Greater Large Artery Stiffness Research Articles

Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank.

Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03-1.76]; P=0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08-1.48]; P=0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00-1.35]; P=0.049). Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

Mechanisms for the Age‐Related Differences in Cerebral Artery Endothelial Function After Exposure to Elevated Pulse Pressure

Greater large artery stiffness is correlated with increased cerebrovascular dysfunction and damage. One possible mechanism for this correlation is increased pulse pressure in cerebral resistance arteries, a result of less dampening of pulse pressure by the large arteries, leading to reduced cerebral artery endothelial function. Old age is associated with increases in large artery stiffness and cerebrovascular impairment; however, the effect of age on the response to elevated pulse pressure in cerebral arteries is unclear. Thus, we hypothesized that cerebral resistance arteries exhibit an age-related decline in endothelial function following exposure to pulsatile pressure. In young (n=41, 5-10 mo.) and old (n=26, 25-30 mo.) male C57BL6 mice, we measured cerebrovascular function by the ex vivo endothelium-dependent dilation (EDD) to acetylcholine (ACh) in isolated posterior cerebral arteries following exposure to static pressure (50 mmHg), low pulse pressure (50-75 mmHg), or high pulse pressure (37.5-87.5 mmHg)(400bpm). We also determined the effects of nitric oxide synthase inhibition (L-NAME) and decomposition of hydrogen peroxide (PEG-catalase) on the response to ACh. We measured endothelium-independent dilation (EID) by the dose response to sodium nitroprusside. We also measured posterior cerebral artery wall thickness in young and old mice using histological analysis. Compared with young mice, cerebral arteries from old mice had a 37.3% lower maximal EDD during exposure to static pressure (p<0.001), but EID did not differ with age (p=0.86). Exposure to low pulse pressure did not affect maximal EDD for either young or old cerebral arteries (p>0.05). In young cerebral arteries, maximal EDD was 43.9% lower after exposure to high pulse pressure compared with static pressure (p<0.005); however, high pulse pressure had no effect on maximal EDD in old cerebral arteries (p=0.39). Addition of L-NAME reduced maximal EDD in both old (p=0.001) and young (p<0.001) cerebral arteries during all pressure conditions, such that maximal EDD was no longer different between groups (p>0.05). In young cerebral arteries, the presence of PEG-catalase led to a lower maximal EDD in the static pressure (p=0.045) and low pulse pressure (p=0.001) conditions and trended towards greater maximal EDD in the high pulse pressure condition (p=0.08). Cerebral arteries from old mice had a 22% greater wall thickness compared with cerebral arteries from young mice (p=0.047). In conclusion, these results suggest high pulse pressure impairs endothelial function in cerebral resistance arteries from young mice, and this impairment results from lowered bioavailability of the products of nitric oxide synthase and reduced contribution by hydrogen peroxide to vasodilation. Contrary to our hypothesis, cerebral arteries from old mice were protected from the deleterious effects of high pulse pressure, perhaps as a result of arterial remodeling in response to chronic exposure to higher pulse pressure in vivo.

Large artery stiffness and brain health: insights from animal models.

There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression to identify novel therapeutic targets. Age-related changes to the vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence, whereas animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini-review is to highlight the recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.

Serum MMP‐3 and its Association with Large Artery Stiffness

Large artery stiffness is an independent predictor of cardiovascular disease (CVD) and all‐cause mortality. Stiffening of the large arteries (e.g., the aorta) is characterized by a marked reduction in the elastin‐collagen ratio in the extracellular matrix (ECM) of the arterial wall, and is largely the result of fatigue and fragmentation of ECM components due to cyclic stress. Matrix metalloproteinases (MMPs), a family of zinc‐dependent endopeptidases, may be important in the progression of arterial stiffness due to their involvement in ECM homeostasis and arterial wall remodeling. MMP‐3 may be of particular importance in arterial wall remodeling due to its ability to degrade numerous constituents of the arterial ECM, such as elastin and collagen. Previous studies have examined the effects of MMP‐3 genotype and expression on arterial wall stiffness in different disease populations; however, none have examined the association between MMP‐3 expression and large artery stiffness in a population of healthy young adults. Thus, the purpose of this study was to examine the association between serum MMP‐3 and carotid‐femoral pulse wave velocity (cfPWV), a non‐invasive measure of large artery stiffness, in a sample of healthy young adults. It is expected that individuals with higher serum MMP‐3 levels will present with larger cfPWVs. 156 participants (n = 68 males) aged 20–25 years were recruited as part of the Niagara Longitudinal Heart Study (NLHS), and all participants were free of any clinically diagnosed CVD. cfPWV (m/s) was determined using applanation tonometry as a non‐invasive surrogate of large artery stiffness. Serum MMP‐3 concentrations (pg/mL) were measured using standard ELISA techniques. Linear regression analyses were used to investigate the cross‐sectional association between serum MMP‐3 and cfPWV. Analyses were adjusted for age, sex, mean arterial pressure (MAP), body mass index (BMI), and smoking status. Data on cfPWV and MMP‐3 were available on 139 participants (n = 63 males), and were subsequently used in analysis. After adjustment for age, sex, MAP, BMI, and smoking status, serum MMP‐3 was significantly and positively associated with cfPWV (p = 0.038). cfPWV was also significantly and positively associated with MAP and smoking status (both p &lt; 0.001), but not age (p = 0.336). The association between cfPWV and both sex and BMI showed a positive trend, but only reached borderline significance (p = 0.059 and p = 0.054, respectively). Together, MAP, smoking status and serum MMP‐3 predicted 22% of the variation in cfPWV (adjusted R2 = 0.220, p &lt; 0.001). These data suggest that greater serum MMP‐3 levels are associated with larger cfPWVs and thus, greater large artery stiffness. Physiologic MMP‐3 levels function to maintain ECM homeostasis; however, greater MMP‐3 levels may exacerbate ECM degradation and contribute to stiffening of the large arteries. Future research should examine the potential functional role of MMP‐3 in CVD progression.Support or Funding InformationThe NLHS is funded by the Canadian Institute of Health Research (CIHR #363774 and #399332). KSD is funded by CIHR Doctoral Research Award—Frederick Banting and Charles Best Canada Graduate scholarship (RFN #167014). ARRM is supported by the Ontario Graduate Scholarship program

