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. Author manuscript; available in PMC: 2012 Oct 24.
Published in final edited form as: Ther Adv Cardiovasc Dis. 2009 Sep 1;3(5):347–356. doi: 10.1177/1753944709345790

Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure

Kristen L Jablonski 1, Phillip E Gates 2, Gary L Pierce 3, Douglas R Seals 4
PMCID: PMC3480332  NIHMSID: NIHMS411713  PMID: 19723834

Abstract

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 Δ) to 52% (% Δ) 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 Δr =−0.40, p <0.05; %Δr =−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 ≥ 0.24) and was not related to sodium intake in the overall group (p ≥ 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.

Keywords: aging, brachial artery flow-mediated dilation, cardiovascular risk

Introduction

Cardiovascular diseases (CVD) remain the leading cause of death in modern societies and this is attributable in large part to dysfunction of the endothelial layer of arteries [Bonetti et al. 2003; Widlansky et al. 2003]. Aging is associated with development of vascular endothelial dysfunction and is a major risk factor for CVD [Lakatta and Levy, 2003; Taddei et al. 1995; Celermajer et al. 1992]. Systolic blood pressure (BP) increases with age and contributes to the age-associated increase in CVD [Rosamond et al. 2007; Lakatta and Levy, 2003]. Middle-aged and older (MA and O) adults with elevated systolic BP demonstrate greater vascular endothelial dysfunction and risk of CVD than their peers with normal systolic pressure [Taddei et al. 2001, 1995]. Thus, identifying factors that influence vascular endothelial function in MA and O adults with elevated systolic BP has important clinical implications for preventing age-associated CVD.

Indirect evidence suggests that dietary sodium intake may be one such factor. Self-reported sodium intake is positively related to CVoutcomes among MA and O adults [Umesawa et al. 2008] and BP sensitivity to sodium increases with age in healthy adults [Elliott et al. 1996; Zemel and Sowers, 1988]. In rodents, increased sodium intake causes impaired endothelium-dependent dilation, the most common measure of vascular endothelial dysfunction, independent of effects on arterial BP [Nurkiewicz and Boegehold, 2007; Zhu et al. 2004; Boegehold, 1993]. In humans, impaired endothelium-dependent dilation is observed in young healthy men in response to acute sodium loading [Tzemos et al. 2008] as well as in patients with essential hypertension who demonstrate BP sensitivity to changes in sodium compared with patients who are resistant to sodium [Larrousse et al. 2006; Bragulat et al. 2001; Miyoshi et al. 1997]. Taken together, these observations suggest that MA and O adults with lower dietary sodium intake may have enhanced vascular endothelial function compared with their peers with higher intake of sodium. However, presently there are no data addressing this issue.

To provide initial insight to this question, we compared groups of unmedicated MA and O adults with elevated baseline systolic BP who consumed a diet either low or within the average range for sodium intake in the U.S. The groups did not differ in BP and other subject characteristics, risk factors and diet composition (e.g. potassium intake) that could independently affect vascular endothelial function, allowing us, as much as is possible in a cross-sectional investigation, to isolate the effects of dietary sodium intake. Brachial artery flow-mediated dilation (FMD), a measure of endothelium-dependent dilation, was used to assess vascular endothelial function. Endothelium-independent dilation was also assessed as a control to ensure that any effect of dietary sodium intake on brachial FMD reflected an endothelium-dependent influence.

Methods

Subjects

Subjects were 25 MA and O (48–73 years) men (n =16) and postmenopausal women (n =9) with high normal systolic BP or stage I systolic hypertension (130–159 mmHg). All but one subject (93 mmHg), had a diastolic BP <90 mmHg and all subjects were otherwise free of cardiovascular diseases, diabetes and other clinical disorders as assessed by medical history, physical examination, blood chemistries and resting and exercise ECG. All subjects were nonsmokers, not taking medications (prescription or over the counter) or dietary supplements (including those with antioxidant properties) and not regularly exercising. All procedures were approved by the Human Research Committee of the University of Colorado at Boulder. The nature, benefits and risks of the study were explained to the volunteers and their written informed consent was obtained prior to participation.

