The role of hyaluronan in endothelial glycocalyx and potential preventative lifestyle strategy with advancing age.

The endothelial glycocalyx (EG) is a gel-like structure that forms a layer in between the surface of the endothelium and lumen. EG was once thought to be merely a structural support for the endothelium. However, in recent years, the importance of EG as a first line of defense and a key regulator to endothelial integrity has been illuminated. With advanced age, EG deterioration becomes more noticeable and at least partially associated with endothelial dysfunction. Hyaluronan (HA), one of the critical components of the EG, has distinct properties and roles to the maintenance of EG and endothelial function. Therefore, given the intimate relationship between the EG and endothelium during the aging process, HA may serve as a promising therapeutic target to prevent endothelial dysfunction.

Impact of blood pressure perturbations on arterial stiffness.

Although the associations between chronic levels of arterial stiffness and blood pressure (BP) have been fairly well studied, it is not clear whether and how much arterial stiffness is influenced by acute perturbations in BP. The primary aim of this study was to determine magnitudes of BP dependence of various measures of arterial stiffness during acute BP perturbation maneuvers. Fifty apparently healthy subjects, including 25 young (20-40 yr) and 25 older adults (60-80 yr), were studied. A variety of BP perturbations, including head-up tilt, head-down tilt, mental stress, isometric handgrip exercise, and cold pressor test, were used to encompass BP changes induced by physical, mental, and/or mechanical stimuli. When each index of arterial stiffness was plotted with mean BP, all arterial stiffness indices, including cardio-ankle vascular index or CAVI (r = 0.50), carotid-femoral pulse wave velocity or cfPWV (r = 0.51), brachial-ankle pulse wave velocity or baPWV (r = 0.61), arterial compliance (r = -0.42), elastic modulus (r = 0.52), arterial distensibility (r = -0.32), ß-stiffness index (r = 0.19), and Young's modulus (r = 0.35) were related to mean BP (all P < 0.01). Changes in CAVI, cfPWV, baPWV, and elastic modulus were significantly associated with changes in mean BP in the pooled conditions, while changes in arterial compliance, arterial distensibility, ß-stiffness index, and Young's modulus were not. In conclusion, this study demonstrated that BP changes in response to various forms of pressor stimuli were associated with the corresponding changes in arterial stiffness indices and that the strengths of associations with BP varied widely depending on what arterial stiffness indices were examined.

Sirt1 overexpression attenuates Western-style diet-induced aortic stiffening in mice.

Increased arterial stiffness is a cardiovascular disease risk factor in the setting of advancing age and Western diet (WD) induced obesity. Increases in large artery stiffness, as measured by pulse wave velocity (PWV), occur within 8 weeks of WD feeding in mice. Sirtuin-1 (Sirt1), a NAD-dependent deacetylase, regulates cellular metabolic activity and activation of this protein has been associated with vasoprotection in aged mice. The aim of the study was to elucidate the effect of global Sirt1 overexpression (Sirttg ) on WD-induced arterial stiffening. Sirt1 overexpression did not influence PWV in normal chow (NC) fed mice. However, PWV was higher in wild-type (WT) mice (p < 0.04), but not in Sirttg mice, after 12 weeks of WD and this effect was independent of changes in blood pressure or the passive pressure diameter relation in the carotid artery. Overexpression of Sirt1 was associated with lower collagen and higher elastin mRNA expression in the aorta of WD fed mice (both p < 0.05). Although MMP2 and MMP3 mRNA were both upregulated in WT mice after WD (both p < 0.05), this effect was reversed in Sirttg mice compared to WT mice fed WD (both p < 0.05). Surprisingly, histologically assessed collagen and elastin quality were unchanged in the aortas of WT or Sirttg mice after WD. However, Sirttg mice were protected from WD-induced glucose intolerance, although there was no difference in insulin tolerance between groups. These findings demonstrate a vasoprotective effect of Sirt1 overexpression that limits the increase in arterial stiffness in response to consumption of a WD.

Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions.

