The damaging duo: Obesity and excess dietary salt contribute to hypertension and cardiovascular disease

Summary

Hypertension is a primary risk factor for cardiovascular disease. Cardiovascular disease is the leading cause of death among adults worldwide. In this review, we focus on two of the most critical public health challenges that contribute to hypertension−obesity and excess dietary sodium from salt (i.e., sodium chloride). While the independent effects of these factors have been studied extensively, the interplay of obesity and excess salt overconsumption is not well understood. Here, we discuss both the independent and combined effects of excess obesity and dietary salt given their contributions to vascular dysfunction, autonomic cardiovascular dysregulation, kidney dysfunction, and insulin resistance. We discuss the role of ultra-processed foods−accounting for nearly 60% of energy intake in America−as a major contributor to both obesity and salt overconsumption. We highlight the influence of obesity on elevated blood pressure in the presence of a high-salt diet (i.e., salt sensitivity). Throughout the review, we highlight critical gaps in knowledge that should be filled to inform us of the prevention, management, treatment, and mitigation strategies for addressing these public health challenges.

1 |. INTRODUCTION

Nearly 4 in 10 adults have obesity,¹ and 9 in 10 adults overconsume dietary salt in the United States,^2,3 each of which independently contributes to the development of hypertension and cardiovascular (CV)-related mortality.^4–11 Previous articles have detailed how obesity and dietary salt independently affect different physiological systems.^5,12 However, there is a critical need to comprehensively integrate the physiological systems that contribute to CV disease, the leading cause of death, and hypertension, the leading modifiable risk factor for CV disease.¹³ This review article addresses the independent and interdependent effects of obesity and excess salt intake on hypertension and CV disease, inclusive of the common methodological approaches for studying these factors and epidemiological findings. Moreover, we discuss how obesity and excess dietary salt can elicit vascular dysfunction, autonomic cardiovascular dysregulation, kidney dysfunction, and insulin resistance. We close the article by introducing ultra-processed foods as one target to reduce the burden of obesity and reduce sodium intake, discuss how the presence of obesity can affect blood pressure (BP) responses to high salt feeding, and the role of leptin. In summary, this review article provides a foundation for the interplay between obesity and excess salt intake on CV health.

2 |. OBESITY

2.1 |. The prevalence of obesity

The World Health Organization (WHO) considers obesity to be a global epidemic, with a growing prevalence in American adults (Figure 1A).^14,15 Among 36 countries, at least 3 in 10 adults have obesity.¹⁵ Of those 36 countries, several have a population where 7 in 10 individuals have obesity.¹⁵ In the United States, more than 2 in 3 have overweight or obesity,^8,16,17 and over 4 in 10 adults have obesity (Figure 1B).¹ Likewise, among American adults aged 18 to 25 years, the prevalence of obesity increased from 6% in the late 1970s to 33% In 2018.¹⁸ Even before adulthood, the prevalence of obesity in children aged 5 to 19 years rose from less than 1% in 1975 to 6% for girls and 8% for boys in 2016. In total, 37 million children had overweight or obesity in 2016.¹⁴ While obesity is associated with significant morbidities, such as hypertension (i.e., high blood pressure (BP)), the most prevalent condition among individuals with obesity is CV disease.¹³ This increased risk presents a major health and economic burden, with about 4 in 10 individuals with obesity having a CV comorbidity. Notably, over 44 billion dollars (in 2020 dollars) is spent annually on excess body mass-related CV disease alone.¹⁹ There are no significant differences in obesity prevalence between men and women.²⁰ However, there are racial and ethnic disparities in obesity prevalence, which are likely largely attributable to socioeconomic position and neighborhood disadvantages.²¹ As reviewed at length elsewhere, several factors can contribute to obesity, including unhealthy diets, a lack of physical activity,^22–24 hormonal imbalances, sleep deprivation, and certain medications. While some people may have a genetic predisposition to obesity, environmental factors also play a significant role in the development of the condition.²² Nonetheless, there is a clear health crisis related to obesity that must be addressed by exploring the underlying physiological consequences.

FIGURE 1.

The criterion for adults with obesity was a body mass index value above 30 kg/m² for both figure panels. (A) The prevalence of obesity in American adults rose dramatically from 1975 to 2016.¹⁴ (B) Data collected from 2017 to 2020 demonstrate that over 4 in 10 American adults have obesity.¹ For both reports, an adult was defined as ≥20 years old.

