Acute effects of MitoQ on vascular endothelial function are influenced by cardiorespiratory fitness and baseline FMD in middle-aged and older adults.

A key mechanism promoting vascular endothelial dysfunction is mitochondrial-derived reactive oxygen species (mtROS). Aerobic exercise preserves endothelial function in preclinical models by lowering mtROS. However, the effects of mtROS on endothelial function in exercising and non-exercising adults is limited. In a double-blind, randomized, placebo-controlled crossover study design 23 (10 M/13 F, age 62.1 ± 11.5 years) middle-aged and older (MA/O, ≥45 years) adults were divided into two groups: exercisers (EX, n = 11) and non-exercisers (NEX, n = 12). All participants had endothelial function (brachial artery flow-mediated dilatation, FMDBA) measured before and ∼1 h after mitoquinone mesylate (MitoQ) (single dose, 80 mg) and placebo supplementation. A two-way repeated measures ANOVA was used to determine the effects of MitoQ and placebo on FMDBA. Pearson correlations assessed the association between the change in FMDBA with MitoQ and baseline FMDBA and cardiorespiratory fitness (CRF). Compared with placebo, MitoQ increased FMDBA in NEX by + 2.1% (MitoQ pre: 4.9 ± 0.4 vs. post: 7.0 ± 0.4 %, P = 0.004, interaction) but not in EX (P = 0.695, interaction). MitoQ also increased endothelial function in adults with a FMDBA <6% (P < 0.0001, interaction) but not >6% (P = 0.855, interaction). Baseline FMDBA and CRF were correlated (r = 0.44, P = 0.037), whereas the change in FMDBA with MitoQ was inversely correlated with CRF (r = -0.66, P < 0.001) and baseline FMDBA (r = -0.73, P < 0.0001). The relationship between the change in FMDBA and baseline FMDBA remained correlated after adjusting for CRF (r = -0.55, P = 0.007). These data demonstrate that MitoQ acutely improves FMDBA in NEX and EX adults who have a baseline FMDBA <6%. KEY POINTS: A key age-related change contributing to increased cardiovascular disease (CVD) risk is vascular endothelial dysfunction due to increased mitochondrial-derived reactive oxygen species (mtROS). Aerobic exercise preserves endothelial function via suppression of mtROS in preclinical models but the evidence in humans is limited. In the present study, a single dose of the mitochondria-targeted antioxidant, mitoquinone mesylate (MitoQ), increases endothelial function in non-exercisers with lower cardiorespiratory fitness (CRF) but not in exercisers with higher CRF. The acute effects of MitoQ on endothelial function in middle-aged and older adults (MA/O) are influenced by baseline endothelial function independent of CRF. These data provide initial evidence that the acute MitoQ-enhancing effects on endothelial function in MA/O adults are influenced, in part, via CRF and baseline endothelial function.

Lower estimates of myocardial perfusion are associated with greater aortic perivascular adipose tissue density in humans independent of aortic stiffness.

Aortic perivascular adipose tissue (aPVAT) density is associated with age-related aortic stiffness in humans and therefore, may contribute to cardiovascular dysfunction. A lower subendocardial viability ratio (SEVR), an estimate of myocardial perfusion, indicates greater cardiovascular disease (CVD) risk and is associated with aortic stiffness in clinical populations. However, the influence of aortic stiffness on the relation between aPVAT density and SEVR/cardiovascular (CV) hemodynamics in apparently healthy adults is unknown. We hypothesize that greater aPVAT density will be associated with lower SEVR and higher CV hemodynamics independent of aortic stiffness. Fourteen (6 males/8 females; mean age, 55.4 ± 5.6 yr; body mass index, 25.5 ± 0.6 kg/m2) adults completed resting measures of myocardial perfusion (SEVR), CV hemodynamics (pulse wave analysis), aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)], and a computed tomography scan to acquire aPVAT and visceral adipose tissue (VAT) density. Greater aPVAT density (i.e., higher density) was associated with lower SEVR (r = -0.78, P < 0.001) and a higher systolic pressure time integral (r = 0.49, P = 0.03), forward pulse height (r = 0.49, P = 0.03), reflected pulse height (r = 0.55, P = 0.02), ejection duration (r = 0.56, P = 0.02), and augmentation pressure (r = 0.69, P = 0.003), but not with the diastolic pressure time integral (r = -0.22, P = 0.22). VAT density was not associated with SEVR or any CV hemodynamic endpoints (all, P > 0.05). Furthermore, the relation between aPVAT density and SEVR remained after adjusting for aortic stiffness (r = -0.66, P = 0.01) but not age (r = -0.24, P > 0.05). These data provide initial evidence for aPVAT as a novel yet understudied local fat depot contributing to lower myocardial perfusion in apparently healthy adults with aging.NEW & NOTEWORTHY Aortic perivascular adipose tissue (aPVAT) density is associated with aging and aortic stiffness in humans and, therefore, may contribute to lower myocardial perfusion. We demonstrate that greater aPVAT, but not visceral adipose tissue density is associated with lower myocardial perfusion and augmentation pressure independent of aortic stiffness, but not independent of age. These data provide novel evidence for aPVAT as a potential therapeutic target to improve myocardial perfusion and cardiovascular function in humans with aging.

