate aortic BP and pressure waves at rest, during a 2-min IHG at 30% of maximal force, and during a 3-min PEMI. RESULTS: BP responses to IHG were similar in both groups. Brachial PP (POST: Δ9 ± 1 mmHg vs PRE: Δ0 ± 2 mmHg, P < 0.01), aortic PP (POST: Δ8 ± 1 mmHg vs PRE: Δ3 ± 2 mmHg, P = 0.03), Pf (POST: Δ6 ± 1 mmHg vs PRE: Δ0 ± 1 mmHg, P < 0.01), and Pb (POST: Δ5 ± 1 mmHg vs PRE: Δ2 ± 1 mmHg, P = 0.02) responses to PEMI were significantly increased in POST compared to PRE women. Aortic DBP (POST: Δ6 ± 1 mmHg vs PRE: Δ11 ± 2 mmHg, P = 0.04) responses to PEMI was significantly lower in POST than PRE women. Brachial and aortic SBP significantly (P < 0.001) increased during PEMI in both PRE and POST women, but there was no difference (P > 0.05) between groups. CONCLUSION: Normotensive POST women have augmented aortic PP response to PEMI compared to PRE women due to increases in pressure of the forward and backward waves and a decrease in DBP. Our findings suggest that the age-related increase in muscle metaboreflex activation does not induce a systolic overload and the increase in aortic PP is attributed to reduced DBP in normotensive POST women.

Age-related Aortic Stiffness Can Be Transferred and Ameliorated via Fecal Microbiota Transplant in Mice.

Age-related increases in aortic stiffness contribute to the development of cardiovascular diseases (CVD). To determine whether the gut microbiome (GM) modulates age-related aortic stiffening, we performed fecal microbiota transplants (FMT) between young (Y; 3 month) and older (O; 25 month) male C57BL/6N mice. Following antibiotic treatment (to suppress endogenous microbiota), mice received weekly FMT (fecal samples collected at baseline) via oral gavage for 8-16 weeks from their own (i.e., sham condition: Y-y, O-o [RECIPIENT-donor]) or opposite age group (Y-o, O-y) (N=8-12/group). In vivo aortic stiffness (pulse wave velocity [PWV]) was higher in older vs. young mice at baseline (382±8 vs. 328±7cm/sec, mean±SE, P<0.001). Arterial phenotypes were transferred such that old microbiota transplanted into young mice increased, while young into old decreased, PWV (Y-y: 325±10 vs. Y-o: 362±10cm/sec, P=0.022; O-o: 409±10 vs. O-y: 335±6cm/sec, P<0.001). Intrinsic mechanical stiffness of excised aortic rings (elastic modulus) increased after transplant of old into young (Y-y: 2141±223 vs. Y-o: 3218±394kPA, P=0.022), and decreased with young into old (O-O: 3263±217 vs. O-y: 2602±136kPA, P=0.016), indicating the GM mediates aortic stiffening by modulating structural changes in the arterial wall. Age-related increases in aortic abundance of advanced glycation end products (AGEs), which cross-link arterial structural proteins, tended to be transferred by the GM (Y-y: 0.022±0.001 vs. Y-o: 0.038±0.006 A.U., P=0.11; O-o: 0.120±0.029 vs. O-y: 0.038±0.009 A.U., P=0.06). The aging GM can induce aortic stiffening via promoting AGEs accumulation and crosslinking of arterial structural proteins, and thus might be a promising target for preventing/treating age-related aortic stiffening and CVD.