Study procedures

All measurements were performed at the University of Colorado at Boulder General Clinical Research Center (GCRC) after an overnight fast (water only) and a 24-hour abstention from alcohol and vigorous physical activity.

Group selection

Initially, subjects were identified from our laboratory database of individuals previously characterized for vascular endothelial function and nutritional profile, according to the inclusion/exclusion criteria described above. Among subjects meeting those criteria, individuals then were identified as having dietary sodium intake <100 mmol/d (low sodium) or between 100–200 mmol/d (normal sodium). The upper cutoff for the low sodium group was based in part on the Dietary Reference Intake tolerable upper limit for sodium intake of 100 mmol/d [Panel on Dietary Reference Intakes, 2004] and to achieve a low sodium group mean value as close as possible to the Dietary Approaches to Stop Hypertension (DASH) recommended level of ~60 mmol/d [Sacks et al. 2001]. The range of 100–200 mmol/d was selected to provide a normal sodium group mean value consistent with the average American dietary sodium intake of ~150 mmol/d [Wright et al. 2003].

Dietary analysis

Diet composition and caloric intake were estimated from 3-day food intake records (The Food Processor 8.2, ESHA Research) [Pierce et al. 2008] (n =15, 7 low sodium/8 normal sodium) or food-frequency questionnaires (FFQ) (NHANES III food-intake database) [Eskurza et al. 2005] (n =10, 5 low sodium/5 normal sodium) previously analyzed by a GCRC bionutritionist.

Subject characteristics and blood assays

Body mass index (BMI) was calculated from height and weight to the nearest 0.1 kg, and waist and hip circumferences were measured by anthropometry [Christou et al. 2005]. Total body fat was determined using dual energy X-ray absorptiometry (DPX-IQ, GE/Lunar, Inc.) [Christou et al. 2005]. Arterial BP was measured over the brachial artery during seated rest using a semi-automated device (Dynamap XL, Johnson and Johnson) on at least two occasions with a minimum of three readings averaged in each session [Monahan et al. 2000]. Habitual physical activity was assessed from estimates of daily energy expenditure using the Stanford Physical Activity Questionnaire as previously described [Donato et al. 2007]. Peak oxygen consumption was determined with online, computer-assisted, open-circuit spirometry and was used as a measure of maximal aerobic exercise capacity [Desouza et al. 2000].

All assays were performed by the University of Colorado GCRC core laboratory. Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, glucose and insulin were determined using standard assays. The homeostasis model of insulin resistance (HOMA-IR) was calculated using the formula: [fasting glucose (mg/dl) × fasting insulin μU/L)]/405 [Bonora et al. 2000]. Plasma norepinephrine concentrations were measured by high performance liquid chromatography. Serum endothelin-1 (Peninsula Laboratories, Inc), oxidized LDL (Alpco, Inc), total antioxidant status (Randox Laboratories, Inc.), interleukin-6 (IL-6; R&D Systems, Inc) and tumornecrosis factor-α (TNF-α) were measured by ELISA. Serum concentrations of C-reactive protein were measured using a high-sensitivity Chemistry Immuno Analyzer (AU400e, Olympus America Inc.).

Brachial artery FMD and endothelium-independent dilation

Brachial artery FMD (occlusion cuff on the upper forearm), peak shear rate during FMD, and endothelium-independent dilation (brachial artery dilation in response to sublingual nitroglycerin) were determined using duplex ultrasonography (Power Vision 6000, Toshiba) with a linear array transducer as described previously by our laboratory [Pierce et al. 2009, 2008]. In our laboratory, this technique has a reproducibility of 3 ± 2% and 3 ± 3% (coefficient of variation) for baseline and peak brachial diameters, respectively [Eskurza et al. 2001]. Responses are expressed as mm and percentage change from baseline diameter [Donald et al. 2008]. Measurements were performed within two weeks of establishing baseline subject characteristics.