Cardiorespiratory fitness is associated with estimates of myocardial perfusion: influence of age and sex.

Cardiorespiratory fitness (CRF) and the subendocardial viability ratio (SEVR) decline with age and predict future cardiovascular disease (CVD) events in a sex-dependent manner. However, the relation between CRF and SEVR in apparently healthy males and females across the age span is largely unknown. We hypothesized higher CRF is associated with greater SEVR in older females but not in males. Two-hundred sixty-two (126 M/136 F, age range 20-84 yr) participants underwent measures of CRF (maximal O2 consumption, V̇o2max) and SEVR (pulse wave analysis, PWA). A two-way analysis of variance (ANOVA) was used to examine differences in baseline characteristics between younger (<45 yr) and middle-aged and older (MA/O, ≥45 yr) males and females. Bivariate correlations assessed the relation between CRF, SEVR, and age in males and females. Partial correlations adjusted for CVD risk factors and medications. MA/O females had the lowest CRF and SEVR compared with all other groups (P < 0.05, both). SEVR was negatively correlated with age (r = -0.29) and positively correlated with CRF (r = 0.53) in females (P < 0.05, both) that persisted after controlling for CVD risk factors and medications (P < 0.05, all). SEVR was correlated with CRF in males only after adjusting for CVD risk factors and medications (r = 0.26, P < 0.05). These findings collectively demonstrate higher CRF is associated with greater SEVR in males and females after adjusting for CVD risk factors and medications, therefore highlighting subtle sex-specific nuances that warrant further investigation.NEW & NOTEWORTHY Cardiorespiratory fitness (CRF) and the subendocardial viability ratio (SEVR) are independent predictors of mortality and decline with age. However, the sex-specific relationship between CRF and SEVR with aging in adult males and females is unknown. Our findings demonstrate higher CRF is associated with greater age-related SEVR in males and females, after adjusting for traditional cardiovascular disease (CVD) risk factors and medications. However, subtle sex-related nuances exist in the relationship between SEVR and CRF that require further investigation.

Perivascular adipose tissue-mediated arterial stiffening in aging and disease: An emerging translational therapeutic target?

Cardiovascular diseases (CVD) are the leading cause of mortality in modernized societies. Arterial stiffening with aging and disease is a key pathological event leading to increased CVD morbidity and mortality. Perivascular adipose tissue (PVAT) is a fat depot not widely studied yet has direct and profound effects on arterial stiffening. Identifying PVAT as a novel therapeutic target to lower arterial stiffness and thereby CVD risk has potentially important clinical ramifications. Thus, herein, we will overview the current preclinical evidence and the associated mechanisms for PVAT to promote arterial stiffness with aging and other disease conditions. We will also discuss viable translational lifestyle and pharmacological interventions for altering PVAT function that may de-stiffen arteries. Last, the translational potential for PVAT as a therapeutic target to lower arterial stiffness and CVD risk for clinical populations will be discussed.

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature.