Conductance artery stiffness impairs atrio-ventriculo-arterial coupling before manifestation of arterial hypertension or left ventricular hypertrophic remodelling

As part of normal ageing, conductance arteries lose their cushion function, left ventricle (LV) filling and also left atrial emptying are impaired. The relation between conductance artery stiffness and LV diastolic function is normally explained by arterial hypertension and LV hypertrophy as needed intermediaries. We examined whether age-related aortic stiffening may influence LV diastolic function in normal healthy subjects. Aortic distensibility and pulse wave velocity (PWV) were related to LV emptying and filling parameters and left atrial emptying parameters as determined by magnetic resonance imaging in 36 healthy young (< 35 years) and 16 healthy middle-aged and elderly (> 35 years) with normal arterial blood pressure and myocardial mass. In the overall cohort, total aorta PWV correlated to a decrease in LV peak-emptying volume (r = 0.43), LV peak-filling (r = 0.47), passive atrial emptying volume (r = 0.66), and an increase in active atrial emptying volume (r = 0.47) (all p < 0.001). PWV was correlated to passive atrial emptying volume even if only the > 35-year-old were considered (r = 0.53; p < 0.001). Total peripheral resistance demonstrated similar correlations as PWV, but in a regression analysis only the total aorta PWV was related to left atrial (LA) passive emptying volume. Via impaired ventriculo-arterial coupling, the increased aortic PWV seen with normal ageing hence affects atrio-ventricular coupling, before increased aortic PWV is associated with significantly increased arterial blood pressure or LV hypertrophic remodelling. Our findings reinforce the existence of atrio-ventriculo-arterial coupling and suggest aortic distensibility should be considered an early therapeutic target to avoid diastolic dysfunction of the LV.

Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans.

[Figure: see text].

The Gut Microbiome Targeted Compound 3,3‐Dimethyl‐1‐butanol Attenuates In Vivo Aortic Stiffening with Aging

Increases in aortic stiffness occur with aging and predict cardiovascular (CV) mortality, but the upstream mechanism(s) by which this occurs are not fully understood. Age-related aortic stiffening can occur due to both structural (i.e., mechanical) changes, as well as functional changes, including increases in blood pressure (BP), autonomic nervous system activity, and impairments in endothelial function with consequent effects on vascular tone. Our laboratory has shown that the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) increases in circulation with aging, and supplementation with TMAO directly induces aortic stiffening in mice. Gut microbiome-dependent TMAO production can be suppressed by the naturally-occurring compound 3,3-dimethyl-1-butanol (DMB). Purpose To determine if supplementation with DMB prevents the development of age-related aortic stiffening and elucidate potential underlying mechanisms. Methods and Results Middle-aged (18 mo) male C57BL/6 mice received normal drinking water (control) or drinking water with 1% DMB until sacrifice at 21, 24, or 27 mo of age (n=11-21/age/treatment). Aortic stiffness was assessed in vivo by aortic pulse wave velocity (aPWV). In control mice, there were no apparent age-related increases in aPWV at 18 or 21 mo (365±6 and 374±11 cm/s) compared to a reference group of young (5 mo) male C57BL/6 mice (n=11; 356±14 cm/s; 18 and 21 mo both p>0.32 vs. young), but aortic stiffening developed with advancing age (24 mo: 413±14, 27 mo: 444±14 cm/s, both p≤0.001 vs. 18 mo). The increase from 18 to 27 mo was attenuated by ~70% in mice treated with DMB (aPWV at 24 mo: 358±8, 27 mo: 388±9 cm/s, both p≤0.01 vs. control).To determine if attenuation of aortic stiffening with DMB was due to prevention of structural changes in the aorta with advancing age, we measured intrinsic mechanical stiffness (elastic modulus; EM) in aortic rings by wire myography in a subset of mice (n=5-6/group). In control mice, there was a progressive increase in aortic EM from 5 to 18 to 21 mo (2106±186, 2550±217, 2924±304 kPa; ANOVA time effect: p=0.053) but no further increase after 21 mo (27 mo: 2696±344 kPa; p=0.77 vs. 21 mo). DMB treatment did not affect this age-related intrinsic mechanical stiffening (i.e., no difference between control vs. DMB at any time point, all p>0.5), indicating the prevention of increased aPWV in DMB mice was likely due to functional (vs. structural) changes in the aorta. To investigate this, we measured BP by the tail-cuff method in a subset of mice (n=4-11/group) but found no differences between control and DMB mice at any timepoint (all p>0.12). Conclusion DMB prevented the development of aortic stiffening in vivo but had no effect on intrinsic mechanical (wall) stiffness or tail cuff BP. Thus, DMB may prevent age-related increases in aPWV via other in vivo contributing factors, such as endothelial function and vascular tone, autonomic nervous system activity, or central BP. DMB holds promise for attenuating the development of aortic stiffening with age and consequent risk of CV diseases.

