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[Figure: see text].

Background High-resistance inspiratory muscle strength training (IMST) is a novel, time-efficient physical training modality. Methods and Results We performed a double-blind, randomized, sham-controlled trial to investigate whether 6 weeks of IMST (30 breaths/day, 6 days/week) improves blood pressure, endothelial function, and arterial stiffness in midlife/older adults (aged 50-79 years) with systolic blood pressure ≥120 mm Hg, while also investigating potential mechanisms and long-lasting effects. Thirty-six participants completed high-resistance IMST (75% maximal inspiratory pressure, n=18) or low-resistance sham training (15% maximal inspiratory pressure, n=18). IMST was safe, well tolerated, and had excellent adherence (≈95% of training sessions completed). Casual systolic blood pressure decreased from 135±2 mm Hg to 126±3 mm Hg ( P <0.01) with IMST, which was ≈75% sustained 6 weeks after IMST ( P <0.01), whereas IMST modestly decreased casual diastolic blood pressure (79±2 mm Hg to 77±2 mm Hg, P =0.03); blood pressure was unaffected by sham training (all P >0.05). Twenty-four hour systolic blood pressure was lower after IMST versus sham training ( P =0.01). Brachial artery flow-mediated dilation improved ≈45% with IMST ( P <0.01) but was unchanged with sham training ( P =0.73). Human umbilical vein endothelial cells cultured with subject serum sampled after versus before IMST exhibited increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity ( P <0.05). IMST decreased C-reactive protein ( P =0.05) and altered select circulating metabolites (targeted plasma metabolomics) associated with cardiovascular function. Neither IMST nor sham training influenced arterial stiffness ( P >0.05). Conclusions High-resistance IMST is a safe, highly adherable lifestyle intervention for improving blood pressure and endothelial function in midlife/older adults with above-normal initial systolic blood pressure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03266510.

Increased aortic stiffness may contribute to kidney damage by transferring excessive flow pulsatility to susceptible renal microvasculature, leading to constriction or vessel loss. We previously demonstrated that 5 weeks of dietary sodium restriction (DSR) reduces large-elastic artery stiffness as well as blood pressure in healthy middle-aged/older adults with moderately elevated systolic blood pressure (SBP) who are free from chronic kidney disease (CKD). We hypothesized that DSR in this cohort would also reduce urinary concentrations of renal tubular injury biomarkers, which predict incident CKD in the general population. We performed a post hoc analysis using stored 24 hours urine samples collected in 13 participants as part of a randomized, double-blind, crossover clinical trial of DSR (low sodium (LS) target: 50 mmol/day; normal sodium (NS) target: 150 mmol/day). Participants were 61±2 (mean±SEM) years (8 M/5 F) with a baseline blood pressure of 139±2/82±2 mm Hg and an estimated glomerular filtration rate of 79±3 mL/min/1.73 m 2 Twenty-four hour urinary sodium excretion was reduced from 149±7 to 66±8 mmol/day during week 5. Despite having preserved kidney function, participants had a 31% reduction in urinary neutrophil gelatinase-associated lipocalin concentrations with just 5 weeks of DSR (LS: 2.8±0.6 vs NS: 4.2±0.8 ng/mL, p<0.05). Results were similar when normalized to urinary creatinine (urinary creatinine did not change between conditions). Concentrations of another kidney tubular injury biomarker, kidney injury molecule-1, were below the detectable limit in all but one sample. In conclusion, DSR reduces an established clinical biomarker of kidney tubular damage in adults with moderately elevated SBP who are free from prevalent kidney disease., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Impaired endothelial function is thought to contribute to the increased cardiovascular risk associated with above-normal blood pressure (BP). However, the association between endothelial function and BP classified by 2017 American College of Cardiology/American Heart Association guidelines is unknown. Our objective was to determine if endothelial function decreases in midlife/older adults across the 2017 American College of Cardiology/American Heart Association guidelines BP classifications and identify associated mechanisms of action. Methods and Results A retrospective analysis of endothelial function (brachial artery flow-mediated dilation) from 988 midlife/older adults (aged 50+ years) stratified by BP status (normal BP; elevated BP; stage 1 hypertension; stage 2 hypertension) was performed. Endothelium-independent dilation (sublingual nitroglycerin), reactive oxygen species-mediated suppression of endothelial function (∆brachial artery flow-mediated dilation with vitamin C infusion), and endothelial cell and plasma markers of oxidative stress and inflammation were assessed in subgroups. Compared with normal BP (n=411), brachial artery flow-mediated dilation was 12% ( P =0.04), 15% ( P <0.01) and 20% ( P <0.01) lower with elevated BP (n=173), stage 1 hypertension (n=248) and stage 2 hypertension (n=156), respectively, whereas endothelium-independent dilation did not differ ( P =0.14). Vitamin C infusion increased brachial artery flow-mediated dilation in those with above-normal BP ( P ≤0.02) but not normal BP ( P =0.11). Endothelial cell p47 phox ( P <0.01), a marker of superoxide/reactive oxygen species-generating nicotinamide adenine dinucleotide phosphate oxidase, and circulating interleukin-6 concentrations ( P =0.01) were higher in individuals with above-normal BP. Conclusions Vascular endothelial function is progressively impaired with increasing BP in otherwise healthy adults classified by 2017 American College of Cardiology/American Heart Association guidelines. Impaired endothelial function with above-normal BP is mediated by excessive reactive oxygen species signaling associated with increased endothelial expression of nicotinamide adenine dinucleotide phosphate oxidase and circulating interleukin-6.