Aging increases the risk of atherosclerotic cardiovascular disease which is associated with arterial senescence; however, the mechanisms responsible for the development of cellular senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) remain elusive. Here, we study the effect of aging on arterial DNA damage and telomere dysfunction. Aging resulted in greater DNA damage in ECs than VSMCs. Further, telomere dysfunction-associated DNA damage foci (TAF: DNA damage signaling at telomeres) were elevated with aging in ECs but not VMSCs. Telomere length was modestly reduced in ECs with aging and not sufficient to induce telomere dysfunction. DNA damage and telomere dysfunction were greatest in atheroprone regions (aortic minor arch) versus non-atheroprone regions (thoracic aorta). Collectively, these data demonstrate that aging results in DNA damage and telomere dysfunction that is greater in ECs than VSMCs and elevated in atheroprone aortic regions.

Converting and Standardizing Various Measures of Arterial Stiffness to Pulse Wave Velocity.

BACKGROUND: A variety of arterial stiffness measures have been used to assess the impacts of disease states and various interventions without clear consensus among them. One of the primary problems faced by investigators conducting systematic reviews and meta-analyses is the lack of standardized methodology with a same unit to evaluate and compare investigations using different arterial stiffness measures. Therefore, the purpose of this study was to derive and summarize standardized equations to convert commonly used image-based measures of arterial stiffness to local pulse wave velocity (PWV). METHODS: We first conducted a literature search to obtain and summarize conversion equations in the published literature such that these equations can be found in one convenient location. Then, we generated regression equations using the data collected in a well-controlled laboratory-based study, in which all measures of arterial stiffness were obtained in 49 apparently healthy participants. RESULTS: All literature-based conversion equations produced similar local PWV values and were moderately and significantly correlated with directly measured carotid-femoral PWV (cfPWV) with a Pearson's r ranging from 0.41 to 0.50. The local PWV using laboratory-based equations were modestly associated with cfPWV (r = 0.39-0.49) with an exception of incremental elastic modulus (r = 0.15, p > 0.05). CONCLUSION: Commonly used measures of ultrasound-based arterial stiffness can be converted to local PWV and compared with a reference standard measure of arterial stiffness.

Effect of all-extremity high-intensity interval training vs. moderate-intensity continuous training on aerobic fitness in middle-aged and older adults with type 2 diabetes: A randomized controlled trial.

Aging and diabetes are associated with decreased aerobic fitness, an independent predictor of mortality. Aerobic exercise is prescribed to improve aerobic fitness; however, middle-aged/older diabetic patients often suffer from mobility limitations which restrict walking. Non-weight-bearing/low-impact exercise is recommended but the optimal exercise prescription is uncertain. The goal of this randomized controlled trial was twofold: 1) to test if high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), implemented on a non-weight-bearing all-extremity ergometer, are feasible, well-tolerated and safe in middle-aged/older adults with type 2 diabetes; and 2) to test whether all-extremity HIIT is more effective in improving aerobic fitness than MICT. A total of 58 sedentary individuals with type 2 diabetes (46 to 78 years; 63 ±â€¯1) were randomized to all-extremity HIIT (n = 23), MICT (n = 19) or non-exercise control (CONT; n = 16). All-extremity HIIT and MICT, performed 4×/week for 8 weeks under supervision, resulted in no adverse events requiring hospitalization or medical treatment. Aerobic fitness (VO2peak) improved by 10% in HIIT and 8% in MICT and maximal exercise tolerance increased by 1.8 and 1.3 min, respectively (P ≤ 0.002 vs. baseline; P ≥ 0.9 for HIIT vs. MICT). In conclusion, all-extremity HIIT and MICT are feasible, well-tolerated and safe and result in similar improvements in aerobic fitness in middle-aged/older individuals with type 2 diabetes. These findings have important implications for exercise prescription for diabetic patients; they indicate that all-extremity exercise is a feasible alternative to weight-bearing exercise and those who are unable or unwilling to engage in HIIT may receive similar benefits from MICT.

Nonfat milk attenuates acute hyperglycemia in individuals with android obesity: A randomized control trial.