2.2 |. Methodological assessment of obesity: Body mass index, waist and hip circumference, and body fat percentage

Body mass index (BMI) is the most common approach to estimate body fatness because of the ease of assessment, low cost, and minimal equipment required. BMI categories are underweight (<18.5 kg/m²), normal or healthy weight (18.5–24.9 kg/m²), overweight (25–29.9 kg/m²), class 1 obesity (30–34.9 kg/m²), class 2 obesity (35–39.9 kg/m²), and class 3 obesity (>40 kg/m²).²⁵ Waist circumference is also easy to assess and a relatively inexpensive measure of central adiposity,²⁶ with excessive abdominal adiposity defined as above 102 cm for males and above 88 cm for females. High BMI and waist circumference are both strongly associated with greater future metabolic disease, hypertension, and CV disease risk.^13,27,28 Individuals can also be classified as having obesity if their waist-to-hip circumference is above 0.90 for males and 0.85 for females.²⁹ Assessing body fat percentage (e.g., dual x-ray absorptiometry scan) is the most accurate measure of body composition but is time-consuming and expensive. However, the advantage of body fat percentage is that it may be a stronger predictor of CV disease risk than other methods.³⁰ In the following sections, we will discuss how obesity adversely impacts BP and general CV health. But first, we will briefly discuss the methodological limitations of the so-called ‘obesity paradox’, which has been discredited.

2.2.1 |. The obesity paradox

The obesity paradox posits that excess adiposity could be protective against mortality in certain disease states. This term was introduced after data from patients undergoing hemodialysis demonstrated that individuals with a BMI of >27.5 kg/m² had a 30% reduced relative risk of death compared with individuals with a BMI of 20–27.5 kg/m².³¹ Epidemiological studies have mixed findings for associations between BMI and mortality, resulting in controversy.^16,32–37 To explain the paradoxical, “protective” health effects of obesity (e.g., J- or U-shaped associations), it appears that greater obesity-related lean mass compared with more frail adults without obesity may explain why adults with obesity have a better prognosis.³⁶ Alternatively, it is possible that having a higher BMI contributes to earlier medical treatment, potential cardioprotective effects with a higher body fat content, and/or a greater metabolic reserve.^16,37,38 However, several confounding variables (e.g., pre-existing illness) in observational studies inflate the mortality rate for the normal BMI category, leading to reverse causality.^16,27,37,38 When mortality risk models incorporate weight history instead of current weight (i.e., representing only a snapshot in time), these models are not only more predictive but also demonstrate that the obesity paradox does not exist.³⁹ Indeed, participants with normal weight with a history of obesity were more likely to have higher mortality compared with those who never had obesity, which inflated the mortality rate for those with normal weight.³⁹ Thus, it appears that the obesity paradox has largely been confounded by comorbidities that contribute to weight loss later in life. Developing obesity in adulthood does not confer cardioprotection and more likely increases the risk of future all-cause mortality.

2.3 |. Obesity, hypertension, cardiovascular disease, and all-cause mortality

Obesity is a complex metabolic disease with deleterious effects on nearly every organ system investigated.⁵ Common obesity-associated diseases include type 2 diabetes mellitus, obstructive sleep apnea, multiple types of cancer (e.g., pancreatic and gastrointestinal), mental health conditions (e.g., depression and anxiety), liver and kidney disease, osteoarthritis, and CV diseases, the leading cause of death in America.^4–8 Further, obesity is often accompanied by other risk factors such as hypertension, dyslipidemia, physical inactivity, smoking, and caloric overconsumption, thereby compounding the disease risk, increasing the likelihood of severe disease development (e.g., atherosclerosis, stroke, and heart failure) and death.⁹ For example, obesity more than doubles the risk of developing hypertension.⁴⁰ Moreover, the presence of hypertension is predicted to more than double the risk of excess body weight-associated CV disease deaths.⁴¹ While life expectancy for individuals with obesity is predicted to decrease in the presence of additional risk factors,⁹ adopting positive health behaviors can reduce the burden of CV disease risk factors. For instance, increasing physical activity and/or exercise training reduces hypertension risk,^42,43 increases high-density lipoprotein (HDL),⁴⁴ improves glucose regulation, and reduces insulin resistance.⁴² Therefore, targeting health behaviors, such as dietary salt reduction, smoking cessation, increasing physical activity/exercise training, and reducing caloric intake, is critical for combatting obesity-associated CV disease morbidity and mortality.⁹