Cardiovascular diseases (CVD) remain the leading cause of death in developed societies, and "midlife" (50-64 yr) and older (65+) men and women bear the great majority of the burden of CVD. Much of the increased risk of CVD in this population is attributable to CV dysfunction, including adverse changes in the structure and function of the heart, increased systolic blood pressure, and arterial dysfunction. The latter is characterized by increased arterial stiffness and vascular endothelial dysfunction. Conventional aerobic exercise training, as generally recommended in public health guidelines, is an effective strategy to preserve or improve CV function with aging. However, <40% of midlife and older adults meet aerobic exercise guidelines, due in part to time availability-related barriers. As such, there is a need to develop evidence-based time-efficient exercise interventions that promote adherence and optimize CV function in these groups. Two promising interventions that may meet these criteria are interval training and inspiratory muscle strength training (IMST). Limited research suggests these modes of training may improve CV function with time commitments of ≤60 min/wk. This review will summarize the current evidence for interval training and IMST to improve CV function in midlife/older adults and identify key research gaps and future directions.

Nicotinamide adenine dinucleotide (NAD + ) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD + precursors to augment NAD + bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD + precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD + metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.

Background and Objectives: Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous α1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading., Design, Setting, Participants, & Measurements: The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60 ± 2 years) with moderately elevated systolic BP (139 ± 2/83 ± 2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77 ± 9 mmol/d) and 5 weeks of a normal-sodium (144 ± 7 mmol/d) diet., Results: Urinary marinobufagenin excretion (weekly measurements; 25.4 ± 1.8 versus 30.7 ± 2.1 pmol/kg per day), systolic BP (127 ± 3 versus 138 ± 5 mmHg), and aortic pulse-wave velocity (700 ± 40 versus 843 ± 36 cm/s) were lower during the low- versus normal-sodium condition (all P<0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P<0.001) and sodium excretion (slope=0.46, P<0.001). These associations persisted during the normal- but not the low-sodium condition (both P<0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006)., Conclusions: These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets.

Background: Age and increasing systolic blood pressure (BP) are associated with vascular endothelial dysfunction, but the factors involved are incompletely understood. We tested the hypothesis that vascular endothelial function is related to dietary sodium intake among middle-aged and older adults (MA and O) with elevated systolic BP., Methods: Data were analyzed on 25 otherwise healthy adults aged 48-73 years with high normal systolic BP or stage I systolic hypertension (130-159 mmHg). Self-reported sodium intake was <100 mmol/d in 12 (7 M) subjects (low sodium, 73+/-6 mmol/d) and between 100 and 200 mmol/d in 13 (9 M) subjects (normal sodium, 144+/-6 mmol/d)., Results: Groups did not differ in other dietary factors, age, body weight and composition, BP, metabolic risk factors, physical activity and maximal aerobic capacity. Plasma concentrations of norepinephrine, endothelin-1, oxidized low-density lipoproteins (LDL), antioxidant status and inflammatory markers did not differ between groups. Brachial artery flow-mediated dilation (FMD) was 42% (mm Delta) to 52% (% Delta) higher in the low versus normal sodium group (p < 0.05). In all subjects, brachial artery FMD was inversely related to dietary sodium intake (FMD mm Delta r =-0.40, p < 0.05; %Delta r =-0.53, p < 0.01). Brachial artery FMD was not related to any other variable. In contrast, endothelium-independent dilation did not differ between groups (p >or= 0.24) and was not related to sodium intake in the overall group (p >or= 0.29)., Conclusions: Low sodium intake is associated with enhanced brachial artery FMD in MA and O with elevated systolic BP. These results suggest that dietary sodium restriction may be an effective intervention for improving vascular endothelial function in this high-risk group.