Statistics

Statistical analyses were performed with SPSS (version 16.0). Group differences were determined by t-tests for independent sample comparisons. Pearson correlation analysis was used to assess bivariate relations of interest. Statistical significance for all analyses was set at p <0.05.

Results

Subject characteristics and circulating humoral factors

Characteristics of the groups are shown in Table 1. There were no differences in age, body mass, BMI, waist : hip ratio, percentage total body fat, systolic and diastolic BP, plasma lipids and lipo-proteins, plasma glucose and insulin, HOMA, physical activity and peak oxygen consumption between groups (all p ≥ 0.11). Circulating humoral factors for the groups are shown in Table 2. Plasma norepinephrine, endothelin-1, oxidized LDL, total antioxidant status, C-reactive protein, IL-6 and TNF-α did not differ between groups (all p ≥ 0.16).

Table 1.

Subject characteristics.

Normal Na+ Low Na+ p-value
n (m/f) 13 (9/4) 12 (7/5)
Age (years) 60±2 62±1 0.44
Body mass (kg) 84±3 80±7 0.61
BMI (kg/m2) 28.1±0.7 26.3±1.3 0.22
Waist : hip ratio 0.94±0.03 0.87±0.03 0.11
Total body fat (%) 34±2 34±2 0.90
Systolic BP (mmHg) 138±2 138±1 0.93
Diastolic BP (mmHg) 81±2 79±2 0.68
Total Cholesterol (mg dL−1) 197±7 214±9 0.16
LDL-C (mg dL−1) 121±7 135±9 0.19
HDL-C (mg dL−1) 50±4 50±4 0.92
VLDL-C (mg dL−1) 26±3 28±5 0.71
Triglycerides (mg dL−1) 128±17 142±25 0.62
Glucose (mg dL−1) 95±3 95±3 0.91
Insulin (μU/l) 7.2±1.6 8.3±1.9 0.66
HOMA 1.76±0.46 2.08±0.58 0.67
Physical activity (MET hrs wk−1) 78±23 42±19 0.24
Peak VO2 (ml kg− min−1) 26±1 25±1 0.82
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Data are mean ± S.E.; BMI, body mass index; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol; HOMA, insulin sensitivity index (homeostasis model assessment); physical activity, average daily leisure and occupational activity; MET, metabolic equivalent; VO2, volume of oxygen consumption.

Table 2.

Circulating humoral factors.

Normal Na+ Low Na+ p-value
Norepinephrine (pg/ml) 271±17 336±46 0.16
ET-1 (pg/ml) 6.2±0.4 6.9±0.4 0.26
Oxidized LDL (U/L) 56.1±3.0 63.9±6.2 0.25
Total antioxidant status (mmol/l) 1.40±0.09 1.18±0.08 0.24
C-reactive protein (mg/l) 0.76±0.06 0.84±0.22 0.68
IL-6 (pg/ml) 1.8±0.4 1.3±0.1 0.23
TNF-α(pg/ml) 1.7±0.2 1.4±0.1 0.24
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Data are mean ± S.E. ET-1, endothelin-1; IL-6, interleukin-6; TNF-alpha, tumor necrosis factor-α.

Diet

Diet composition of the groups is shown in Table 3. Sodium intake was 144 ± 6 and 73 ± 6 mmol/d for the normal and low sodium groups, respectively (p <0.0001). Potassium and calcium intake, and carbohydrate, fat and protein composition did not differ between groups (all p ≥ 0.53). Total energy intake tended to be lower in the low sodium group (p =0.07).

Table 3.

Subject diet composition.

Normal Na+ Low Na+ p-value
Sodium intake (mmol/d) 144±6 73±6 <0.01
Potassium intake (mmol/d) 66±8 64±9 0.89
Calcium (mmol/d) 21±2 20±3 0.75
Carbohydrates (% of total kilojoules/day) 52±3 53±2 0.69
Fat (% of total kilojoules/day) 32±2 31±1 0.53
Protein (% of total kilojoules/day) 16±3 16±2 0.94
Total kilojoules/day 8709±475 7140±697 0.07
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Data are mean ± S.E.

