Large Elastic Arteries Research Articles

Morphological rationale for surgical treatment of patients with true splenic artery aneurysm

Aim. To study the morphological features of the wall structure of the splenic artery aneurysm in order to identify the safest and most effective method of surgical treatment.Materials and methods. From 2020 to 2023, 43 patients underwent surgery for true splenic artery aneurysm. Interventions involved laparoscopic clipping of aneurysm branches, laparoscopic resection of aneurysm, laparoscopic splenectomy, and resection of giant splenic artery aneurysm. A clinical and morphological study of 16 slides of splenic artery aneurysm was performed. The aneurysm wall and the adjacent wall of the splenic artery without macroscopic signs of lumen dilatation for 1 cm from the aneurysmal dilatation were examined.Results. Microscopic study revealed fragments of loose, edematous wall of large elastic arteries with atherosclerosis, atheromatosis and calcification. Atherosclerotic plaques were observed in the intima; calcium deposits were detected in 81.25% of slides, and defects in elastic fibers – in all slides. The elastic membrane was thinned or had a discontinuous structure. Morphological changes in the wall of the splenic artery persisted up to 1.0 ± 0.2 cm proximal and distal to the aneurysm.Conclusion. Taking into account the revealed features of the morphological structure of the aneurysm, the formation of an end-to-end vascular anastomosis of the splenic artery, clipping or suturing of the aneurysm neck pose a significant risk of aneurysm recurrence. Laparoscopic clipping of splenic artery aneurysm branches at a distance of >1.5 cm from the edges of the aneurysm becomes the operation of choice for patients in this category.

Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclincal models.

With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, the initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature of the aging vasculature is the increase in stiffness of the large elastic arteries. This increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature. Evidence from both humans and rodents supports that increases in large elastic artery stiffness are associated with cerebrovascular impairments. These impacts on cerebrovascular function are wide-ranging and include reductions in global and regional cerebral blood flow, cerebral small vessel disease, endothelial cell dysfunction, and impaired perivascular clearance. Furthermore, recent findings suggest that the relationship between arterial stiffness and cerebrovascular function may be influenced by genetics, specifically APOE and NOTCH genotypes. Given the strength of the evidence that age-related increases in arterial stiffness have deleterious impacts on the brain, interventions that target arterial stiffness are needed. The purpose of this review is to summarize the evidence from human and rodent studies, supporting the role of increased arterial stiffness in age-related cerebrovascular impairments.

Reimagining the Value of Brachial-Ankle Pulse Wave Velocity as a Biomarker of Cardiovascular Disease Risk-A Call to Action on Behalf of VascAgeNet.

This review critiques the literature supporting clinical assessment and management of cardiovascular disease and cardiovascular disease risk stratification with brachial-ankle pulse wave velocity (baPWV). First, we outline what baPWV actually measures-arterial stiffness of both large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb. Second, we argue that baPWV is not a surrogate for carotid-femoral pulse wave velocity. While both measures are dependent on the properties of the aorta, baPWV is also strongly dependent on the muscular arteries of the lower extremities. Increased lower-extremity arterial stiffness amplifies and hastens wave reflections at the level of the aorta, widens pulse pressure, increases afterload, and reduces coronary perfusion. Third, we used an established evaluation framework to identify the value of baPWV as an independent vascular biomarker. There is sufficient evidence to support (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. However, there is limited or no evidence to support (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values. Fourth, we address future research requirements. The majority of the evaluation criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets, whereas the (5) clinical outcomes and (6) cost-effectiveness criteria require prospective investigation. The (8) methodological consensus criteria will require an expert consensus statement. Finally, we finish this review by providing an example of a future clinical practice model.

Correlation Between the Level od Atherosclerosis and Pathological Features of Coronary Artery Disease: A Study of 100 Autopsy Cases

Objective: Atherosclerosis is a generalized, chronic disease of large and medium-sized muscular elastic arteries. Relation between intensity of atherosclerosis and coronary artery disease, and risk factors of atherosclerosis could not been revealed completely by autopsy studies. We aimed to renew this shortage of knowledge with our autopsy study prospectively. 
 Methods: One hundred cases were autopsied within 48 h after death. Atherosclerotic risk factor data were collected including age, gender, height, weight, smoking and any chronic coronary artery disease. Atherosclerosis severity was evaluated macroscopically by examining the inner surfaces of the vascular lumens and revealed with postmortem pathological findings of coronary artery disease.
 Results: The mean age was 42 ± 22 years. Seventy-four percent of cases were male, while 26% were female. Smoking duration ranged from 1 to 50 years with a mean duration of 17 ± 12 years. Existence of atherosclerosis in main vessels were also in correlation with age, duration of smoking and BMI (Body Mass Index) (p

Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.