Many factors that accompany obesity contribute to hypertension, which makes elucidating the exact mechanistic links between obesity and CV disease difficult. For example, obesity is associated with insulin resistance,⁴⁵ chronic kidney disease, stimulation of the renin-angiotensin-aldosterone system (RAAS),^46–48 and greater sympathetic outflow.^49–51 Germane to the current review, the association between obesity and salt sensitivity is not as well understood. Thus, in the following sections, we discuss the possible roles of dietary salt in the development of obesity and obesity-associated hypertension.

3 |. DIETARY SALT

3.1|. The prevalence of dietary salt overconsumption

Nine in 10 American adults consume excess dietary salt (NaCl).^2,3 Ultra-processed food consumption⁵² accounts for the majority of salt intake.¹⁰ American adults’ salt intake far exceeds the recommendations set by the Dietary Guidelines for Americans (DGA)⁵³ and American Heart Association (AHA) for optimal cardiovascular health (Figure 2).⁵⁵ Further, the proportion of adults meeting these recommendations has decreased in recent years, highlighting a critical need to understand and mitigate the adverse effects of excess dietary salt.³ In the following section, we discuss the various methodologies employed to assess sodium intake and summarize epidemiological and experimental findings linking excess sodium intake with adverse CV health.

FIGURE 2.

Americans overconsume sodium (Quader et al.⁵⁴ and Bailey et al.²), relative to the recommendations from the American Heart Association (AHA; recommendation: <1,500 mg of sodium per day)⁵⁵ and the Dietary Guidelines for Americans (DGA; recommendation: <2,300 mg of sodium per day)⁵³ for optimal cardiovascular health.

3.2 |. Methodological assessment of sodium excretion: Dietary recall, spot urine samples, and 24-h urine samples

Approximately 90% of dietary sodium consumed is excreted in urine over the subsequent 24-h cycle.^56,57 Thus, 24-h urine collections are a gold standard approach for assessing dietary sodium intake. Higher participant burden, expense, and technical difficulty (e.g., missed voids) associated with 24-h collections have led investigators to rely on dietary recall or various equations to estimate 24-h sodium excretion from the spot and single-void urine samples.⁵⁸ Food frequency questionnaires and 24-h recalls for sodium intake estimation should be interpreted with caution due to limited validity.⁵⁹ Spot urine prediction equations, such as the Kawasaki,⁶⁰ Tanaka,⁶¹ and INTERSALT,⁶² are common approaches to estimate sodium intake. However, spot urine prediction equations cannot provide valid estimates of sodium intake.^58,63–66 Employing these estimation equations in epidemiological studies has yielded controversy in the field, with reports that ~3,000 to 5,000 mg of sodium per day is associated with a reduced risk of adverse CV events while both higher and lower intake increases risk. In other words, there is paradoxical J- or U-shaped relation between sodium intake and mortality whereby sodium consumption under 3,000 mg per day elicits greater mortality than sodium consumption of ~3,000 to 5,000 mg per day.^67–69 However, the notion that >3,000 mg of sodium per day is optimal for cardiovascular health opposes recommendations by the DGA⁵³ and the AHA.⁵⁵ Additionally, a recent prospective cohort study of nearly 3,000 participants with 24-h urine samples demonstrated the use of different formulas used to predict sodium intake led to variations in the estimated sodium intake, which in turn affected associations between sodium intake and mortality. Specifically, while spot sample equations demonstrated a J-shaped relation with mortality, there was no J-shaped relation with actual measured 24-h sodium intakes.⁶⁶ For additional discussion of these methodological issues, we refer the reader to previous articles from our group^12,70 and others.^59,71 In fact, spurious use of spot samples has led to so much confusion in the field the International Society of Hypertension recently published a position statement pleading with journals not to publish research studies that use spot urine samples with estimating equations to assess individuals’ sodium intake in association with health outcomes.⁷²

3.3 |. Dietary sodium, hypertension, cardiovascular disease, and all-cause mortality