Brachial artery FMD and endothelium-independent dilation

Baseline brachial artery diameter was smaller in the low compared with the normal sodium intake group (3.46 ± 0.17 versus 3.96 ± 0.16 mm, p <0.05), whereas peak shear rate during FMD was similar in the two groups (392 ± 57 versus 384 ± 42 s−1, p =0.91). Brachial artery FMD was 42% (mmΔ) to 52% (%Δ) higher in the low sodium compared with the normal sodium group (both p <0.05) (Figure 1). In contrast, endothelium-independent dilation did not differ between groups (p ≥ 0.24) (Figure 1). In all subjects, brachial artery FMD was inversely related to dietary sodium intake (%Δr =−0.53, p <0.01; mmΔr =−0.40, p <0.05) (Figure 2). Sodium intake was not related to endothelium-independent dilation (p ≥ 0.29). FMD and endothelium-independent dilation were not related to any other subject characteristic, including baseline brachial artery diameter and total kilojoules per day.

Figure 1.

Figure 1

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Endothelium-dependent dilation (brachial artery FMD; percentage change (%Δ), absolute change (mmΔ); top) in normal and low dietary sodium groups, and endothelium-independent dilation (brachial artery dilation in response to sublingual nitroglycerin (NTG); bottom) in normal and low dietary sodium groups. Values are mean ± S.E. *p <0.05 versus normal sodium group.

Figure 2.

Figure 2

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Relation between brachial artery flow-mediated dilation (FMD; percentage change (%Δ); left, absolute change (mmΔ); right) and daily dietary sodium (Na+) intake.

Discussion

To our knowledge this is the first study to report an association between vascular endothelial function and the normal dietary sodium intake of humans. We found that in MA and O adults with elevated baseline systolic BP, brachial artery FMD, a well-established measure of endothelium-dependent dilation and vascular endothelial function, was greater in those with low compared with average sodium intake based on U.S. norms. Consistent with these group differences, brachial FMD was inversely related to dietary sodium intake among individuals in the entire sample. In contrast, no such relations were observed with endothelium-independent dilation. Considered together, these findings indicate that sodium intake in the diet may exert an important influence on vascular endothelial function in this group.

Biomedical significance

Recent evidence suggests that self-reported sodium intake [Umesawa et al. 2008] and urinary sodium excretion [Tuomilehto et al. 2001] are positively related to the risk of CV events among MA and O adults, whereas dietary sodium restriction improves CV outcomes [Cook et al. 2007], suggesting a link with age-associated CVD. Previous investigations in rodents and young adult humans have established that experimentally increasing sodium intake or sodium loading results in impaired vasodilatory responses to the endothelium-dependent dilator, acetycholine [Tzemos et al. 2008; Nurkiewicz and Boegehold, 2007; Boegehold, 1993].

The present findings extend and complement these earlier observations by demonstrating that in MA and O adults with elevated systolic BP, a group with baseline vascular endothelial dysfunction and increased risk of CVD, brachial artery FMD is inversely related to self-reported dietary sodium intake. Importantly, our results show that the relation between sodium intake and vasodilatory responsiveness is specific to the vascular endothelium, as endothelium-independent dilation did not differ between the low and normal sodium intake groups, nor was it related to sodium intake among individual subjects. Our findings also are important because brachial artery FMD predicts future risk of CV events in MA and O adults [Yeboah et al. 2007; Widlansky et al. 2003]. Overall, the present results provide new clinical insight that vascular endothelial dysfunction is a possible intermediary pathophysiological mechanism linking dietary sodium intake to future CV events in MA and O adults [Umesawa et al. 2008].