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly twofold increased risk of death compared with those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome data set in the RV of a preclinical model of cardiometabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, n = 5) or Western diet and aortic-banding (WD-AB; n = 4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared with CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using principal component analysis, weighted gene co-expression network analysis, module enrichment analysis, and ingenuity pathway analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardiometabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.

Influence of curcumin on performance and post-exercise recovery.

Intense exercise, especially involving eccentric contractions, causes muscle damage concomitant with increased reactive oxygen species (ROS), which can lead to increased fatigue and decrements in physical performance. Additionally, inflammatory cytokines and advanced glycation end-products (AGEs) are produced as a result of eccentric exercise and may further lead to decreased exercise performance. Nutritional interventions may provide an avenue to respond to and reduce the symptoms associated with muscle damage. Of recent interest, curcumin, the main constituent in the spice turmeric, has been the focus of various studies considering post-exercise recovery. Curcumin has potent anti-oxidant and anti-inflammatory properties and can reduce the accumulation of AGEs. This review considers the current evidence for curcumin to impact muscle recovery following exercise to improve performance and the potential mechanisms of action. To date, clinical studies have considered the potential role of curcumin to reduce muscular damage following treadmill running (downhill and flat), conventional walking/running, cycling (acute and chronic), single-leg jumping (downhill), and eccentric muscular fitness exercises of the upper and lower body (single- and double-leg). Studies have been conducted in sedentary to highly active men and women, both young and old, with supplementation duration lasting from a single, acute dose to daily dosages for three months. Various curcumin-based interventions have improved self-perceived measures of pain and tenderness, reduced evidence of muscle damage, ameliorated inflammatory markers, increased markers of antioxidant capacity, diminished markers of oxidative stress, reduced markers of AGEs, and attenuated loss in mean power of single-leg sprints. However, these findings have not been consistently reported.

Caffeine ingestion alters central hemodynamics following aerobic exercise in middle-aged men.

PURPOSE: To examine the acute influence of caffeine on post-exercise central blood pressures, arterial stiffness, and wave reflection properties. METHODS: In a double-blind randomized placebo-controlled crossover study design, ten middle-aged males (55 ± 5 year) completed two exercise trials after ingestion of caffeine (400 mg) or placebo. Measurements were taken before and 30 min post-ingestion via cuff-based pulse wave analysis (PWA) and carotid-femoral pulse wave velocity (PWV). Participants performed a 40-min cycling bout at 70% HRmax with matched workloads between trials. PWA and PWV were reassessed 30 min post-exercise. RESULTS: Prior to exercise, compared to placebo, caffeine increased brachial systolic blood pressure (bSBP) (+ 12.3 ± 2.4 mmHg; p = 0.004), brachial diastolic blood pressure (bDBP) (+ 7.7 ± 0.9 mmHg; p = 0.011), central systolic blood pressure (cSBP) (+ 11.1 ± 2.1 mmHg; p = 0.005) and central diastolic blood pressure (cDBP) (+ 7.6 ± 1.0 mmHg; p = 0.012). PWV was higher 30 min after pill ingestion (p = 0.021 for time) with a trend for a greater increase in caffeine (p = 0.074 for interaction). bSBP (p = 0.036) and cSBP (p = 0.007) were lower after exercise but remained higher (both p < 0.001) in caffeine compared to placebo. PWV remained higher (p = 0.023) after exercise in caffeine compared to placebo but was not influenced by exercise. At rest, augmentation pressure (AP) and index (AIx) were not influenced by caffeine ingestion. Conversely, AIx was lower (p = 0.009) after exercise in placebo only. CONCLUSION: In healthy and active middle-aged men, pre-exercise caffeine ingestion led to higher central and peripheral systolic blood pressures, PWV and AIx at 30 min post-exercise, indicating an increased left ventricular workload which may have implications for cardiovascular event risk.

Effects of Curcumin and Fenugreek Soluble Fiber on the Physical Working Capacity at the Fatigue Threshold, Peak Oxygen Consumption, and Time to Exhaustion.