High dietary salt contributes to the development of hypertension and CV disease.^9–11 As mentioned in Section 3.2, some studies demonstrate a J-shaped relation between salt intake and all-cause mortality, such that low salt intake−and to a greater extent high salt intake−is associated with greater mortality.^67–69,73 For the most part, this relation has been demonstrated in studies using spurious spot urine samples with estimating equations to assess individuals’ sodium.^70,72 However, some of these studies have even included 24-h urine sodium excretion.^74,75 There is a possibility of reverse causality given the inclusion of patient populations in some of these previous reports. For example, in patients with type 1 diabetes, low and high salt intake was associated with reduced survival.⁷⁵ These findings were subsequently critiqued for inadequate adjustment and inadequate statistical power.⁷¹ Thus, while unclear, it is more likely that a positive association exists between sodium intake and CV disease mortality, as reported in a majority of epidemiological and cohort studies using 24-h urine collections to estimate sodium intake.^76–79 Pertinent to this review, one report suggests that the relation between dietary sodium and CV disease is driven by adults with excess body mass.⁸⁰ Specifically, adults with a BMI below 27.8 for men and 27.3 for women did not exhibit a significant relation between dietary salt intake and CV risk, whereas adults above this threshold (e.g., overweight) did exhibit a strong independent relation between salt intake and CV disease.⁸⁰ Thus, it will be important to conduct randomized clinical trials with various salt intake amounts to fully elucidate the impact of varying dietary salt intake on cardiovascular health for adults with and without obesity. We discuss the putative mechanisms governing vascular endothelial dysfunction, a major indicator of future CV disease development, in obesity and with high salt intake in the following section.

4 |. VASCULAR FUNCTION AND HYPERTENSION

Obesity-induced and excess salt-induced vascular dysfunction may contribute to the increased CV disease risk associated with obesity^6–8 and high salt intake.^76,81 Vascular endothelial dysfunction is associated with greater CV disease risk.^82–85 The vascular endothelium is the interphase between the blood circulation and blood vessels. A healthy vascular endothelium is essential to arterial and tissue homeostasis by regulating vascular tone, permeability, and angiogenesis. The arterial endothelium is uniquely sensitive to nutrient overload relative to other tissues exhibiting dysfunction before adipose tissue, skeletal muscle, or developing insulin resistance in preclinical models.⁸⁶ As such, endothelial dysfunction is an important early indicator of CV disease. However, measuring endothelial function is not part of routine clinical care.⁸⁷ Below, we discuss the mechanisms underlying dietary salt and obesity-related endothelial dysfunction.

4.1 |. Obesity

There is a compelling body of literature spanning preclinical findings to observational studies linking obesity to endothelial dysfunction (Figure 3). Indeed, adults with obesity exhibit reduced brachial artery flow-mediated dilation.^88–90 While the exact mechanisms of obesity-induced endothelial function are complex, the loss of nitric oxide (NO·) bioavailability through decreased endothelial-derived nitric oxide synthase (eNOS) expression or function plays a role.⁹¹ Normal endothelial function depends on sufficient NO· bioavailability.^92,93 The role of eNOS in obesity-induced endothelial dysfunction is often observed as impaired dilation to endothelium-dependent agonists known to induce significant NO· production (e.g., acetylcholine, flow).^94–96 Also, attenuated effects of NOS inhibitors (e.g., L-NAME and L-NMMA) on vasodilation suggest decreased reliance on NO.^97,98 Obesity (diet or genetically induced) in rodents reduces eNOS protein levels in various tissues including the aorta, adipose, skeletal muscle, and heart.^99–102 Moreover, tumor necrosis factor α (TNFα) mediates the reduction of eNOS in rodents with obesity.¹⁰⁰ Conversely, multiple studies have identified an altered microRNA profile in obesity. However, a direct link to the regulation of eNOS expression in obesity by microRNAs has yet to be determined.¹⁰³ Future translational studies are needed to identify the microRNAs upregulated in human obesity that may regulate eNOS expression.

FIGURE 3.

Mechanisms of obesity affecting vascular function. eNOS, endothelial NO· synthase; NO·, nitric oxide; NOX, NADPH oxidase; O₂⁻, superoxide; ONOO⁻, peroxynitrite; ROS, reactive oxygen species; TNFα, tumor necrosis factor α.