Late‐Life Treatment with the Senolytic ABT‐263 Reverses Aortic Stiffening and Improves Endothelial Function with Aging

Advancing age is the primary risk factor for the development of cardiovascular diseases (CVD), driven largely by age-related arterial dysfunction. Two key manifestations of arterial dysfunction with advancing age are aortic stiffening and vascular endothelial dysfunction. Excessive reactive oxygen species (ROS)-induced oxidative stress is a major macro-mechanistic process causing arterial dysfunction during aging; however, the upstream mechanistic event(s) driving oxidative stress are incompletely understood. A rapidly emerging candidate is cellular senescence, a state of irreversible cell-cycle arrest that can be cleared with senolytics. Purpose We tested the hypotheses that late-life treatment with the senolytic ABT-263 (ABT) would: 1) reverse age-related aortic stiffening by reducing aortic intrinsic mechanical wall stiffness (elastic modulus [EM]); and 2) increase endothelial function by increasing nitric oxide (NO) bioavailability and reducing oxidative stress. Methods Old (27 mo) male C57BL6/N mice were treated with vehicle ([V]; 10% EtOH, 30% PEG400 and 60% Phosal 50 PG; n = 7) or ABT (50 mg/kg/day in [V]; n = 6) by oral gavage using a 1 week on – 2 weeks off – 1 week on dosing paradigm. A cohort of young adult mice (6 mo; n = 5) served as a young control (YC) reference group. Aortic pulse wave velocity (PWV), an in vivo measure of aortic stiffness, was measured pre- and post-treatment. Aortic elastic modulus was assessed by performing stress-strain testing in excised aortic rings. Endothelial function was assessed via ex vivo carotid artery endothelial-dependent dilation (EDD) with increasing concentrations of acetylcholine (ACh). NO bioavailability (ACh in the presence of the NO-synthase inhibitor, L-NAME) and the role of excessive ROS in regulating EDD (ACh with the addition of the ROS scavenger, TEMPOL) were assessed as potential mechanisms. Results Aortic stiffness. ABT reversed aortic PWV in old mice (pre: 456 ± 7 vs post: 375 ± 11 cm/sec, P = 0.0003), to levels of YC (348 ± 13 cm/sec; P = 0.14 vs. ABT), whereas no effect was observed in the [V]-treated group. Reduced aortic PWV with ABT was accompanied by lower aortic EM (V: 2738 ± 152 kPa, ABT: 2228 ± 155 kPa, YC: 2120 ± 362 kPa; P = 0.03). Endothelial function. ABT-treated mice had greater peak EDD relative to [V]-treated animals and comparable to YC (ABT: 94 ± 3% vs. V: 78 ± 5%, P = 0.01; YC: 91 ±2). Group differences in peak EDD were abolished in the presence of L-NAME, suggesting that ABT rescued EDD by restoring NO bioavailability. TEMPOL restored peak EDD in [V]-treated old mice to YC levels (92 ±5%, P = 0.003 vs. ACh alone), while having no effect in ABT or YC animals, suggesting that ABT selectively ameliorated the tonic ROS-related suppression of EDD with aging. Conclusion Cellular senescence is mechanistically implicated in age-related arterial dysfunction, and treatment with the senolytic compound ABT-263 may be a therapeutic strategy for improving arterial function, with the potential for reducing CVD risk with aging.

Lifelong SIRT-1 overexpression attenuates large artery stiffening with advancing age.