Herrick, LP, Goh, J, Menke, W, Campbell, MS, Fleenor, BS, Abel, MG, and Bergstrom, HC. Effects of curcumin and fenugreek soluble fiber on the physical working capacity at the fatigue threshold, peak oxygen consumption, and time to exhaustion. J Strength Cond Res 34(12): 3346-3355, 2020-The purpose of this study was to examine the effects of curcumin in combination with fenugreek soluble fiber (CUR + FEN) or fenugreek soluble fiber alone (FEN) on the neuromuscular fatigue threshold (PWCFT), peak oxygen consumption (V˙o2peak), and time to exhaustion (Tlim) on a graded exercise test (GXT), in untrained subjects. The PWCFT estimates the highest power output that can be maintained without evidence of neuromuscular fatigue. Forty-seven untrained, college-aged subjects were randomly assigned to one of 3 supplementation groups; placebo (PLA, n = 15), CUR + FEN (500 mg·d, n = 18), or FEN (300 mg·d, n = 14). The subjects completed a maximal GXT on a cycle ergometer to determine the PWCFT, V˙o2peak, and Tlim before (PRE) and after (POST) 28 days of daily supplementation. Surface electromyographic signals were recorded from a bipolar electrode arrangement on the vastus lateralis of the right leg during each test. Separate one-way analysis of covariances were used to determine if there were between-group differences for adjusted POST-PWCFT, POST-V˙o2peak, and POST-Tlim values, covaried for the respective PRE-test scores. The adjusted POST-PWCFT for the CUR + FEN group (mean ± SD: 196 ± 58 W) was greater (p = 0.016) than the PLA group (168 ± 49 W) but the FEN group (185 ± 32 W) was not different from the CUR + FEN or PLA groups (p > 0.05). There were no differences for adjusted POST-V˙o2peak (p = 0.612) or POST-Tlim (p = 0.508) among the groups. These findings suggested curcumin combined with fenugreek soluble fiber might delay neuromuscular fatigue.

Curcumin and arterial function in health and disease: impact on oxidative stress and inflammation.

PURPOSE OF REVIEW: The purpose of this review is to provide a concise overview of the polyphenol curcumin for improving arterial health, specifically endothelial function and arterial stiffness, to reduce cardiovascular disease (CVD) risk and to highlight potential mechanisms of action by which curcumin may improve artery function. RECENT FINDINGS: The primary findings of this review support the notion for curcumin to improve arterial health both with aging and obesity. There are few clinical trials on curcumin, and those that currently exist are small in scale but provide evidence for curcumin to improve endothelial function in older adults and reduce arterial stiffness in young, obese men. The antioxidant and anti-inflammatory properties of curcumin appear to be important targets of curcumin that are related to improved arterial health. Mechanistic studies have revealed superoxide dismutase, heme oxygenase-1 and nuclear factor erythroid 2-related factor 2 as emerging targets for the beneficial effects of curcumin on the vasculature. SUMMARY: In summary, the efficacy of curcumin for improving arterial function is promising in the limited number of clinical studies performed to date. Still, much investigation is needed to elucidate the effectiveness of curcumin for improving arterial health to lower CVD risk.

The emerging role of curcumin for improving vascular dysfunction: A review.

Curcumin, when administered in a bioavailable form, has potential to influence vascular health of various populations, leading to decreases in cardiovascular disease risk. Clinical intervention studies with curcumin have demonstrated significant improvements in endothelial function, arterial compliance, arterial stiffness, and other measures of vascular hemodynamics in young, middle-aged, old, post-menopausal, healthy, diabetic, and obese individuals. Mechanistically, curcumin is believed to improve vascular function through its effects on inflammation, oxidative stress, nitric oxide bioavailability, and structural proteins of the artery. Current data give support for curcumin to be administered for improvements in vascular health to individuals that may or may not be at risk for cardiovascular disease. This review briefly summarizes the techniques used for the establishment of vascular health and overviews the literature investigating the role of curcumin in the improvement of vascular health.

Arterial hemodynamics are impaired at rest and following acute exercise in overweight young men.