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<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.

Biological sex influences aortic hemodynamic responses to maximal exercise in healthy older adults

Aging is associated with stiffening of large elastic arteries resulting in early wave reflection, which increases aortic systolic blood pressure (BP) and left ventricular afterload. These age-related alterations predispose older adults to cardiovascular disease (CVD). Exercise is recommended for reducing CVD risk in older adults, but the acute aortic hemodynamic responses to exercise have not been fully described. We have previously shown that exercise intensity influences acute aortic hemodynamic responses to submaximal exercise in older adults, however, the responses to maximal exercise have not been investigated. In young adults, the influence of maximal exercise on aortic wave characteristics is impacted by sex. Therefore, the objective of this study was to investigate the acute effects of maximal exercise on aortic wave characteristics in healthy older adults and to test the hypothesis that the acute aortic hemodynamic responses to maximal exercise will be influenced by sex. Twenty-two older men and postmenopausal women (66.4±1.0 yrs, mean±SE, 11M/11W) completed the study. Research participants were free of major clinical disease, were not using hormone replacement therapy or participating in endurance exercise training. Aortic wave characteristics were assessed using wave separation analysis (SphygmoCor XCEL) before and immediately after maximal exercise, based on a modified Balke treadmill test. We found that wave reflection, assessed as augmentation index (AIx) at heart rate of 75 bpm (AIx@75), was not different between older men and women prior to maximal exercise ( P=0.2). Following maximal exercise, AIx@75 increased in older men (21.1±2.6 vs. 28.2±2.4 %, pre- vs. post-exercise, P=0.02) and women (27.4±3.3 vs. 33.9±3.2 %, P=0.03), but the response was not influenced by sex ( P=0.9 for sex × time interaction). Aortic systolic and diastolic BP (AoSBP and AoDBP) were not different in older men compared with women prior to maximal exercise ( P≥0.4). In response to maximal exercise, AoSBP and AoDBP significantly increased in older men (AoSBP: 113±3 vs. 118±2 mmHg, P=0.01 and AoDBP: 75±2 vs. 80±2 mmHg, P<0.01), but not in women (AoSBP: 113±4 vs. 113±4 mmHg, P=0.9; P=0.04 for sex × time interaction and AoDBP: 73±2 vs. 74±2 mmHg, P=0.054; P=0.02 for sex × time interaction). In conclusion, sex influences the aortic BP response to maximal exercise, but not the wave reflection response in older adults. This finding suggests that left ventricular afterload remains elevated during recovery from maximal exercise in older men which may differentially expose them to a transient risk of experiencing a cardiac complication. This work was supported by National Institute of Aging grant AG063143. 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.

Abstract 13452: Age-Related Increases in Arterial Stiffness is Attenuated With Long-Term Senolytic Therapy in Mice

Introduction: It has been established that with advancing age, large elastic arteries (i.e. aorta) demonstrate increased stiffening resulting in detrimental CV health outcomes. Cellular senescence, the permanent arrest of the cell cycle, within the vasculature is characterized by a population of cells that are profibrotic and proinflammatory. Profibrotic and proinflammatory environments have been shown to directly lead to increased large artery stiffness (LAS) with aging. We tested the hypothesis that treatment with the senolytic cocktail dasatinib and quercetin (D&Q) will attenuate LAS in aging mice. Methods: 21-month-old C57Bl/6 mice were treated with D&Q or vehicle via oral gavage on a bi-monthly basis for three months. LAS was measured pre, mid and post treatment by quantifying the aortic pulse wave velocity (aPWV) using a combined Doppler and EKG recording system. Expression of inflammatory genes was assessed by quantitative polymerase chain reaction. Aortic tissue histology was assessed by standard histological methods. Results: D&Q treatment attenuated the age-associated increase in LAS in mice. In the vehicle group, we observed that aPWV increased steadily with age in the vehicle group at 21, 22.5 and 24 months of age (338.9 ± 10.84 cm/s, 351.6 ± 11.53 cm/s, and 369.5 ± 18.57 cm/s respectively, intragroup p=0.004). However, in the D&Q group, we observed a blunted response with corresponding aPWVs (339.5 ± 12.96 cm/s, 322.9 ± 13.9 cm/s, and 342.1 ± 5.67 cm/s; intragroup p=0.7729). Intergroup analysis confirms a significant difference with a p<0.001. Inflammatory markers (TGF-β and TNF-α) were significantly reduced in the D&Q compared to the vehicle group (p<0.05). Extracellular matrix collagen content was lower in aortic tissue from D&Q treated compared to vehicle mice (p<0.01). Conclusions: Chronic, intermittent administration of D&Q prevented the progression of aortic stiffening with advancing age as measured in a longitudinal preclinical mouse study. Aortic inflammatory markers were reduced in the treatment group and similarly the treatment group had attenuated fibrosis vs. vehicle controls. Overall, senolytic therapy represents a potential therapy for aortic fibrosis and age-related increases in large artery stiffness.