Advanced age is accompanied by aortic stiffening that is associated with decreased vascular expression of sirtuin-1 (SIRT-1). Interventions that increase SIRT-1 expression also lower age-related aortic stiffness. Therefore, we sought to determine if lifelong SIRT-1 overexpression would attenuate age-related aortic stiffening. Aortic pulse wave velocity (PWV) was assessed from 3-24 months in SIRT-1 transgenic overexpressing (SIRTTG) and wild-type (WT) mice. To determine the role of aortic structural changes on aortic stiffening, histological assessment of aortic wall characteristics was performed. Across the age range (3-24 mo), PWV was 8-17% lower in SIRTTG vs. WT (P<0.05). Moreover, the slope of age-related aortic stiffening was lower in SIRTTG vs. WT (2.1±0.2 vs. 3.8±0.3 cm/sec/mo, respectively). Aortic elastin decreased with advancing age in WT (P<0.05 old vs. young WT), but was maintained in SIRTTG mice (P>0.05). There was an age-related increase in aortic collagen, advanced glycation end products, and calcification in WT (P<0.05 old vs. young WT). However, this did not occur in SIRTTG (P>0.05). These findings indicate that lifelong SIRT-1 overexpression attenuates age-related aortic stiffening. These functional data are complemented by histological assessment, demonstrating that the deleterious changes to the aortic wall that normally occur with advancing age are prevented in SIRTTG mice.

Increased Serum Klotho With Age-Related Aortic Stiffness and Peripheral Vascular Resistance in Young and Middle-Aged Swine.

The anti-aging function of Klotho gene has been implicated in age-related diseases. The physiological importance of Klotho in the progression of arterial stiffness with aging, however, remains unclear. The goal of this study is to determine the correlation of circulating Klotho with early age-related aortic stiffening and peripheral hemodynamics. We measured serum Klotho levels in a group of pigs with age ranges of 1.5–9 years and investigated the relationship between Klotho levels and biomarkers of aortic stiffening with aging, including aortic pulse wave velocity (PWV), augmentation index (AIx), and pulse pressure (PP). The effects of aortic stiffening on peripheral vascular resistance, compliance, and function were also evaluated. We found that increased aortic stiffness occurred at middle age (>5 years old), as evidenced by an increase in PWV and AIx (p < 0.001), but with no changes in blood pressure and PP. With advancing age, increased femoral vascular resistance positively correlated with aortic PWV and AIx (p < 0.01). No significant difference in endothelium function and arterial compliance for femoral and small peripheral arteries was observed between young and middle-aged groups. The serum Klotho levels were lower in young and higher in middle-aged pigs (p < 0.001), and a positive correlation was found between Klotho and aortic PWV, AIx, and femoral vascular resistance (p < 0.01). Our findings suggest that early-aged aortic stiffening has adverse effect on peripheral hemodynamics, independent of blood pressure levels. Elevated Klotho secretion was associated with increased aortic stiffness and peripheral vascular resistance with aging.