Higher body mass index (BMI) is associated with greater cardiovascular disease (CVD) risk, in part due to aortic stiffening assessed by carotid-femoral pulse wave velocity (cfPWV). Importantly, greater cardiorespiratory fitness (CRF; VO2peak) decreases CVD risk, and is associated with reductions in aortic stiffness. We tested the hypothesis that young adult overweight (OW, n=17) compared with healthy-weight (HW, n=17) men will have greater resting aortic stiffness, reduced CRF and an impaired post-exercise hemodynamic response. Resting cfPWV was greater in OW versus HW individuals (5.81 ± 0.13 vs 4.81 ± 0.12 m/sec, p<0.05). Relative CRF (VO2peak; mL/kg/min) was lower in OW compared with HW individuals (49.4 ± 1.3 vs 57.6 ± 1.0 mL/kg/min, p<0.05), and was inversely related with cfPWV (p<0.05). However, CRF as absolute VO2peak (L/min) was not different between groups and there was no relation between cfPWV and absolute VO2peak (L/min), indicating reduced relative CRF in OW men is due to greater body mass. Following the maximal treadmill exercise test, cfPWV was greater in OW compared with HW subjects from rest to 60 minutes post-exercise (p<0.05). Compared with HW, OW individuals had higher systolic blood pressure (main effect, p<0.05) and diastolic blood pressure was selectively increased for up to 60 minutes following exercise (p<0.05). Overweight individuals had an attenuated post-exercise decrease in mean arterial pressure (p<0.05). Collectively, these results indicate that young, apparently healthy, OW men have greater resting aortic stiffening and an impaired post-exercise hemodynamic response.

Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice.

We tested the hypothesis that aortic perivascular adipose tissue (PVAT) from young low-density lipoprotein receptor-deficient (LDLr(-/-)) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived IL-6 secretion. Arterial stiffness was assessed by aortic pulse wave velocity and with ex vivo intrinsic mechanical properties testing in young (4-6 mo old) wild-type (WT) and LDLr(-/-) chow-fed mice. Compared with WT mice, LDLr(-/-) mice had increased aortic pulse wave velocity (407 ± 18 vs. 353 ± 13 cm/s) and intrinsic mechanical stiffness (5,308 ± 623 vs. 3,355 ± 330 kPa) that was associated with greater aortic protein expression of collagen type I and advanced glycation end products (all P < 0.05 vs. WT mice). Aortic segments from LDLr(-/-) compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6,092 ± 480 vs. 3,710 ± 316 kPa), and this was reversed in LDLr(-/-) mouse arteries cultured without PVAT (3,473 ± 577 kPa, both P < 0.05). Collagen type I and advanced glycation end products were increased in LDLr(-/-) mouse arteries cultured with PVAT (P < 0.05 vs. WT mouse arteries), which was attenuated when arteries were cultured in the absence of PVAT (P < 0.05). PVAT from LDLr(-/-) mice secreted larger amounts of IL-6 (3.4 ± 0.1 vs. 2.3 ± 0.7 ng/ml, P < 0.05), and IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr(-/-) aortic segments cultured with PVAT (P < 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow-fed LDLr(-/-) mice.

Corrigendum: A natural sustained-intestinal release formulation of red chili pepper extracted capsaicinoids (Capsifen®) safely modulates energy balance and endurance performance: a randomized, double-blind, placebo-controlled study.

[This corrects the article DOI: 10.3389/fnut.2024.1348328.].

A natural sustained-intestinal release formulation of red chili pepper extracted capsaicinoids (Capsifen®) safely modulates energy balance and endurance performance: a randomized, double-blind, placebo-controlled study.

Introduction: Overweight and obesity are major public health concerns, with a sharp increase in prevalence over the last few decades. The primary cause is an imbalance between calorie intake and expenditure due to a rise in calorie-rich processed food and reduced physical activity. Energy balance in humans involves complex processes including thermogenesis, a crucial factor in regulating energy expenditure. Methods: In this randomized, double-blinded, placebo-controlled three-arm three-sequence study, we investigated the efficacy of Capsifen® (CapF), a pungency-masked sustained-intestinal release formulation of red chili extract, on energy expenditure, fat oxidation, and endurance using the Quark C-PET system in healthy overweight participants, with and without exercise. In the study, 105 healthy participants were randomized to receive either placebo, CapF 100 mg/day, or CapF 200 mg/day for 28 days. Results: CapF demonstrated a dose-dependent response to increased energy expenditure and fatty acid oxidation with a concomitant reduction in body weight. Both CapF 100 and CapF 200 also increased the time to exhaustion. Discussion: These results demonstrate the plausible efficacy of CapF in energy expenditure and physical performance in otherwise healthy adults who have a high body mass index. Clinical trial registration: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjQzNTg=&Enc=&userName=CTRI/2018/04/013157 dated 04 October 2018.