Findings from studies in which endothelium-dependent dilation was assessed under experimentally controlled sodium intake conditions in humans have been inconsistent. No effects of dietary sodium restriction on the forearm blood flow responses to acetylcholine were observed in patients with sodium-sensitive or sodium-resistant forms of essential hypertension [Higashi et al. 2001; Miyoshi et al. 1997]. In contrast, brachial artery FMD was improved in overweight and obese adults with normal BP [Dickinson et al. 2009]. The results of the present study are in agreement with the latter investigation, which together support an association between dietary sodium intake and brachial artery FMD in groups with impaired baseline function. The discrepancy with findings of the earlier studies could, in part, be the result of differences in methodology, including the effects of sodium intake on FMD of a conduit (brachial) artery compared with pharmacological stimulation of endothelium-dependent dilation in resistance vessels [Eskurza et al. 2001].

Physiological influence of sodium intake

The influence of sodium intake on brachial artery FMD in our study appears to be physiologically significant. Depending on which of the two standard clinical expressions of FMD are used (mmΔ or %Δ), the low versus normal sodium intake group differences were 42–52%. Moreover, a moderately strong correlation coefficient of r =−0.53 was observed for the relation between brachial FMD and sodium intake among all subjects. As with most correlations, this correlation coefficient likely significantly underestimates the true physiological relation between endothelium-dependent dilation and dietary sodium intake because of the inherent measurement error associated with each of the variables, which would reduce the correlation coefficient.

In our laboratory, using the same procedures as in the present study, we find a mean %Δ brachial FMD of 7.2% in healthy young adult men and women with normal BP (n =62) [see Pierce et al. 2009]. In comparison, the values for the low and normal sodium intake groups in the present study were 5.0% and 3.3%; that is, 30% versus 55% lower, respectively, than the values for young healthy controls. Together, these observations suggest that although brachial artery FMD is impaired in MA and O adults with elevated systolic BP regardless of dietary sodium intake, those consuming a diet <100 mmol/d in sodium demonstrate less impairment than those consuming even average amounts of sodium.

Strengths of the study design

A major strength of our study was that the low and normal sodium intake groups were carefully selected for similar subject characteristics (e.g. body fatness, physical activity, maximal aerobic capacity) and coronary risk factors (e.g. plasma lipids and lipoproteins, fasting glucose and insulin) (Table 1) that could independently influence brachial FMD. This allowed us to isolate the effects of sodium intake as much as is possible using cross-sectional group comparisons. Consistent with observations in rodents [Liu et al. 1999; Boegehold, 1995], arterial BP was similar in our two groups and thus cannot explain the differences in brachial artery FMD. Several other dietary factors that could influence endothelium-dependent dilation were also controlled for, including potassium intake (Table 3). This experimental approach limited the number of subjects that could be included in our groups, but allowed much clearer interpretation of our results than would otherwise be possible. Although estimated total energy intake and brachial artery baseline diameter tended to be or were significantly different, respectively, in the two groups, neither was related to FMD.

Potential influence of plasma sodium

Increased dietary sodium intake can elevate plasma sodium [De Wardener et al. 2004] and sodium decreases nitric oxide bioavailability in cell culture [Li, 2009; Oberleithner et al. 2007]. As such, we recognize that plasma sodium could influence endothelium-dependent dilation. However, plasma sodium did not differ between groups in the present study (low sodium, 141±0.7 mmol/l; high sodium, 141±0.4 mmol/l) or correlate with FMD (p =0.19).

Limitations of the study

There are several limitations of our study that we wish to emphasize. We recognize that our sample size is small and, therefore, our results are preliminary findings used to provide an experimental basis for future investigation.

We only can provide limited insight into the mechanisms by which low sodium intake was associated with enhanced vascular endothelial function. Results from studies in rodents suggest that sodium intake may be positively related to oxidative stress, which limits nitric oxide bioavailability and impairs endothelium-dependent dilation [Nurkiewicz and Boegehold, 2007; Zhu et al. 2007; Zhu et al. 2004]. In the present study, plasma oxidized LDL, an indirect measure of oxidative stress, and plasma total antioxidant status did not differ between groups. Plasma concentrations of norepinephrine, a measure of sympathetic nervous system activity, endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, and the inflammatory markers C-reactive protein, IL-6 and TNF-α also did not differ between groups. However, these plasma measures do not necessarily reflect differences in the vascular endothelium that would directly influence FMD, particularly among a relatively homogeneous group of adults such as those studied here.