The effects of obesity on eNOS expression are well documented. The deleterious effects of obesity on post-translational eNOS function are predicated on two potential mechanisms: (1) uncoupling of the Akt/eNOS complex resulting in reduced eNOS phosphorylation^104–106 and (2) uncoupling of the eNOS dimerization required for NO· production, resulting in a pathological positive feed-back loop involving the production of superoxide from eNOS monomers, which further reduces the bioavailability of NO.^106,107 Most of the NO-inducing stimuli converge on signaling pathways that phosphorylate/dephosphorylate eNOS at residues that promote NO· production.¹⁰⁸ In mice, obesity causes endothelial ceramide accumulation (metabolic derivatives of free fatty acids thought to be major contributors to endothelial dysfunction),¹⁰⁹ which increases protein phosphatase 2A activity and prevents Akt/eNOS signaling complex formation (required for eNOS activation).^110,111 Hyperglycemia, dyslipidemia, and insulin resistance−all hallmarks of obesity−reduce ser1177 phosphorylation (i.e., an indirect measure of eNOS-induced NO·production).^91,106 The dimerization of eNOS monomers is another essential prerequisite for NO· production that is dependent on specific heat shock proteins.¹⁰⁷ Additionally, overfed mice develop endothelial dysfunction through elevated peroxynitrite production in the aorta and the femoral artery.⁹⁵ This effect was dependent on the decreased activation of eNOS and subsequent reductions in eNOS dimerization, enabling eNOS monomers to produce reactive oxygen species (ROS) that affected the available NO· to produce peroxynitrite (ONOO⁻). Importantly, ONOO⁻, which broadly contributes to cellular nitrosative and oxidative stress,^112–114 can also further uncouple eNOS.¹¹⁵ While the eNOS/NO· deficit in obesity has garnered the most attention in the literature, putative ancillary and/or upstream mechanisms that may lead to the decline in NO· production and result in endothelial dysfunction in obesity are gaining traction. For example, increased expression of the pro-oxidant enzyme complex NADPH Oxidase (NOX) isoforms is associated with excess ROS production and reduced NO· bioavailability.¹¹⁶ NOX expression is also elevated by diet- and obesity-associated insults.¹¹⁷ Further, NOX isoforms may represent a target in reducing obesity-induced endothelial dysfunction. Interestingly, aerobic exercise reduces NOX expression in the endothelium¹⁰⁵ and increases flow-mediated dilation in individuals with obesity.^90,118

Apart from influencing pro-oxidant enzyme expression, obesity may also impair vasodilation by influencing the architecture of the endothelium. For example, obesity is associated with endothelial glycocalyx damage.^96,119,120 The endothelial glycocalyx is a mechanosensing complex composed of glycoproteins that traverse the endothelial membrane into the vascular lumen, which is essential for adequate NO· production. In humans, glycocalyx thickness is assessed using orthogonal polarization spectral imaging of the sublingual microvasculature.¹¹⁹ Studies using this approach have determined that glycocalyx thickness negatively correlates with BMI, providing evidence of a potential deficit in glycocalyx structure/function with obesity.¹¹⁹ Moreover, obesity alters the biophysical properties of the glycocalyx as assessed using atomic force microscopy in mice.^96,120 Importantly, these preclinical studies demonstrate that obesity induces a stiffening¹²⁰ and/or a decrease in the length of the glycocalyx.⁹⁶ These alterations may render the glycocalyx insensitive to luminal shear stress associated with blood flow, resulting in subsequent reductions in NO· production.

It is clear obesity induces endothelial dysfunction early in the CV disease process.^121–123 However, identifying the exact mechanisms and factors that lead to impairment in a multifaceted disease like obesity is a difficult task. Differences in methodologies such as genetic versus diet-induced rodent models of obesity, duration of obesity, diet composition, and vascular bed examined contribute to the varying mechanisms involved in obesity-induced vascular dysfunction. Additional translational studies aimed at isolating the independent risk factors associated with obesity-induced endothelial dysfunction in diverse populations are warranted to develop viable therapeutic targets.