Aortic Stiffness Is Associated With Higher Nighttime Ambulatory Blood Pressure in Middle-Aged and Older Adults.

PURPOSE: The objective of this study was to determine the relationship between aortic stiffening and brachial and central ambulatory blood pressure (AMBP) in a nonclinical sample of middle-aged and older adults (MA/O). We hypothesized aortic stiffness would be positively associated with 24-hr, daytime, and nighttime brachial and central AMBP. METHODS: Fifty-one participants aged ≥50 yr (21 males and 30 females, mean age 63.4 ± 9.0 yr) with a body mass index <35 kg/m 2 who also had a resting brachial blood pressure (BP) <160/100 mmHg with or without BP medications were recruited for this cross-sectional analysis. All participants underwent measures of aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and 24-hr AMBP monitoring. Bivariate correlations assessed the relationship between cfPWV, brachial, and central AMBP. Partial correlations were used to independently adjust for traditional cardiovascular disease (CVD) risk factors including age, sex, waist circumference, glucose, and augmentation index normalized to heart rate 75 bpm, a surrogate measure of arterial stiffness, and in a multivariable combined model. RESULTS: Nighttime brachial systolic BP ( r = 0.31) and central systolic BP ( r = 0.30) were correlated with cfPWV in the multivariable combined model ( P ≤ .05). Nighttime brachial pulse pressure and central pulse pressure were correlated with cfPWV after independently adjusting for all CVD risk factors ( P ≤ .05, all) but not when combined in the multivariable model ( P > .05). CONCLUSIONS: Higher nighttime brachial and central AMBP with older age are related, in part, to greater aortic stiffening. Therefore, interventions to lower or prevent aortic stiffening may also lower nighttime BP in MA/O adults to lower CVD risk.

Chronic Use of Antihypertensive Medications and Peak Exercise Blood Pressure in Adult Men and Women from the BALL ST Cohort.

PURPOSE: To determine if individuals chronically (>1 yr) prescribed antihypertensive medications have a normal BP response to peak exercise compared with unmedicated individuals. METHODS: Participants included 2555 adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy cohort who performed a peak treadmill exercise test. Participants were divided into groups by sex and antihypertensive medication status. Individuals prescribed antihypertensive medications for >1 yr were included. Exaggerated and blunted SBP within each group was categorized using the Fitness Registry and the Importance of Exercise: A National Database (FRIEND) and absolute criteria as noted by the American Heart Association. RESULTS: The unmedicated group had a greater prevalence ( P < 0.05) of blunted SBP responses, whereas the medicated group had a higher prevalence ( P < 0.05) of exaggerated SBP responses using both the FRIEND and absolute criteria. Peak SBP was higher ( P < 0.01) in medicated compared with unmedicated participants in the overall cohort when controlling for age and sex, but not after controlling for resting SBP ( P = 0.613), risk factors ( P = 0.104), or cardiorespiratory fitness ( P = 0.191). When men and women were assessed independently, peak SBP remained higher in the medicated women after controlling for age and resting SBP ( P = 0.039), but not for men ( P = 0.311). Individuals on beta-blockers had a higher peak SBP even after controlling for age, sex, risk factors, and cardiorespiratory fitness ( P = 0.022). CONCLUSIONS: Individuals on antihypertensive medications have a higher peak SBP response to exercise. Given the prognostic value of exaggerated peak SBP, control of exercise BP should be considered in routine BP assessment and in the treatment of hypertension.

Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth-restricted fetal sheep.