Lifelong SIRT‐1 Overexpression Attenuates Aortic Stiffening with Advancing Age

Advanced age is accompanied by aortic stiffening that is associated with decreased vascular expression of the cellular deacetylase, sirtuin‐1 (SIRT‐1). Interventions, such as caloric restriction, that increase SIRT‐1 expression also lower age‐related aortic stiffness. Thus, we sought to determine if lifelong whole body SIRT‐1 overexpression attenuates age‐related aortic stiffening. Aortic stiffness, as determined by aortic pulse wave velocity (PWV), was assessed in SIRT‐1 transgenic overexpressing (SIRTTG) and littermate wild type (WT) control mice at 3‐mo intervals from 3–24 mo of age. To determine the role of aortic structural changes on age‐related aortic stiffening, histological assessment of aortic wall characteristics was performed in young (~5 mo), middle‐age (~12 mo), and old (~24 mo) mice. Aortic SIRT‐1 mRNA gene expression, measured by RT‐PCR, was ~3‐fold higher in young SIRTTG vs. WT mice (P&lt;0.05). Advanced age resulted in a ~6 fold decrease in SIRT‐1 mRNA expression in both old SIRTTG and WT mice (P&lt;0.05), still, SIRT‐1 expression remained &gt;3‐fold higher in old SIRTTG vs. WT mice (P&lt;0.05). Although there was a similar increase in aortic lumen diameter with advancing age in both WT and SIRTTG mice, an age‐related increase in media‐to‐lumen ratio was only present in WT mice (Table 1, P&lt;0.05). Across the age range (3–24 mo), aortic PWV was 8–17% lower in SIRTTG vs. WT mice (P&lt;0.05). Moreover, the slope of age‐related aortic stiffening was 45% lower in SIRTTG vs. WT mice (2.1±0.2 vs. 3.8±0.3 cm/sec/mo, respectively; Figure 1). Aortic elastin content decreased with advancing age in WT mice (Table 1, P&lt;05 old vs. young WT), whereas elastin content was maintained across the lifespan in SIRTTG mice (Table 1, P&gt;0.05). There was an age‐related increase in aortic collagen content, advanced glycation end products (AGEs), and calcification in WT mice (Table 1, P&lt;0.05 old vs. young WT). However, age‐related increases in aortic collagen content, AGEs, or calcification did not occur in SIRTTG mice (Table 1, P&gt;0.05). These findings indicate that lifelong SIRT‐1 overexpression attenuates aortic stiffening with advancing age. These functional data are complemented by histological assessment of aortic wall characteristics, demonstrating that the deleterious changes to the aorta that normally occur with advancing age, such as medial wall hypertrophy, reduced elastin, accumulation of collagen, AGEs, and aortic calcification are all prevented in SIRTTG mice. Thus, the use of SIRT‐1 activators to prevent or reverse the age‐related aortic stiffness may be a viable approach compared to other lifestyle interventions, such as caloric restriction.Support or Funding InformationThis study was funded in part by grants from the National Institutes of Health (R01 AG060395, R01 AG050238, R01 AG048366, K02 AG045339, K99 AT010017) and US Department of Veterans Affairs (I01 BX002151).Scatter plot of aortic stiffening, as determined by pulse wave velocity (PWV), with advancing age in wild type (WT) and sirtuin‐1 transgenic overexpressing (SIRTTG) mice. Separate regression lines are given for WT and SIRTTG mice (dotted lines define 95% confidence intervals).Figure 1 Characteristics of animals used for aortic histology. Table 1 ‐ Animal Characteristics WT SIRTTG Young Middle‐Age Old Young Middle‐Age Old Male:female, n 7:7 7:8 6:4 3:2 7:4 4:6 Age, mo 5.6±0.2 12.2±0.1 † 23.8±0.2 † ‡ 6.0±0.4 12.4±0.0 † 23.9±0.2 † ‡ Body mass, g 26.8±0.9 32.8±1.6 † 30.8±1.5 † ‡ 28.0±1.8 33.4±1.9 † 28.6±0.8 ‡ Lumen Diameter, μm 611±20 634±21 707±31 † ‡ 649±±8 644±18 737±26 † ‡ Medial CSA, mm2 0.81±0.09 0.92±0.08 1.32±0.14 † ‡ 0.90±0.09 0.92±0.12 1.01 ±0.07 * Media‐to‐Lumen Ratio, U 0.27±0.02 0.29±0.03 0.33±0.01 † 0.27±0.03 0.28±0.02 0.24±0.01 * Elastin, AU 1.00±0.06 1.02 ±0.04 0.85±0.05 † ‡ 1.04±0.06 1.06±0.03 1.04±0.04 * Collagen, AU 1.00±0.21 1.60±0.38 2.27±0.50 † 0.78±0.28 1.21±0.35 1.24±0.32 * AGEs, AU 1.00±0.09 1.17±0.16 1.62±0.29 † 1.00±0.21 1.17±0.16 1.21±0.18 Calcified Area, AU 1.00±0.27 1.56±0.15 † 1.47±0.20 † 0.79±0.16 0.47±0.11 * 0.67±0.19 * *P&lt;0.05 vs. WT. †P&lt;0.05 vs. Young. ‡P&lt;0.05 vs. Middle‐Age. Data are mean±SEM. AGEs, advanced glycation endproducts; CSA, cross‐sectional area; SIRTTG, sirtuin‐1 transgenic overexpressing; WT, wild type.

Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening

BackgroundAging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable. ObjectivesThe purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening. MethodsUntrained healthy individuals underwent 6 months of training for the London Marathon. Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological “aortic age” was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D). Data are mean changes (95% confidence intervals [CIs]). ResultsA total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 × 10−3 mm Hg−1, respectively (p < 0.05 for all). Training decreased systolic and diastolic central (aortic) blood pressure by 4 mm Hg (95% CI: 2.8 to 5.5 mm Hg) and 3 mm Hg (95% CI: 1.6 to 3.5 mm Hg). Descending aortic distensibility increased (Ao-P: 9%; p = 0.009; Ao-D: 16%; p = 0.002), while remaining unchanged in the Ao-A. These translated to a reduction in “aortic age” by 3.9 years (95% CI: 1.1 to 7.6 years) and 4.0 years (95% CI: 1.7 to 8.0 years) (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times (p < 0.05 for all). ConclusionsTraining for and completing a marathon even at relatively low exercise intensity reduces central blood pressure and aortic stiffness—equivalent to a ∼4-year reduction in vascular age. Greater rejuvenation was observed in older, slower individuals.

The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

Clinical Implications

HomeHypertensionVol. 71, No. 6Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published9 May 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11323Hypertension. 2018;71:955Biological Sex Modulates Aldosterone Levels (p 1083)Download figureDownload PowerPointSex differences in cardiovascular disease exist, with women being at greater risk than men for some hypertension-related cardiovascular diseases such as increased left ventricular hypertrophy. Salt sensitivity of blood pressure, the change in systolic blood pressure between high- and low-salt diet, is a risk factor for cardiovascular morbidity and mortality. In this study of 1592 normotensive and hypertensive individuals who participated in the Hypertensive Pathotype Consortium, women had increased salt sensitivity of blood pressure and increased blood pressure and aldosterone responses to angiotensin II as compared with men. In an animal model of aldosterone-dependent cardiovascular injury, female compared with male rodents had increased cardiovascular injury with increased aldosterone levels; mineralocorticoid receptor blockade was equally effective in both sexes in preventing the damage. These sex differences likely contribute to the increased salt sensitivity of blood pressure and to increased aldosterone-mediated cardiovascular disease in women compared with men. Thus, as compared with men, women are likely to receive a greater cardiovascular risk reduction from mineralocorticoid receptor blockade.MitoQ Treatment and Vascular Function With Aging (p 1056)Download figureDownload PowerPointAdvancing age is the primary risk factor for cardiovascular disease. The development of vascular dysfunction, including vascular endothelial dysfunction and stiffening of the large elastic arteries (aorta and carotid arteries), is a major mechanism of increased cardiovascular disease risk with aging. Excessive production of reactive oxygen species by mitochondria has emerged as a key driver of vascular dysfunction with aging. Results of preclinical studies from our laboratory demonstrate that 4 weeks of oral supplementation with the mitochondria-targeted antioxidant MitoQ ameliorates age-related endothelial dysfunction and aortic stiffening in mice. In this issue of Hypertension we report the successful translation of these preclinical findings to humans. We show that 6 weeks of supplementation with MitoQ is safe and well tolerated and improves vascular endothelial function in healthy late middle-aged and older adults. We present data from a unique functional bioassay suggesting that the mechanism of action for the improvement in endothelial function with MitoQ supplementation involves a reduction in mitochondrial reactive oxygen species-associated suppression of endothelium-dependent dilation. We also show that MitoQ treatment reduces aortic stiffness in individuals exhibiting age-related aortic stiffening and that MitoQ supplementation decreases plasma concentrations of oxidized low-density lipoprotein, a circulating marker of oxidative stress. Collectively, these findings indicate that mitochondria-targeted therapies such as MitoQ may hold promise for reducing mitochondrial-derived oxidative stress, improving vascular function and decreasing cardiovascular disease risk with aging.Media/Lumen Reference Values in Small Arteries (p 1193)Download figureDownload PowerPointSmall artery remodeling is an early feature of target organ damage in hypertension and retains a negative prognostic value. The gold standard for its assessment, media/lumen ratio (M/L), can be obtained by tissue biopsies. In this article, a cohort of 291 individuals with or without cardiovascular risk factors was pooled from 4 Italian centers to establish age- and sex-specific reference values and to explore M/L relationship with risk factors. M/L reference values obtained in a sufficiently large healthy population are useful in pathophysiological studies to establish the impact of classical and emerging risk factors on the microvasculature as well as the effect of treatment. Indeed, not only blood pressure, but also body mass index, cholesterol, smoking, and blood glucose were associated with increased M/L, highlighting especially the role of metabolic factors in inducing microvascular damage. From a clinical perspective, microvascular alterations are increasingly recognized as crucial mechanisms of cardiovascular and cerebrovascular disease, and they can be reversed by appropriate treatment. A better comprehension of microvascular damage accrual with age and risk factors may thus help identify novel treatment targets. Furthermore, the identification of a different impact of risk factors on M/L in the 2 sexes suggests a possible explanation for the well-known sex differences in the pathophysiology of cardiovascular disease, thus opening a novel pathway to personalized medicine. Previous Back to top Next FiguresReferencesRelatedDetails June 2018Vol 71, Issue 6 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.118.11323 Originally publishedMay 9, 2018 PDF download Advertisement