Increases in hydraulic conductance and solute permeability in a mouse model of ascending thoracic aortic aneurysm

Large elastic arteries, such as the aorta, contain concentric layers of elastic laminae composed mainly of the extracellular matrix protein elastin. The structure of the elastic laminae could affect transmural mass transport and contribute to aortic disease progression. We studied the effects of a genetic mutation (LoxM292R/+, referred to as MU) in mice associated with ascending thoracic aortic aneurysm (TAA) on the mass transport and elastic laminae structure. Solute absent fluid flux and hydraulic conductance through the ascending aortic wall were not significantly different between groups, however solute present fluid flux, hydraulic conductance, solute flux, and solute permeability of 4 kDa FITC-dextran were significantly increased in the MU group, indicating that movement of small molecules into the aortic wall is facilitated in MU mice. Quantification from light microscopy images of the ascending aorta showed no significant differences in wall thickness, or inner elastic lamina fenestration size and density, but an increase in the number of elastic laminae breaks in the MU group. Ultrastructural comparisons from transmission electron micrographs suggest less dense and disorganized elastic laminae in MU aorta that may also contribute to the transport differences. Our results provide an initial investigation into the connections between mass transport and elastic laminae structure, specifically in a genetic mouse aneurysm model, which can be further used to understand TAA pathology and develop treatment strategies.

Vascular Aging and Arterial Stiffness.

ResumoO envelhecimento biológico é reflexo da interação entre genética, idade cronológica e fatores externos; é a base para novos conceitos em envelhecimento vascular, cuja progressão é determinada pela diferença entre idade biológica e cronológica. Do ponto de vista estrutural, os efeitos do envelhecimento vascular são mais evidentes na camada média das grandes artérias elásticas e resultam em aumento da rigidez arterial, da dilatação do lúmen e da espessura da parede. Esses efeitos são descritos no continuum de envelhecimento cardiovascular (proposto por Dzau em 2010) em que as etapas progressivas de lesões da microvasculatura de coração, rins e cérebro, têm início a partir do processo de envelhecimento. O aumento da rigidez arterial pode ser verificado de forma não invasiva por vários métodos. Os eventos cardiovasculares têm sido tradicionalmente previstos utilizando escores que combinam fatores de risco convencionais para aterosclerose. No continuum cardiovascular clássico (Dzau, 2006), é desafiador avaliar o peso exato da contribuição de cada fator de risco; entretanto, por refletir o dano precoce e cumulativo desses fatores de riscos cardiovascular, a rigidez arterial reflete o verdadeiro dano à parede arterial. Este artigo fornece uma visão geral dos mecanismos da fisiopatogenia, alterações estruturais das artérias e consequências hemodinâmicas do envelhecimento arterial; métodos não invasivos para a avaliação da rigidez arterial e da medida central da pressão arterial; o continuum de envelhecimento cardiovascular, e aplicação do conceito de rigidez arterial na estratificação de risco cardiovascular.

The effect of aging on carotid artery wall mechanics during maximal resistance exercise.

Age-related stiffening of the large elastic arteries (e.g., common carotid artery [CCA]) may impair wall dynamics (i.e., strain) and amplify transmission of pulsatile blood flow into the brain with large increases in pressure that occur during maximal resistance exercise (RE). The purpose of this study was to compare CCA arterial wall dynamics, central hemodynamics, and cerebral blood velocity responses during maximal RE between young and older adults. Thirty-one young (YA; 26 ± 5 yrs; 23.8 ± 3.3kg/m2) and 25 older adults (OA; 60 ± 6 yrs; 30.0 ± 5.5kg/m2) performed a unilateral maximal isokinetic knee flexion/extension exercise protocol (i.e., maximal RE). All measures were recorded at baseline and during the last 10s of maximal RE. Common carotid artery strain, CCA strain time to peak, and CCA strain rate (i.e., variables of arterial wall dynamics) were analyzed using 2D speckle tracking software from circumferential ultrasound images. Transcranial Doppler was used to measure right middle cerebral artery (MCA) blood velocity. Non-invasive arterial blood pressure measurements were obtained using finger photoplethysmography. Older adults had greater reductions in CCA strain time to peak from baseline to maximal RE (345 ± 39 to 242 ± 52ms) than YA (308 ± 35 to 247 ± 42ms; interaction effect, p < 0.01). MCA velocity was similar between YA and OA during maximal RE (p = 0.48), despite a greater arterial pressor response in OA (p < 0.01). These data suggest cerebral blood velocity responds similarly during maximal RE among OA compared to YA, despite subtle age-related differences in the pressor and extracranial vascular response during maximal RE.

Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults.

BackgroundAging is the primary risk factor for cardiovascular diseases, the leading cause of death worldwide. Age-related increases in systolic blood pressure (SBP) link advancing age to cardiovascular disease risk. A key mechanism mediating the increase in SBP with aging is stiffening of the large elastic arteries, which occurs due to increases in oxidative stress, inflammation, and vascular smooth muscle tone. Nicotinamide adenine dinucleotide (NAD+) is a key molecule in energy metabolism and cellular functioning which declines with advancing age and chronic disease. Dietary supplementation with NAD+ precursors, such as nicotinamide riboside, boosts NAD+ bioavailability and may improve cardiovascular health. Here, we present the protocol for a randomized, controlled trial investigating the efficacy of 3 months of oral supplementation with nicotinamide riboside for decreasing SBP and arterial stiffness in midlife and older adults with initial above-normal (120–159 mmHg) SBP (ClinicalTrials.gov Identifier: NCT03821623). The primary outcome is casual (resting) SBP and secondary outcomes include 24-h SBP and aortic stiffness. Other outcomes include assessment of safety; tolerability; adherence; diastolic BP; systemic NAD+ bioavailability; and circulating biomarkers of oxidative stress, inflammation, and sympathoadrenal activity.MethodsA randomized, double-blind, placebo-controlled, single-site parallel-group design clinical trial will be conducted in 94 (47/group) midlife and older (age ≥ 50 years) adults with initial above-normal SBP. Participants will complete baseline testing and then will be randomized to either nicotinamide riboside (500 mg, 2×/day, NIAGEN®; ChromaDex Inc.) or placebo supplementation. Outcome measures will be assessed again after 3 months of treatment.DiscussionThis study is designed to establish the safety and efficacy of the NAD+ boosting compound, nicotinamide riboside, for reducing casual and 24-h SBP and aortic stiffness in midlife and older adults with above-normal SBP at baseline, a population at increased risk of cardiovascular diseases.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03821623].

Non-Invasive Assessment of Arterial Stiffness: Pulse Wave Velocity, Pulse Wave Analysis and Carotid Cross-Sectional Distensibility: Comparison between Methods.

Background: The stiffening of large elastic arteries is currently estimated in research and clinical practice by propagative and non-propagative models, as well as parameters derived from aortic pulse waveform analysis. Methods: Common carotid compliance and distensibility were measured by simultaneously recording the diameter and pressure changes during the cardiac cycle. The aortic and upper arm arterial distensibility was estimated by measuring carotid–femoral and carotid–radial pulse wave velocity (PWV), respectively. The augmentation index and blood pressure amplification were derived from the analysis of central pulse waveforms, recorded by applanation tonometry directly from the common carotid artery. Results: 75 volunteers were enrolled in this study (50 females, average age 53.5 years). A significant inverse correlation was found between carotid distensibility and carotid–femoral PWV (r = −0.75; p < 0.001), augmentation index (r = −0.63; p < 0.001) and central pulse pressure (r = −0.59; p < 0.001). A strong correlation was found also between the total slope of the diameter/pressure rate carotid curves and aortic distensibility, quantified from the inverse of the square of carotid–femoral PWV (r = 0.67). No correlation was found between carotid distensibility and carotid–radial PWV. Conclusions: This study showed a close correlation between carotid–femoral PWV, evaluating aortic stiffness by using the propagative method, and local carotid cross-sectional distensibility.

Sex Differences in Large Artery Stiffness: Implications for Cerebrovascular Dysfunction and Alzheimer's Disease.