Our subjects were otherwise healthy MA and O adults with elevated systolic BP, and therefore, likely to be more sensitive to sodium than younger adults with normal BP. As a result, the relation we observed between brachial FMD and sodium intake may not be apparent in younger adults, as sodium-sensitivity increases with age [Elliott et al. 1996; Zemel and Sowers, 1988].

In the present study we were able to determine the influence of low compared with average sodium intake. However, we did not have sufficient data on subjects with higher sodium intake who fit our eligibility requirements to compare with the low and average sodium intake groups. As such, we do not know if higher than average sodium intake is associated with greater impairments in brachial FMD in this population.

Baseline brachial artery diameter was smaller in the low sodium group, likely because of the slightly higher percentage of female subjects compared with the normal sodium group. However, it is unlikely that this confounded the interpretation of our results. First, FMD was not related to baseline diameter. Second, if smaller baseline diameter per se contributed to greater FMD we would also expect to see this effect in endothelium-independent dilation, which was not the case. Last, FMD in percentage change accounts for differences in baseline diameter and group differences in FMD were also observed with this expression.

Shear rate produced by the hyperemic stimulus also influences FMD. We do not believe this factor explains our group differences in FMD as shear rate did not differ between groups and was not related to FMD among individuals. Moreover, Donald et al. [2008] recently established that percent and absolute change in FMD are the most sensitive and reproducible expressions of FMD for depicting differences among groups.

Abdominal fat generally is inversely related to FMD [Brook et al. 2001] and there was a non-significant (p =0.11) trend for waist : hip ratio to be smaller in our low sodium group (possibly due to a slightly higher percentage of females). However, waist : hip ratio was not related to FMD. Percentage body fat was identical in the two groups.

Finally, the available methods of assessing dietary sodium intake in our subjects were limited because of the retrospective nature of the data analysis. Sodium intake was assessed using two different methods, and urinary sodium excretion, an objective measure of sodium intake [Dahl, 1958], was available on only a small number of the total subjects (n =6). Diet composition assessed using FFQ and 3-day diet records are generally in agreement [Mares-Perlman et al. 1993; Block et al. 1990; Margetts et al. 1989], and the percent of subjects in each group assessed with these instruments was similar in the present study. Moreover, sodium intake measured by these self-report instruments correlates with urinary sodium excretion [Leiba et al. 2005; Day et al. 2001; McKeown et al. 2001; Caggiula et al. 1985]. In a separate group of 32 MA and O adults (mean 60±1 years, 17 males/15 females) in whom we previously had obtained one of these self-report measures of sodium intake and urinary sodium excretion, we found surprisingly similar mean values of 126±10 versus 127±10 mmol/d, respectively, between the two methods.

Despite these collective limitations, however, in the present study we were able to show associations between brachial artery FMD and sodium intake both in group comparisons and among individuals.

Conclusion

In summary, the results of our study suggest that low sodium intake is associated with enhanced brachial artery FMD in MA and O adults with elevated systolic BP. As such, our findings provide evidence for a possible link between dietary sodium intake, the development of vascular endothelial dysfunction and increased risk of CVD in this group.

Importantly, our results and those of others [Dickinson et al. 2009] provide an experimental basis for conducting an intervention trial aimed at determining the efficacy of dietary sodium restriction for improving vascular endothelial function in MA and O adults with elevated systolic BP, as previously demonstrated for large elastic artery stiffness [Gates et al. 2004].

Acknowledgments

We would like to thank Kathleen Farrell for diet analyses.

Sources of funding

This work was supported by National Institutes of Health awards AG006537, AG013038, AG022241, AG000279, AG033994 and RR00051.

Footnotes

Conflict of interest statement

None declared.

Contributor Information

Kristen L. Jablonski, Department of Integrative, Physiology, University of, Colorado, Boulder, Colorado, USA.

Phillip E. Gates, Peninsula Medical School, University of Exeter, Exeter, UK

Gary L. Pierce, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA

Douglas R. Seals, Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA.

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