Greater Progression of Age-Related Aortic Stiffening in Adults with Poor Trunk Flexibility: A 5-Year Longitudinal Study.

Purpose: Having a low level of physical fitness, especially cardiorespiratory fitness, appears to accelerate age-related aortic stiffening. Whereas, some studies have reported that trunk flexibility is a component of physical fitness, it is also negatively associated with arterial stiffening independent of cardiorespiratory fitness in cross-sectional studies. However, no long-term longitudinal study has determined whether poor trunk flexibility accelerates the progression of age-related aortic stiffening. We examined trunk flexibility and aortic stiffness progression in a 5-year longitudinal study.Methods and Results: A total of 305 apparently healthy men and women participated in this study (49.6 ± 9.5 years of age). Trunk flexibility was measured using a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. Analysis of covariance (ANCOVA) was used to assess the association of the annual rate of cfPWV across flexibility levels (low, middle, high). There were no significant differences in baseline cfPWV among the three groups (835 ± 164, 853 ± 140, 855 ± 2.68 cm/s; P = 0.577). Annual ΔcfPWV was significantly higher in the low-flexibility group than in the high-flexibility group (P = 0.009). ANCOVA revealed an inverse relationship between flexibility level and annual ΔcfPWV (14.41 ± 2.73, 9.79 ± 2.59, 2.62 ± 2.68 cm/s/year; P for trend = 0.011). Multiple regression analysis revealed that baseline sit and reach (β = −0.12, −0.70 to −0.01) was independently correlated with ΔcfPWV following adjustment for baseline peak oxygen uptake, age, sex, body fat, heart rate, and cfPWV. The 5-year change in cfPWV was not significantly correlated with 5-year change in sit-and-reach performance (P = 0.859).Conclusion: Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in healthy adults. However, we failed to confirm a significant association between 5-year change in aortic stiffness and 5-year change in trunk flexibility. The association between increased age-related increase in aortic stiffness and deterioration in flexibility due to age may require observation for more than 5 years.

Abstract 13728: Poor Trunk Flexibility is Associated With Greater Progression of Age-related Arterial Stiffening: A 5-year Longitudinal Study