4.1.1 |. How adipose tissue affects the vasculature in obesity

The idea of adipose tissue as a simple storage site for lipids has been reimagined with observations of adipose as a dynamic paracrine/endocrine tissue. Adipose tissue secretes adipokines that act on a variety of organ systems, including the vasculature.^123,124 However, the role of lipid storage appears to be important to the paracrine/endocrine function as an expansion of adipocytes due to excess lipid accumulation (e.g., in obesity) shifts the secretory profile of adipose from promoting vascular health to inducing inflammation.^123,125 Specifically, such changes reduce adiponectin production and increase the release of proinflammatory/proatherogenic mediators including leptin, TNFα, proinflammatory interleukins, and ROS.^121,123 Adiponectin has anti-atherosclerotic properties and promotes insulin sensitivity. Further, adiponectin production is reduced in certain metabolic diseases, such as type 2 diabetes.¹²⁶ In contrast, elevated production of leptin from adipocytes (likely in an attempt to promote satiety and prevent further lipid accumulation) may be responsible for inducing other harmful adipokine generation and directly promoting endothelial dysfunction.^127,128 Loss of the CV benefits of adiponectin and promoting a proinflammatory, proatherogenic state with increased adipose tissue may be a major contributor to CV disease progression. Importantly, there is a dichotomy between spatially distinct adipose depots and vascular dysfunction. Visceral adipose depots (e.g., mesenteric, aorta, and coronary periventricular adipose [PVAT]) are associated with vascular dysfunction of resident arteries, while subcutaneous adipose depots are not.¹²⁹ An exclusive dysfunction of the visceral adipose and its impact on visceral artery function supports the link between visceral adiposity and worse outcomes compared to individuals with low visceral adipose but subcutaneous obesity.^130,131

In humans with obesity, arteries isolated from visceral adipose tissue exhibit vascular dysfunction, whereas subcutaneous adipose arteries retain their function.^{130,132–135} In porcine coronary arteries, visceral adipose depots (mesenteric adipose and coronary PVAT) increase coronary artery tone by acting on smooth muscle L-type Ca²⁺ and K⁺ channels. These effects may contribute to coronary artery disease in obesity.¹³⁶ Other studies point to cellular mechanisms of endothelial dysfunction related to dysregulated eNOS/NO· production and elevated levels of ROS, which promote endothelial dysfunction in visceral adipose arteries.^130,133,134 Why these pathological mechanisms are absent in subcutaneous adipose/vasculature is incompletely understood. Nonetheless, visceral depots (e.g., mesenteric) and visceral PVAT likely become dysfunctional through both common and distinct mechanisms.^135,137

The potentially exclusive underlying mechanisms of visceral adipose on the resident vasculature in obesity remain difficult to identify.¹³⁴ It is enticing to hypothesize that, as adipose tissue grows with lipid accumulation, the resultant inadequate tissue perfusion cannot meet the metabolic demand, thereby inducing (1) the production of ROS from a worsening hypoxic environment, (2) a shift to a proinflammatory gene expression profile, and (3) impairment of the embedded vasculature.¹³⁷ Indeed, subcutaneous adipose tissue has a greater capacity for angiogenesis than visceral adipose in humans with obesity; however, this effect is lost in adults with class 3 obesity, suggesting this capacity can be overwhelmed past a certain point.¹³⁸ Additionally, the loss of angiogenesis was correlated with insulin resistance.¹³⁸ These findings highlight the ability of the subcutaneous adipose tissue to resist dysfunction in obesity compared with visceral adipose. However, it is not entirely clear why visceral adipose tissue has significantly lower angiogenic gene expression in adults with classes 1 and 2 obesity. In contrast, other work suggests no difference in the capacity for subcutaneous compared to visceral adipose tissue to recruit new vessels.¹³⁹ While it remains unclear if a perfusion mismatch is to blame for this discrepancy, the effects of the separate adipose depots on the embedded vasculature may be different. For example, increased salt intake (>15 g NaCl/d) for 7 days was accompanied by visceral adipose tissue hypoxia and an increase in activated, proinflammatory monocytes in healthy humans. Such effects were ameliorated following a low salt diet (<5 g NaCl/d) for 7 days.¹⁴⁰ Without data from subcutaneous adipose tissue, it is unknown whether these effects are specific to visceral adipose tissue. While obesity and salt intake have well-documented independent effects,^141–144 the complex interplay between the two is less well understood. Future studies should elucidate the effects of dietary salt on adipose depots, vascular dysfunction, and other cardiometabolic consequences in adults with obesity.