Two in every three Alzheimer’s disease diagnoses are females, calling attention to the need to understand sexual dimorphisms with aging and neurodegenerative disease progression. Dysfunction and damage to the vasculature with aging are strongly linked to Alzheimer’s disease. With aging there is an increase in stiffness of the large elastic arteries, and this stiffening is associated with cerebrovascular dysfunction and cognitive impairment. However, it is unclear how the deleterious effects of arterial stiffness may differ between females and males. While environmental, chromosomal, and sex hormone factors influence aging, there is evidence that the deficiency of estrogen post-menopause in females is a contributor to vascular aging and Alzheimer’s disease progression. The purpose of this mini review is to describe the recent developments in our understanding of sex differences in large artery stiffness, cerebrovascular dysfunction, and cognitive impairment, and their intricate relations. Furthermore, we will focus on the impact of the loss of estrogen post-menopause as a potential driving factor for these outcomes. Overall, a better understanding of how sex differences influence aging physiology is crucial to the prevention and treatment of neurodegenerative diseases.

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness. Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness. MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

Narrative Review of Carotid disease and the kidney.

Patients with chronic kidney disease (CKD) have an increased cardiovascular (CV) risk that is only in part explained by established risk factors. Carotid arteriosclerosis and atherosclerosis are increased in CKD, play a role in the causation of CV disease in these patients and can affect the progression of renal disease. The arterial stiffening process is evident even in CKD patients with a very mild reduction of glomerular filtration rate (GFR) whereas arterial thickening is evident in more advanced stages. Possible mechanisms include functional and structural alterations of the arterial wall. Arterial stiffness can mediate the effect of CKD on target organs (i.e., brain, kidney and heart). In this review we discuss the arterial phenotype of patients with CKD. This is characterized by increased common carotid artery stiffness and outward remodeling (enlargement and thickening of the arterial wall) and a normal/reduced stiffness paired with an inward remodeling (narrowing of the arterial wall) of muscular arteries. We also discuss the consequences of carotid dysfunction, including the involvement of large elastic arteries stiffness on ventricular-vascular coupling, the mechanisms linking carotid stiffening and increased cardio- and cerebrovascular risk in CKD patients, and the therapeutic options to improve carotid function.

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

[Figure: see text].

Passive Heat Therapy Reduces Aortic and Carotid Artery Stiffness and Intima‐Media Thickness in Middle‐Aged and Older Adults

Aging is accompanied by stiffening of the large elastic arteries and adverse arterial remodeling, which increase risk for cardiovascular diseases (CVD). Passive heat therapy—chronic use of hot baths and saunas—is associated with lower CVD risk. However, it is unknown if a heat therapy intervention affects arterial stiffness and structure in middle-aged and older (MA/O) adults without overt clinical disorders. Purpose To determine if passive heat therapy, via hot water immersion, in healthy MA/O adults: 1) reduces arterial stiffness, as measured by carotid-femoral pulse wave velocity (c-f PWV; i.e., aortic stiffness) and common carotid artery (CCA) and superficial femoral artery (SFA) β-stiffness index; and 2) alters arterial structure, as measured by CCA and SFA intima-media thickness (IMT) and vessel diameter. Methods 23 healthy, minimally active MA/O men and postmenopausal women (57-79 years) were randomized to participate in 30, 60-minute sessions (3-4x/week over 8-10 weeks) of either hot water immersion (40.5°C, N=12, 5M/7F, 68±2 years) or thermoneutral water immersion (36°C, “sham”, N=11, 4M/7F, 66±2 years). Ultrasound- and tonometry-based measures of arterial stiffness and structure were measured at baseline and 24-72 hours after the final water immersion session. Data are mean ± SEM; P-values were determined by 2-way mixed-design ANOVA with Tukey's post-hoc tests. Results In the large elastic arteries (i.e., the arteries that stiffen with aging), heat therapy reduced c-f PWV from 8.7±0.6 to 8.0±0.7 m/s (p=0.03) and CCA β-stiffness index from 10.6±1.6 to 7.8±0.8 (p=0.02); however, heat therapy did not change SFA β-stiffness index (15.0±1.6 vs. 14.6±1.6, p=0.99), a more muscular artery. Heat therapy also improved selective measures of arterial structure. In the CCA, heat therapy decreased IMT from 0.70±0.01 to 0.66±0.02 mm (p<0.01) without affecting diameter (7.4±0.2 vs. 7.2±0.2 mm, p=0.90). Conversely, in the SFA, heat therapy did not alter IMT (0.56±0.02 vs. 0.57±0.02 mm, p>0.99), but tended to increase diameter from 7.6±0.2 to 7.9±0.3 mm (p=0.06), which likely occurred due to repeated increases in vascular shear stress to the lower body during hot water immersion sessions. No changes were observed in any outcome in sham subjects (c-f PWV: 8.5±0.5 vs. 8.4±0.4 m/s, p=0.85; CCA β-stiffness index: 10.0±2.2 vs. 9.9±2.6, p=0.96; CCA IMT: 0.70±0.02 vs. 0.70±0.02 mm, p=0.92; SFA β-stiffness index: 15.2±2.1 vs. 16.0±2.9, p=0.93; CCA diameter: 7.5±0.1 vs. 7.4±0.1 mm, p=0.42; SFA IMT: 0.57±0.03 vs. 0.56 ±0.03 mm, p=0.85; SFA diameter: 7.8±0.4 vs. 7.9±0.3 mm, p=0.98). Conclusion Heat therapy subjects demonstrated clinically relevant reductions in aortic and carotid artery stiffness, and in CCA IMT, all of which are independent predictors of future CVD risk. As such, heat therapy may be a promising lifestyle-based intervention for improving arterial health and thereby reducing CVD risk in MA/O adults.