Introduction: Low level of physical fitness, especially cardiorespiratory fitness, appear to accelerate age-related aortic stiffening. Whereas, some studies have reported that flexibility, is one of the components of physical fitness, is also associated with arterial stiffening independent of cardiorespiratory fitness in cross sectional studies. However, no longitudinal study has determined whether poor trunk flexibility might accelerate the progression of age-related aortic stiffening. Hypothesis: Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in apparently healthy adults. Methods: We examined trunk flexibility and aortic stiffness progression in a 5-year follow-up study of 361 healthy men and women aged 27-73 years. Trunk flexibility was measured by a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. To assess the effects of flexibility level on the progression of aortic stiffening, the participants were categorized into tertiles (Low, Middle, High) based on their sit-and-reach test values at baseline. ANCOVA was used to analyze the association of the annual rate of cfPWV (cm/ sec/ year) [annual ΔcfPWV = (follow-up cfPWV- baseline cfPWV) / follow-up years] across flexibility levels. Baseline age, BMI, cfPWV, brachial systolic blood pressure, cardiorespiratory fitness and sex were entered as covariates for adjustment. Results: The annual ΔcfPWV was significantly greater in the low (poor) flexibility group (10.95±2.49 cm/sec/year) than in the high flexibility group (2.19±2.41 cm/sec/year) (P=0.041). An inverse relationship was observed between flexibility level and the annual ΔcfPWV (P for trend = 0.042). The multiple regression analysis revealed that baseline sit and reach (β = -0.125), age (β = 0.197), cfPWV (β = - 0.432), cardiorespiratory fitness (β = -0.144), and sex (β = - 0.174) were independent correlates of ΔcfPWV. These data indicate that flexibility is associated with aortic stiffness, independent of other factors already known to be related to arterial stiffness. Conclusions: Poor flexibility is associated with greater progression of age-related aortic stiffening.

Frequency-modulated atomic force microscopy localises viscoelastic remodelling in the ageing sheep aorta

Age-related aortic stiffening is associated with cardiovascular diseases such as heart failure. The mechanical functions of the main structural components of the aorta, such as collagen and elastin, are determined in part by their organisation at the micrometer length scale. With age and disease both components undergo aberrant remodelling, hence, there is a need for accurate characterisation of the biomechanical properties at this length scale. In this study we used a frequency-modulated atomic force microscopy (FM-AFM) technique on a model of ageing in female sheep aorta (young: ~18 months, old: >8 years) to measure the micromechanical properties of the medial layer of the ascending aorta. The novelty of our FM-AFM method, operated at 30kHz, is that it is non-contact and can be performed on a conventional AFM using the ׳cantilever tune’ mode, with a spatial (areal) resolution of around 1.6μm2. We found significant changes in the elastic and viscoelastic properties within the medial lamellar unit (elastic lamellae and adjacent inter-lamellar space) with age. In particular, there was an increase in elastic modulus (Young; geometric mean (geometric SD)=42.9 (2.26)kPa, Old=113.9 (2.57)kPa, P<0.0001), G′ and G″ (storage and loss modulus respectively) (Young; G′=14.3 (2.26)kPa, Old G′=38.0 (2.57)kPa, P<0.0001; Young; G″=14.5 (2.56)kPa, Old G″=32.8 (2.52)kPa, P<0.0001). The trends observed in the elastic properties with FM-AFM matched those we have previously found using scanning acoustic microscopy (SAM). The utility of the FM-AFM method is that it does not require custom AFM hardware and can be used to simultaneously determine the elastic and viscoelastic behaviour of a biological sample.

Arteriosclerosis

See related article, pp 123–128 Over the last 20 years, aortic stiffness has emerged as an important, independent predictor of cardiovascular outcome. Recent data suggest that it may add to existing risk prediction models and improve patient stratification. However, the precise biological pathways and processes underlying aortic stiffening remain unclear. A better understanding of these is an important prerequisite for the rational design of novel antistiffening drugs, which may prove valuable in reducing cardiovascular risk, particularly in those individuals with stiff arteries. In almost all populations, aortic stiffness is positively correlated with age, and in multiple regression analyses age is invariably the dominant determinant of stiffness.1 Consequently, age-related aortic stiffening (arteriosclerosis) is often considered to be inevitable. The process underlying arteriosclerosis is generally believed to be fatigue fracture of elastic fibers within the arterial wall. As such, age is actually a surrogate for cycle number (ie, number of heart beats), which, together with the level of cyclic stress (pulse pressure), determines the rate of elastic fiber degeneration. To a limited extent, this view has been substantiated by animal studies, and our own recent observations in the Caerphilly Heart Study.2 We found that the heart rate pulse pressure product, integrated over a 20-year follow-up period, was independently correlated with current aortic pulse wave velocity (aPWV). However, this cannot be the whole story, not least because the correlation that we observed was quite modest, and several other lines of evidence strongly suggest that arteriosclerosis is more pathological than …