Background: Short-term and tonic regulation of arterial blood pressure (BP) differ in premenopausal women and men of similar age. The autonomic nervous system (ANS) plays a critical role in BP regulation., Methods and Results: To test the hypothesis that women have lower tonic ANS support of BP (reduction in intra-arterial BP during acute ganglionic blockade [GB] with intravenous trimethaphan) and less effective baroreflex buffering (BRB) of BP (potentiation of the systolic BP [SBP] response to bolus phenylephrine during versus before GB) than men, 51 healthy adults, 22 premenopausal women (aged 28+/-1 years, mean+/-SE) and 29 men (aged 27+/-1 years), were studied. Women had lower baseline SBP and plasma catecholamine concentrations than men (P<0.05). Tonic ANS support of BP was approximately 50% to 65% lower in the women (P<0.001). The reductions in BP during GB were related to baseline plasma catecholamine concentrations (r=-0.31 to -0.41, P<0.05). Acute BRB of BP was 47% smaller in the women (3.3+/-0.5 versus 6.3+/-0.9, P=0.006) and was related to the SBP responses to phenylephrine before GB (R2=0.71, P<0.0001). Systemic alpha1-adrenergic vascular responsiveness (SBP response to bolus phenylephrine during GB) was not different (women 21.5+/-2 mm Hg versus men 18.6+/-2 mm Hg, P=0.3)., Conclusions: Premenopausal women have lower tonic sympathoadrenal activity-related ANS support of BP and less effective BRB of BP than men of similar age. The lower tonic ANS support of BP could contribute to the lower chronic BP levels of premenopausal women, whereas attenuated BRB of BP may help explain less effective BP regulation in women in response to vasoactive drugs and acute stress.

We determined the temporal effects of dietary sodium restriction on large elastic artery compliance and systolic blood pressure (SBP) in 12 untreated, older (64+/-2 years) men and women (6 each) with stage 1 systolic hypertension. After baseline measurements subjects were assigned to 4 weeks of low or normal sodium intake (randomized, crossover design). Urinary sodium excretion was reduced by 60% by the end of week 1 of sodium restriction (54+/-11 mmol/d, P<0.01) versus baseline (135+/-14). Compared with baseline (0.11+/-0.01 mm/mm Hg), carotid artery compliance was increased by 27% (to 0.14+/-0.02, P<0.05) at the end of week 1 of sodium restriction, attaining peak levels by week 2 (+46%, to 0.16+/-0.02, P<0.01). Similarly, supine resting brachial artery SBP was reduced by >5 mm Hg by week 1 of sodium restriction, attaining peak reductions by week 2 (-12 mm Hg, P<0.01 versus baseline). The 24-hour ambulatory SBP was approximately 3 mm Hg lower at week 1 of sodium restriction and approximately 6 mm Hg lower by week 2 (P<0.01 versus baseline). The reductions in resting SBP from baseline to week 2 of sodium restriction were strongly related to the corresponding increases in carotid compliance (r=0.80, P<0.01). Urinary sodium excretion, carotid artery compliance, and SBP were not different during normal sodium intake versus baseline. Other subject characteristics were not different across conditions. Sodium restriction rapidly improves large elastic artery compliance in older adults with stage 1 systolic hypertension. These improvements in central arterial compliance appear to be a key mechanism in the rapid normalization of SBP by sodium restriction in these patients.

Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 +/- 1 yr, mean +/- SE) and older (O; 63 +/- 2 yr, mean +/- SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 +/- 0.1 vs. 2.1 +/- 0.1 mm(2)/mmHg x 10(-1), P < 0.01) and central (carotid) BP (systolic: 116 +/- 5 vs. 101 +/- 3 mmHg, P < 0.05, and pulse pressure: 43 +/- 4 vs. 36 +/- 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 +/- 7.8 vs. -20.0 +/- 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 +/- 88 vs. 640 +/- 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 +/- 5 vs. O: 61 +/- 7 micromol/l, P = 0.23), increased (P < 0.001) to supraphysiological levels during infusion (Y: 1240 +/- 57 and O: 1,056 +/- 83 micromol/l), and were slightly elevated (P < 0.001 vs. baseline) with supplementation (Y: 96 +/- 5 micromol/l vs. O: 85 +/- 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1). mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2). affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.

Baroreflex buffering plays an important role in arterial blood pressure control. Previous reports suggest that baroreflex sensitivity may be altered in endurance exercise-trained compared with untrained subjects. It is unknown, however, if in vivo baroreflex buffering is altered in the endurance exercise-trained state in humans. Baroreflex buffering was determined in 36 healthy normotensive men (18 endurance exercise-trained, 41+/-5 [SEM] years; 18 untrained, 41+/-4 years) by measuring the potentiation of the systolic blood pressure responses to a phenylephrine bolus and to incremental phenylephrine infusion during compared with before ganglionic blockade with trimethaphan. The exercise-trained men had a lower resting heart rate and higher maximal oxygen consumption and heart rate variability than the sedentary control subjects (all P=0.01). Mean levels and variability of blood pressure, cardiovagal baroreflex sensitivity (change in heart rate/change in systolic blood pressure), and basal muscle sympathetic nerve activity were not different in the two groups. The systolic blood pressure responses to phenylephrine were not different in the endurance-trained and untrained men before or during ganglionic blockade (P>0.6). Measures of baroreflex buffering with the use of a phenylephrine bolus (3.9+/-0.8 versus 4.0+/-0.7, trained versus untrained, P=0.85) and incremental infusion (2.8+/-0.4 versus 2.5+/-0.6, P=0.67) were similar in the two groups. Baroreflex buffering does not differ in endurance exercise-trained compared with untrained healthy men. These results support the concept that habitual vigorous endurance exercise does not modulate in vivo baroreflex buffering in healthy humans.