BACKGROUND: Fetal intrauterine growth restriction (IUGR) results in increased placental resistance to blood flow, fetal hypertension, and increased pulsatility stresses shown to lead to vascular remodeling. We tested our hypothesis that IUGR causes decreased compliance in the carotid and umbilical arteries due to altered extracellular matrix (ECM) composition and structure. METHODS: A sheep model of placental insufficiency-induced IUGR (PI-IUGR) was created by exposure of the pregnant ewe to elevated ambient temperatures. Umbilical and carotid arteries from near-term fetuses were tested with pressure-diameter measurements to compare passive compliance in control and PI-IUGR tissues. ECM composition was measured via biochemical assay, and the organization was determined by using histology and second-harmonic generation imaging. RESULTS: We found that PI-IUGR increased arterial stiffness with increased collagen engagement, or transition stretch. PI-IUGR carotid arteries exhibited increased collagen and elastin quantity, and PI-IUGR umbilical arteries exhibited increased sulfated glycosaminoglycans. Histomorphology showed altered collagen-to-elastin ratios with altered cellular proliferation. Increased stiffness indicates altered collagen-to-elastin ratios with less elastin contribution leading to increased collagen engagement. CONCLUSION: Because vessel stiffness is a significant predictor in the development of hypertension, disrupted ECM deposition in IUGR provides a potential link between IUGR and adult hypertension.

Nutraceuticals in the Prevention and Therapeutic Treatment of Cardiovascular and Cerebrovascular Disease.

PURPOSE: This review overviews and highlights arterial stiffening as a key physiological process and target for the prevention and/or lowering of cardio- and cerebrovascular disease (collectively CVD) risk. METHODS: We identified nutraceutical approaches from randomized controlled trials and discussed the associated mechanisms by which these compounds lower age-related arterial stiffness. Age-related CVD are the leading cause of mortality in modernized societies. Arterial dysfunction, specifically stiffening of the large elastic arteries during midlife, is a key physiological process resulting in increased CVD risk. Current pharmaceutical approaches for lowering age-related arterial stiffness have limited efficacy, thus highlighting the need to identify novel approaches for lowering arterial stiffness and thereby CVD risk. Lifestyle interventions are a historical first-line approach to prevent and/or lower the adverse arterial stiffening effects observed with aging. Nutraceutical interventions, defined as a food or part of a food providing health benefits, are a nonpharmacological, novel lifestyle approach to lower age-associated arterial stiffness. Therefore, identifying nutraceutical approaches to lower CVD risk is clinically significant. SUMMARY: This review provides a basic, yet essential, understanding for emerging nutraceutical strategies for the prevention and therapeutic treatment of CVD.

Mitochondrial-targeted antioxidant ingestion acutely blunts VO2max in physically inactive females.

PURPOSE: To determine the acute effects of a mitochondrial targeting antioxidant (MitoQ) on the metabolic response during exercise. METHODS: Nine (n = 9) physically inactive females (age 47 ± 22 years) performed two trials (Placebo and MitoQ) in a double-blind randomized cross-over design. In both trials, participants performed an exercise protocol consisting of 3-min stages at submaximal workloads followed by a ramp protocol to volitional exhaustion. Participants received either Placebo or MitoQ (80 mg) 1 h prior to exercise. Indirect calorimetry and cardiovascular measurements were collected throughout the duration of the exercise bout. RESULTS: Submaximal metabolic and cardiovascular variables were not different between trials (p > 0.05). VO2max was higher (p = 0.03) during Placebo (23.5 ± 5.7 mL kg min-1 ) compared to MitoQ (21.0 ± 6.6 mL kg min-1 ). Maximal ventilation was also higher (p = 0.02) in Placebo (82.4 ± 17.7 L/min) compared to MitoQ (75.0 ± 16.8 L/min). Maximal cardiovascular variables and blood lactate were not different between trials (p > 0.05). CONCLUSION: An acute dose of MitoQ blunted VO2max , which was primarily mediated by impairment of ventilatory function. These data suggest that the acute accumulation of exercise-induced mitochondrial reactive oxygen species (mtROS) are necessary for maximal aerobic capacity. Further research is warranted on mtROS-antioxidant cell signaling cascades, and how they relate to mitochondrial function during exercise.

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.