BACKGROUND: Elevated android body fat increases the risk of developing cardiometabolic diseases. Postprandial hyperglycemia contributes to the proatherogenic metabolic state evident in android adiposity. Due to the insulinotropic effect of milk-derived proteins, postprandial hyperglycemia has been shown to be reduced with the addition of dairy products. The purpose of this study was to determine whether one serving of nonfat milk added to an oral glucose tolerance test (OGTT) could attenuate postprandial hyperglycemia in individuals with elevated android adiposity and whether these improvements would be associated with metabolic and/or peripheral hemodynamic effects. METHODS: In this placebo-controlled, randomized, crossover experimental study, 29 overweight/obese adults (26 ± 1 year) consumed an OGTT beverage (75 g glucose) combined with either nonfat milk (227 g) or a placebo control (12 g lactose + 8 g protein + 207 g water) that was matched for both carbohydrate and protein quantities. RESULTS: In the whole sample, blood glucose and insulin concentrations increased over time in both trials with no significant differences between trials. Relative increases in peak blood glucose response were significantly related to android body fat (p < 0.05). The subjects in the highest tertiles of android body fat displayed attenuated hyperglycemic responses as well as improvements in flow-mediated dilation (FMD) after milk intake. CONCLUSIONS: A single serving of nonfat milk may attenuate acute hyperglycemia in individuals with elevated android body fat offering a simple and convenient option for managing elevations in blood glucose.

Sex impacts the flow-mediated dilation response to acute aerobic exercise in older adults.

There is growing evidence of sex differences in the chronic effect of aerobic exercise on endothelial function (flow-mediated dilation; FMD) in older adults, but whether there are sex differences also in the acute effect of aerobic exercise on FMD in older adults is unknown. The purpose of this study was to test the hypothesis that sex modulates the FMD response to acute aerobic exercise in older adults. Thirteen older men and fifteen postmenopausal women (67±1 vs. 65±2years, means±SE, P=0.6), non-smokers, free of major clinical disease, participated in this randomized crossover study. Brachial artery FMD was measured: 1) prior to exercise; 2) 20min after a single bout of high-intensity interval training (HIIT; 40min; 4×4 intervals 90% peak heart rate (HRpeak)), moderate-intensity continuous training (MICT; 47min 70% HRpeak) and low-intensity continuous training (LICT; 47min 50% HRpeak) on treadmill; and 3) following 60-min recovery from exercise. In older men, FMD was attenuated by 45% following HIIT (5.95±0.85 vs. 3.27±0.52%, P=0.003) and by 37% following MICT (5.97±0.87 vs. 3.73±0.47%, P=0.03; P=0.9 for FMD response to HIIT vs. MICT) and was normalized following 60-min recovery (P=0.99). In postmenopausal women, FMD did not significantly change in response to HIIT (4.93±0.55 vs. 6.31±0.57%, P=0.14) and MICT (5.32±0.62 vs. 5.60±0.68%, P=0.99). In response to LICT, FMD did not change in postmenopausal women nor older men (5.21±0.64 vs. 6.02±0.73%, P=0.7 and 5.70±0.80 vs. 5.55±0.67%, P=0.99). In conclusion, sex and exercise intensity influence the FMD response to acute aerobic exercise in older adults.

Interrelationships Among Various Measures of Central Artery Stiffness.

BACKGROUND: A number of different techniques and methodologies have been applied to quantify stiffness of arteries. Because measures of arterial stiffness differ in regards to measurement locations as well as properties, it is not clear how well these measures that are supposed to reflect the same arterial wall properties are related. METHODS: Interrelationships between different measures of arterial stiffness were evaluated in 50 apparently healthy subjects varying in age. RESULTS: Significant relations ranging from mild to strong were observed among measures of arterial stiffness while some measures were not significantly associated. Cardio-ankle vascular index (CAVI) was significantly associated with carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV). Ultrasound-derived measures of arterial stiffness (e.g., compliance, distensibility) were weakly or not significantly related to pulse wave velocity (PWV) measures. The limits of agreement between each of arterial stiffness measures based on the Bland-Altman analyses indicate that there were close agreements (CI = 1.12-1.52) between CAVI, cfPWV, and baPWV. However, agreements between PWV measures and ultrasound-derived measures were mild to moderate. ß-stiffness index demonstrated large 95% CIs with other measures. When associations between relative changes in various measures of arterial stiffness in response to isometric handgrip exercise were evaluated, the general trend of associations was similar to the relations observed at rest. ß-stiffness index was not related to most measures of arterial stiffness. CONCLUSION: These results suggest that the techniques used to assess arterial stiffness may not be interchangeable in clinical and research settings and that comparisons of findings obtained with different arterial stiffness measures should be conducted with caution.