Chronic treatment with dill extract preserves elastic lamellae integrity and induces elastic fibers neosynthesis in the abdominal aorta of adult and aged male and female mice

Elastic fibers are extracellular matrix components made of elastin (90%) and microfibrils (10%). Elastin is synthesized primarily in early life and confers to the large elastic arteries the property of elasticity, allowing storage of energy and stroke volume during the systole, then release of energy and blood volume during the diastole. This phenomenon helps to decrease the load on the heart. With aging, elastin is progressively degraded, leading to arterial stiffening and dysfunction. In a previous study we showed that chronic administration of Dill Extract at 5% or 10% v/v administered in drink water could be considered as an anti-aging product for the cardiovascular system but with different pathways. If 5% and 10% DE treatment increased tropoelastin and LOXL1 expressions in the aorta and induced the neo-synthesis of elastic fibers in the aortic wall of DE-treated aged mice and both had a reversal effect on aged related cardiac hypertrophy, surprisingly, blood pressure was decreased only with 5% DE and has no effect on mechanics properties of ascending aorta contrary to 10% DE. So, we decided to investigate further the effect of 5% DE. In this study, we explored the effects on elastin production (Elisa and histology) and large artery elasticity (pressure arteriography) in aged and adult mice of both genders. In opposite of the previous study, we investigate the effect of DE on the abdominal aorta which has different developmental origins, which could explain the different reaction to DE doses. We showed that chronic treatment with dill extract reduced the age-related cardiac hypertrophy only in male mice and re-induced elastic fibers formation, even in aged animals. Moreover, dill extract-treated mice exhibited increased arterial distensibility, especially in female mice. Our results suggest that dill extract presents an interesting potential for arterial function improvement in an anti-aging perspective, even when treating aged animals.

Physical activity is associated with lower pulsatile stress but not carotid stiffness in children.

The cardiovascular disease (CVD) process may begin early in life when accompanied by atherosclerotic risk factors. CVD risk factors in children are associated with stiffening of the large elastic arteries, a reflection of subclinical atherosclerosis. Physical activity is a preventative lifestyle strategy that may benefit arterial stiffness by attenuating the hemodynamic stress on the artery wall. This study examined the relations between physical activity, carotid pulsatile stress, and carotid stiffness in children. One hundred and forty children (9-11 yrs; 50.0% male, 57.9% African American, 42.10% Caucasian, body mass index (BMI) 20.1±4.7 kg/m2) participated in this study. Physical activity counts were measured using a wrist-worn accelerometer and averaged over 7 days. Carotid artery β-stiffness and pulse pressure (calibrated to brachial mean and diastolic pressure) were assessed as via ultrasound and tonometry, respectively. Pulsatile stress was calculated as the product of carotid pulse pressure and heart rate. Physical activity counts were correlated with pulsatile stress (r= -0.27), and BMI (r= -0.23), but were unrelated to carotid stiffness. In multivariate models, associations between physical activity counts and pulsatile stress remained (B= -1.3 [95%CI, -2.4, -0.2], β= -0.20, p<0.05) after covariate adjustment for age, race, sex, pubertal stage and BMI. Carotid pulsatile stress was related to regional carotid stiffness (r=0.45, p<0.05). These data suggest that higher levels of physical activity at young age are associated with lower hemodynamic stress in the carotid artery. Findings are discussed in the context of an inverse relationship between hemodynamic pulsatile stress and carotid stiffness in children.