We determined if the tonic autonomic nervous system (ANS) contribution to arterial blood pressure (BP) maintenance in humans is related to habitual endurance exercise status. Twenty-three healthy young (age 18-31 years) males, 11 endurance exercise-trained and 12 untrained, were studied. Maximal oxygen consumption was higher (P < 0.001) and resting heart rate and body fatness were lower (P < 0.05) in the exercise-trained men. Plasma noradrenaline concentrations and BP decreased from baseline levels in response to ganglionic blockade (intravenous trimethaphan) in both groups (all P < 0.001). The absolute (Delta mmHg: systolic = -35 +/- 2 vs. -32 +/- 4; diastolic = -13 +/- 2 vs. -10 +/- 2; mean = -21 +/- 2 vs. -17 +/- 3) and relative (Delta%: systolic = -35 +/- 2 vs. -31 +/- 3; diastolic = -26 +/- 3 vs. -20 +/- 3; mean = -31 +/- 2 vs. -26 +/- 3) decreases in BP were not significantly different between the endurance-trained and untrained men. There were no significant group differences in the heart rate, stroke volume, cardiac output or systemic vascular resistance (conductance) responses to trimethaphan. Systemic vascular alpha-adrenergic sensitivity (slope of the increase in mean BP with incremental phenylephrine infusion during ganglionic blockade) also did not differ in the two groups (endurance-trained: 3.2 +/- 0.5; untrained: 3.2 +/- 0.7 mmHg (ng phenylephrine)(-1) (ml plasma)(-1)). In the pooled sample, the decrease in mean BP during trimethaphan was related to baseline and changes in plasma noradrenaline concentrations (r = 0.58-0.65, P < 0.001) and alpha-adrenergic sensitivity (r = 0.49, P < 0.02). Our results suggest that the endurance exercise-trained state is not obviously associated with altered ANS support of BP in healthy young men. Basal sympathetic nervous system (SNS) activity and alpha-adrenergic vascular sensitivity are significant physiological correlates of ANS support of BP in this population.

Above-normal blood pressure (BP) is a primary risk factor for cardiovascular diseases. In a retrospective analysis of five pilot trials, we assessed the BP-lowering effects of high-resistance inspiratory muscle strength training (IMST) in adults aged 18–82 years and the impact of IMST on maximal inspiratory pressure (PIMAX), a gauge of inspiratory muscle strength and independent disease risk factor. Participants were randomized to high-resistance IMST (75% PIMAX) or low-resistance sham (15% PIMAX) training (30 breaths/day, 5–7 days/wk, 6 wk). IMST (n = 67) reduced systolic BP (SBP) by 9 ± 6 mmHg (P < 0.01) and diastolic BP (DBP) by 4 ± 4 mmHg (P < 0.01). IMST-related reductions in SBP and DBP emerged by week 2 of training (−4 ± 8 mmHg and −3 ± 6 mmHg; P ≤ 0.01, respectively) and continued across the 6-wk intervention. SBP and DBP were unchanged with sham training (n = 61, all P > 0.05). Select subject characteristics slightly modified the impact of IMST on BP. Greater reductions in SBP were associated with older age (β = −0.07 ± 0.03; P = 0.04) and greater reductions in DBP associated with medication-naïve BP (β = −3 ± 1; P = 0.02) and higher initial DBP (β = −0.12 ± 0.05; P = 0.04). PIMAX increased with high-resistance IMST and low-resistance sham training, with a greater increase from high-resistance IMST (+20 ± 17 vs. +6 ± 14 cmH2O; P < 0.01). Gains in PIMAX had a modest inverse relation with age (β = −0.20 ± 0.09; P = 0.03) and baseline PIMAX (β = −0.15 ± 0.07; P = 0.04) but not to reductions in SBP or DBP. These compiled findings from multiple independent trials provide the strongest evidence to date that high-resistance IMST evokes clinically significant reductions in SBP and DBP, and increases in PIMAX, in adult men and women. NEW & NOTEWORTHY In young-to-older adult men and women, 6 wk of high-resistance inspiratory muscle strength training lowers casual systolic and diastolic blood pressure by 9 mmHg and 4 mmHg, respectively, with initial reductions observed by week 2 of training. Given blood pressure outcomes with the intervention were only slightly altered by subject baseline characteristics (i.e., age, blood pressure medication, and health status), inspiratory muscle strength training is effective in lowering blood pressure in a broad range of adults. [ABSTRACT FROM AUTHOR]