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.

Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness.

Increased large artery stiffness is a hallmark of arterial dysfunction with advancing age and is also present in other disease conditions such as diabetes. Increased large artery stiffness is correlated with resistance artery dysfunction in humans. Using a mouse model of altered arterial elastin content, this is the first study to examine the cause-and-effect relationship between large artery stiffness and peripheral resistance artery function. Our results indicate that mice with genetically greater large artery stiffness have impaired cerebral artery endothelial function, but generally preserved skeletal muscle feed artery endothelial function. The mechanisms for impaired cerebral artery endothelial function are reduced nitric oxide bioavailability and increased oxidative stress. These findings suggest that interventions that target large artery stiffness may be important to reduce disease risk associated with cerebral artery dysfunction in conditions such as advancing age. Advancing age as well as diseases such as diabetes are characterized by both increased large artery stiffness and impaired peripheral artery function. It has been hypothesized that greater large artery stiffness causes peripheral artery dysfunction; however, a cause-and-effect relationship has not previously been established. We used elastin heterozygote mice (Eln(+/-) ) as a model of increased large artery stiffness without co-morbidities unrelated to the large artery properties. Aortic stiffness, measured by pulse wave velocity, was ∼35% greater in Eln(+/-) mice than in wild-type (Eln(+/+) ) mice (P=0.04). Endothelium-dependent dilatation (EDD), assessed by the maximal dilatation to acetylcholine, was ∼40% lower in Eln(+/-) than Eln(+/+) mice in the middle cerebral artery (MCA, P<0.001), but was similar between groups in the gastrocnemius feed arteries (GFA, P=0.79). In the MCA, EDD did not differ between groups after incubation with the nitric oxide (NO) synthase inhibitor N(ω) -nitro-l-arginine methyl ester (P>0.05), indicating that lower NO bioavailability contributed to the impaired EDD in Eln(+/-) mice. Superoxide production and content of the oxidative stress marker nitrotyrosine was higher in MCAs from Eln(+/-) compared with Eln(+/+) mice (P<0.05). In the MCA, after incubation with the superoxide scavenger TEMPOL, maximal EDD improved by ∼65% in Eln(+/-) (P=0.002), but was unchanged in Eln(+/+) mice (P=0.17). These results indicate that greater large artery stiffness has a more profound effect on endothelial function in cerebral arteries compared with skeletal muscle feed arteries. Greater large artery stiffness can cause cerebral artery endothelial dysfunction by reducing NO bioavailability and increasing oxidative stress.

Central Pulse Pressure and Its Hemodynamic Determinants in Middle-Aged Adults With Impaired Fasting Glucose and Diabetes

OBJECTIVEPulse pressure (PP), a strong predictor of cardiovascular events in type 2 diabetes, is a composite measure affected by several hemodynamic factors. Little is known about the hemodynamic determinants of central PP in type 2 diabetes or whether abnormalities in central pulsatile hemodynamics are already present in individuals with impaired fasting glucose (IFG). In a population-based study, we aimed to compare central PP and its hemodynamic determinants among adults with normal fasting glucose (n = 1654), IFG (n = 240), and type 2 diabetes (n = 33).RESEARCH DESIGN AND METHODSWe measured carotid pressure, left ventricular outflow, aortic root diameter, carotid artery flow, and distension in order to measure various structural and hemodynamic arterial parameters.RESULTSIFG was associated with a greater mean arterial pressure (MAP) but was not associated with intrinsic aortic stiffening or abnormal aortic pulsatile indices after adjustment for MAP. After adjustment for age, sex, and MAP, type 2 diabetes was associated with a higher aortic root characteristic impedance (Zc), aortic root elastance-thickness product (Eh), and aortic root pulse wave velocity (but not aortic root diameter), a greater carotid-femoral pulse wave velocity, and lower total arterial compliance and wave reflection magnitude. Carotid size, Zc, distensibility, or Eh did not significantly differ between the groups.CONCLUSIONSType 2 diabetes, but not IFG, is associated with greater large artery stiffness, without abnormalities in aortic root diameter or carotid stiffness. Subjects with type 2 diabetes demonstrate a decreased reflection magnitude, which may indicate an increased penetration of pulsatile energy to distal vascular beds.

Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression

Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression. MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all P<0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers. Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.