Background: High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such that the prevalence of above-normal SBP (i.e., =120 mmHg) in postmenopausal women exceeds rates in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by excessive reactive oxygen speciesinduced oxidative stress and consequent reductions in nitric oxide bioavailability. Moderate-intensity aerobic exercise is a recommended lifestyle strategy for reducing SBP. However, adherence to aerobic exercise guidelines among postmenopausal women is low (<30%) and aerobic exercise does not consistently enhance endothelial function in estrogen-deficient postmenopausal women. High-resistance inspiratory muscle strength training (IMST) is a time-efficient, adherable lifestyle intervention that involves inhaling against resistance through a handheld device (30 breaths/day). Here, we present the protocol for a randomized controlled trial investigating the efficacy of 3 months of high-resistance IMST compared to guideline-based, "standard-of-care" aerobic exercise training for decreasing SBP and improving endothelial function in estrogen-deficient postmenopausal women with above-normal SBP (120-159 mmHg) at baseline (ClinicalTrials.gov Identifier: NCT05000515). Methods: A randomized, single-blind, parallel-group design clinical trial will be conducted in 72 (36/group) estrogen-deficient postmenopausal women with above-normal SBP. Participants will complete baseline testing and then be randomized to either 3 months of high-resistance IMST (30 breaths/day, 6 days/week, 75% maximal inspiratory pressure) or moderate-intensity aerobic exercise training (brisk walking 25 min/day, 6 days/week, 40-60% heart rate reserve). Outcome measures will be assessed after 3 months of either intervention. Following end-intervention testing, participants will abstain from their assigned intervention for 6 weeks, after which BP and endothelial function will be assessed to evaluate the potential persistent effects of the intervention on the primary and secondary outcomes. Discussion: This study is designed to compare the effectiveness of timeefficient, high-resistance IMST to guideline-based aerobic exercise training for lowering SBP and improving endothelial function, and interrogating potential mechanisms of action, in estrogen-deficient postmenopausal women. [ABSTRACT FROM AUTHOR]

Age-associated cardiovascular (CV) dysfunction increases the risk for CV diseases. Aerobic exercise training can improve CV function, but only a minority of adults meet aerobic exercise guidelines. High-resistance inspiratory muscle strength training is a time-efficient lifestyle intervention that may promote adherence and improve CV function. However, further investigation is needed to translate inspiratory muscle strength training into the public health domain. [ABSTRACT FROM AUTHOR]

Increased aortic stiffness may contribute to kidney damage by transferring excessive flow pulsatility to susceptible renal microvasculature, leading to constriction or vessel loss. We previously demonstrated that 5 weeks of dietary sodium restriction (DSR) reduces large-elastic artery stiffness as well as blood pressure in healthy middle-aged/older adults with moderately elevated systolic blood pressure (SBP) who are free from chronic kidney disease (CKD). We hypothesized that DSR in this cohort would also reduce urinary concentrations of renal tubular injury biomarkers, which predict incident CKD in the general population. We performed a post hoc analysis using stored 24 hours urine samples collected in 13 participants as part of a randomized, double-blind, crossover clinical trial of DSR (low sodium (LS) target: 50 mmol/day; normal sodium (NS) target: 150 mmol/day). Participants were 61±2 (mean±SEM) years (8 M/5 F) with a baseline blood pressure of 139±2/82±2 mm Hg and an estimated glomerular filtration rate of 79±3 mL/min/1.73 m2 Twenty-four hour urinary sodium excretion was reduced from 149±7 to 66±8 mmol/day during week 5. Despite having preserved kidney function, participants had a 31% reduction in urinary neutrophil gelatinase-associated lipocalin concentrations with just 5 weeks of DSR (LS: 2.8±0.6 vs NS: 4.2±0.8 ng/mL, p<0.05). Results were similar when normalized to urinary creatinine (urinary creatinine did not change between conditions). Concentrations of another kidney tubular injury biomarker, kidney injury molecule-1, were below the detectable limit in all but one sample. In conclusion, DSR reduces an established clinical biomarker of kidney tubular damage in adults with moderately elevated SBP who are free from prevalent kidney disease. [ABSTRACT FROM AUTHOR]

It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer's (n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol (n = 22), and 100 µM apocynin (n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine (n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2%CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin (P < 0.01) and Tempol (P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS (P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. [ABSTRACT FROM AUTHOR]

Habitual aerobic exercise enhances physiological function and reduces risk of morbidity and mortality throughout life, but the underlying molecular mechanisms are largely unknown. The circulating proteome reflects the intricate network of physiological processes maintaining homeostasis and may provide insight into the molecular transducers of the health benefits of physical activity. In this exploratory study, we assessed the plasma proteome (SOMAscan proteomic assay; 1,129 proteins) of healthy sedentary or aerobic exercise-trained young women and young and older men (n = 47). Using weighted correlation network analysis to identify clusters of highly co-expressed proteins, we characterized 10 distinct plasma proteomic modules (patterns). In healthy young (24 ± 1 yr) men and women, 4 modules were associated with aerobic exercise status and 1 with participant sex. In healthy young and older (64 ± 2 yr) men, 5 modules differed with age, but 2 of these were partially preserved at young adult levels in older men who exercised; among all men, 4 modules were associated with exercise status, including 3 of the 4 identified in young adults. Exercise-linked proteomic patterns were related to pathways involved in wound healing, regulation of apoptosis, glucose-insulin and cellular stress signaling, and inflammation/immune responses. Importantly, several of the exercise-related modules were associated with physiological and clinical indicators of healthspan, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function. Overall, these findings provide initial insight into circulating proteomic patterns modulated by habitual aerobic exercise in healthy young and older adults, the biological processes involved, and their relation to indicators of healthspan. NEW & NOTEWORTHY This is the first study to assess the relation between plasma proteomic patterns and aerobic exercise status in healthy adults. Weighted correlation network analysis identified 10 distinct proteomic modules, including 5 patterns specific for exercise status. Additionally, 5 modules differed with aging in men, two of which were preserved in older exercising men. Exercise-associated modules included proteins related to inflammation, stress pathways, and immune function and correlated with clinical and physiological indicators of healthspan. [ABSTRACT FROM AUTHOR]

This review summarizes the opening keynote presentation overview of the American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends held in Westminster, CO, in August 2017. Age is the primary risk factor for cardiovascular diseases (CVDs). Without effective intervention, future increases in the number of older adults will translate to a greater prevalence of CVDs and related disorders. Advancing age increases the risk of CVDs partly via direct effects on the heart and through increases in blood pressure; however, much of the risk is mediated by vascular dysfunction, including large elastic artery stiffening and both macro- and microvascular endothelial dysfunction. Although excessive superoxiderelated oxidative stress and chronic low-grade inflammation are the major processes driving cardiovascular aging, the upstream mechanisms involved represent new frontiers of investigation and potential therapeutic targets. Lifestyle practices, including aerobic exercise, energy intake (caloric) restriction, and healthy diet composition, are the most evidence-based strategies (old friends) for optimal cardiovascular aging, but adherence is poor in some groups. Healthy lifestyle "mimicking" approaches, including novel forms of physical training, intermittent fasting paradigms, exercise/healthy diet-inspired nutraceuticals (functional foods and natural supplements), as well as controlled environmental stress exposure (e.g., heat therapy), may hold promise but are unproven. Mitigating the adverse effects of aging on cardiovascular function and health is a high biomedical priority. [ABSTRACT FROM AUTHOR]

Aging impairs arterial function through oxidative stress and diminished nitric oxide ( NO) bioavailability. Life-long caloric restriction ( CR) reduces oxidative stress, but its impact on arterial aging is incompletely understood. We tested the hypothesis that life-long CR attenuates key features of arterial aging. Blood pressure, pulse wave velocity ( PWV, arterial stiffness), carotid artery wall thickness and endothelium-dependent dilation ( EDD; endothelial function) were assessed in young ( Y: 5-7 month), old ad libitum ( Old AL: 30-31 month) and life-long 40% CR old (30-31 month) B6 D2F1 mice. Blood pressure was elevated with aging ( P < 0.05) and was blunted by CR ( P < 0.05 vs. Old AL). PWV was 27% greater in old vs. young AL-fed mice ( P < 0.05), and CR prevented this increase ( P < 0.05 vs. Old AL). Carotid wall thickness was greater with age ( P < 0.05), and CR reduced this by 30%. CR effects were associated with amelioration of age-related changes in aortic collagen and elastin. Nitrotyrosine, a marker of cellular oxidative stress, and superoxide production were greater in old AL vs. young ( P < 0.05) and CR attenuated these increase. Carotid artery EDD was impaired with age ( P < 0.05); CR prevented this by enhancing NO and reducing superoxide-dependent suppression of EDD (Both P < 0.05 vs. Old AL). This was associated with a blunted age-related increase in NADPH oxidase activity and p67 expression, with increases in superoxide dismutase ( SOD), total SOD, and catalase activities (All P < 0.05 Old CR vs. Old AL). Lastly, CR normalized age-related changes in the critical nutrient-sensing pathways SIRT-1 and m TOR ( P < 0.05 vs. Old AL). Our findings demonstrate that CR is an effective strategy for attenuation of arterial aging. [ABSTRACT FROM AUTHOR]

We hypothesized that demographic/anthropometric parameters can be used to estimate effective reflecting distance (EfRD), required to derive aortic pulse wave velocity (APWV), a prognostic marker of cardiovascular risk, from peripheral waveforms and that such estimates can discriminate differences in APWV and EfRD with aging and habitual endurance exercise in healthy adults. Ascending aortic pressure waveforms were derived from peripheral waveforms (brachial artery pressure, n = 25; and finger volume pulse, n = 15) via a transfer function and then used to determine the time delay between forward- and backward-traveling waves (Atf-b). True EfRDs were computed as directly measured carotid-femoral pulse wave velocity (CFPWV) X %Atf-b and then used in regression analysis to establish an equation for EfRD based on demographic/anthropometric data (EfRD = 0.173-age + 0.661-BMI + 34.548 cm, where BMI is body mass index). We found good agree-ment between true and estimated APWV (Pearson's R2 = 0.43; intraclass correlation = 0.64; both P < 0.05) and EfRD (R2 = 0.24; intraclass correlation = 0.40; both P < 0.05). In young sedentary (22 ± 2 years, n = 6), older sedentary (62 ± 1 years, n = 24), and older endurance-trained (61 ± 2 years, n = 14) subjects, EfRD (from demographic/anthropometric parameters), APWV, and %Atf-b (from brachial artery pressure waveforms) were 52.0 ± 0.5, 61.8 ± 0.4, and 60.6 ± 0.5 cm; 6.4 ± 0.3, 9.6 ± 0.2, and 8.1 ± 0.2 m/s; and 82 ± 3, 65 ± 1 and 76 ± 2 ms (all P < 0.05), respectively. Our results demonstrate that APWV derived from peripheral waveforms using age and BMI to estimate EfRD correlates with CFPWV in healthy adults. This method can reliably detect the distal shift of the reflecting site with age and the increase in APWV with sedentary aging that is attenuated with habitual endurance exercise. [ABSTRACT FROM AUTHOR]

BackgroundWe performed a pilot study to test the hypothesis that acute oral ingestion of tetrahydrobiopterin (BH4), a key cofactor modulating vascular nitric oxide (NO) synthase activity, improves large elastic artery stiffness with aging in men.MethodsHealthy older (63 ± 2 years; n = 8) and young (age 25 ± 1 years; n = 6) men were studied 3 h after ingestion of BH4 (10 mg·kg−1 body weight) or placebo on separate days in a randomized, placebo-controlled, double-blind study.ResultsBaseline carotid artery compliance was 37% lower (0.17 ± 0.02 vs. 0.22 ± 0.02 mm/mm Hg·10−1) and β-stiffness was 42% higher (7.3 ± 1.1 vs. 4.2 ± 0.5 AU) in the older men (both P < 0.05). BH4 ingestion markedly increased circulating BH4 concentrations in both groups (17-19-fold, P < 0.05), but increased compliance (+39% to 0.23 ± 0.02 mm/mm Hg.10−1, P < 0.01) and decreased β-stiffness index (-27% to 5.3 ± 0.7 AU, P < 0.01) only in the older men. BH4 also reduced carotid systolic blood pressure (SBP) in the older men (P < 0.05).ConclusionsThese preliminary results support the possibility that limited BH4 bioavailability contributes to impaired carotid artery compliance in healthy older men. Further studies are needed to determine if increasing BH4 bioavailability though oral BH4 supplementation may have therapeutic efficacy for improving large elastic artery compliance and reducing central SBP with aging.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.70 [ABSTRACT FROM AUTHOR]

Autonomic nervous system (ANS) control of the circulation is altered with aging in adult humans. Similar changes are observed in obesity, particularly abdominal obesity. To determine whether age-associated differences in ANS-circulatory function can be partially explained by increased body fatness, we examined ANS function and throe expressions of adiposity (total body fat, abdominal body fat, and abdominal-to-peripheral body fat distribution; dual-energy X-ray absorptiometry) in 43 healthy men: 27 young (25 ± 1 yr) and 16 older (65 ± 1). ANS functions assessed included 1) autonomic support of arterial blood pressure (BP; radial artery catheter), i.e., the reduction in BP during versus before acute ganglionic blockade (GB; intravenous trimethaphan); 2) baroreflex buffering, i.e., the increase in systolic BP with continuous incremental and bolus infusions of phenylephrine during versus before GB; 3) cardiovagal baromflex sensitivity (Oxford technique); and 4) heart rate variability (time- and frequency-domain analyses). Covarying for abdominal-toperipheral fat distribution reduced or abolished age-related differences in ANS support of BP, cardiovagal baroreflex sensitivity, and heart rate variability but did not affect age-related differences in baroreflex buffering. Covarying for abdominal and total fat had small selective or no effects on age-associated differences in autonomic-circulatory control. Abdominal-to-peripheral fat distribution explains a significant portion of the variance in a number of autonomic-circulatory functions attributable to aging. Therefore, the development of this fat pattern may contribute to several changes in ANS-cardiovascular function observed with aging. These results may help explain how changes in body fat distribution with advancing age are linked to impairments in circulatory control. [ABSTRACT FROM AUTHOR]

Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in healthy men. We tested the hypothesis that oxidative stress contributes mechanistically to this age-associated reduction. Eight young (23 ± 1 yrs, means ± SE) and seven older (63 ± 3) healthy men were studied. Cardiovagal BRS was assessed using the modified Oxford technique (bolus infusion of 50-100 µg sodium nitroprusside, followed 60 s later by a 100- to 150-µg bolus of phenylephrine hydrochloride) in triplicate at baseline and during acute intravenous ascorbic acid infusion. At baseline, cardiovagal BRS (slope of the linear portion of the R-R interval-systolic blood pressure relation during pharmacological changes in arterial blood pressure) was 56% lower (P < 0.01) in older (8.3 ± 1.6 ms/mmHg) compared with young (19.0 ± 3.1 ms/mmHg) men. Ascorbic acid infusion increased plasma concentrations similarly in young (62 ± 9 vs. 1,249 ± 72 µmol/l for baseline and during ascorbic acid; P < 0.05) and older men (62 ± 4 vs. 1,022 ± 55 µmol/l; P < 0.05) without affecting baseline blood pressure, heart rate, carotid artery compliance, or the magnitude of change in systolic blood pressure in response to bolus sodium nitroprusside and phenylephrine hydrochloride infusion. Ascorbic acid (vitamin C) infusion increased cardiovagal BRS in older (Δ58 + 16%; P < 0.01), but not younger (Δ - 4 ± 4%) men. These data provide experimental support for the concept that oxidative stress contributes mechanistically to age-associated reductions in cardiovagal BRS in healthy men. [ABSTRACT FROM AUTHOR]

Deals with a study which tested the hypothesis that the elevations in 24-hour systolic blood pressure (SBP) and pulse pressures (PP) with age in sedentary adult females are absent or smaller in women who exercise regularly. Description of the study participants; Casually determined BP under resting conditions; Ambulatory recorded BP; Physiological correlation of 24-hour SBP and PP, SBP variability and SBP load.

Older men have reduced basal leg blood flow compared with young men, but the underlying mechanisms are incompletely understood. We determined if oxidative stress, which develops with aging and can exert a vasoconstrictor influence, plays a role. Common femoral artery blood flow was measured (duplex ultrasonography) under 3 conditions in young (n = 7; 24 ± 1 yrs) and older (n = 9; 64 ± 2 yrs) sedentary men who did not differ in leg fat free mass: acute intravenous infusion of saline or a supraphysiological concentration of ascorbic acid, and after 30 days of oral ascorbic acid supplementation (500 mg/day). At baseline (saline), older men demonstrated reduced leg blood flow (210 ± 16 vs. 288 ± 25 ml/min, P < 0.05) and greater systemic oxidative stress (plasma oxidized LDL 77 ± 8 vs. 53 ± 4 IU/l, P < 0.05) compared with young men. Acute infusion of ascorbic acid restored leg blood flow in older men (277 ± 25 ml/min, P < 0.05) without affecting blood pressure, but did not influence blood flow in young men (299 ± 47 ml/min). Chronic oral ascorbic acid supplementation did not affect femoral blood flow in either group. These results provide evidence that oxidative stress mediates the age related reduction in basal leg blood flow in healthy sedentary men. However, oral supplementation of ascorbic acid does not improve leg blood flow in older men, possibly because circulating concentrations are inadequate to exert a potent antioxidant effect. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) remain the leading cause of death in developed and developing societies and aging is the primary risk factor for CVD. Much of the increased risk of CVD in midlife/older adults (i.e., adults aged 50 years and older) is due to increases in blood pressure, vascular endothelial dysfunction and stiffening of the large elastic arteries. Aerobic exercise training is an effective lifestyle intervention to improve CV function and decrease CVD risk with aging. However, <40% of midlife/older adults meet guidelines for aerobic exercise, due to time availability-related barriers and other obstacles to adherence. Therefore, there is a need for new lifestyle interventions that not only improve CV function with aging but also promote adherence. High-resistance inspiratory muscle strength training (IMST) is an emerging, time-efficient (5 min/day) lifestyle intervention. Early research suggests high-resistance IMST may promote adherence, lower blood pressure and potentially improve vascular endothelial function. However, additional investigation will be required to more definitively establish high-resistance IMST as a healthy lifestyle intervention for CV aging. This review will summarize the current evidence on high-resistance IMST for improving CV function with aging and will identify key research gaps and future directions. [ABSTRACT FROM AUTHOR]