4.2 |. Dietary salt

Similar to our preceding discussion on obesity and endothelial dysfunction, there is compelling data spanning preclinical findings to observational studies linking high dietary salt to vascular dysfunction (Figure 4).¹⁴⁵ High dietary salt reduces vascular function in rodents^{116,146–149} and humans, including large^150–159 and small^{158,160–162} artery function. High dietary salt impairs vascular function through several mechanisms, such as increasing oxidative stress and reducing NO· bioavailability. Regarding oxidative stress, oxidants scavenge NO· to form ONOO⁻ and by uncoupling endothelial NO· synthase.^106,160,163 Rodent data indicate that high dietary salt increases NOX expression.¹¹⁶ Additionally, high dietary salt suppresses angiotensin II¹⁴⁹ subsequently decreasing the expression of copper/zinc-dependent superoxide dismutase (SOD; an enzyme that catalyzes the conversion of superoxide (O₂⁻) to hydrogen peroxide (H₂O₂)).^116,149 Findings of high dietary salt inducing oxidative stress and impairing endothelial function through reduced NO· bioavailability have been translated to humans with consistent results. For example, the antioxidant Apocynin^160–162 and the SOD mimetic tempol^161,162 both prevent high dietary salt-induced reductions in cutaneous microcirculation vasodilator function, suggesting a role for oxidative stress.^161,162 Also, high dietary salt blunts microcirculatory responses to L-NAME, suggesting reduced NO-mediated vasodilation.^158,160 There are cellular studies demonstrating that hypernatremia (high sodium concentrations in media) degrades the endothelial glycocalyx, which may contribute to the impaired endothelial responsiveness to shear stress^164,165 by reducing NO· release. Multiple studies have demonstrated that Human Umbilical Vein Endothelial Cells (HUVEC) exposed to hypernatremic media increased mRNA expression of several pro-inflammatory proteins.

FIGURE 4.

Mechanisms of excess dietary salt affecting vascular function. ADMA, asymmetric dimethylarginine; DDAH, Dimethylarginine dimethylaminohydrolase; eNOS, endothelial NO· synthase; H₂O₂, hydrogen peroxide; NO·, nitric oxide; NOX, NADPH oxidase; O₂⁻, superoxide; ONOO⁻, peroxynitrite; ROS, reactive oxygen species; SOD, superoxide dismutase.

High dietary salt may also reduce NO· bioavailability by increasing asymmetric dimethylarginine (ADMA), a naturally occurring analog of L-arginine that inhibits NO· synthesis through competitive inhibition at endothelial NO· synthase.^166,167 ADMA is hydrolytically degraded into L-citrulline and dimethylamine catalyzed by the enzyme Dimethylarginine Dimethylaminohydrolase. High salt diets increase plasma ADMA and reduce plasma Dimethylarginine Dimethylaminohydrolase, independent of BP in rodents.¹⁶⁸ However, it is unclear whether or not these findings translate to humans.^169,170 Thus, additional mechanistic work is needed to determine the influence of high dietary salt on ADMA-related reductions in NO· bioavailability. In summary, high salt impairs vascular function. Future studies are needed to determine whether those with obesity are more susceptible to high salt-induced reductions in vascular function.

5 |. AUTONOMIC NERVOUS SYSTEM CONTROL OF BLOOD PRESSURE

Both obesity and high dietary salt are associated with altered autonomic regulation. The autonomic nervous system plays an important role in short- and long-term BP regulation.¹⁷¹ Various approaches can be used to estimate para/sympathetic balance in humans, but we will focus on directly measured (i.e., microneurography) muscle sympathetic nerve activity (MSNA) in humans and sympathoregulatory brain regions in animals. Elevated sympathetic outflow is associated with poor CV outcomes.^172,173 Additionally, for a given sympathetic outflow, the end-organ response can be variable (i.e., sympathetic vascular transduction),¹⁷⁴ and recent data in small cohorts demonstrate that dietary salt may influence sympathetic vascular transduction (Section 5.2).^175,176 However, additional data are needed to discern the influence of obesity on sympathetic vascular transduction. Nonetheless, targeting the sympathetic nervous system may be an important strategy to counteract the consequences of obesity and high dietary salt on CV health.

5.1 |. Obesity

In rodents, obesity raises renal and lumbar sympathetic nerve activity.¹⁷⁷ Such changes may be driven by oxidative stress, specifically within the rostral ventrolateral medulla (RVLM).¹⁷⁸ Greater adiposity in humans is associated with higher resting MSNA.^50,179 Chronic elevations in resting MSNA impair heart, kidney, and vascular function, contributing to the development of CV disease development.¹⁷² Moreover, adults with greater visceral adipose tissue have higher MSNA, even when matched for total fat mass and subcutaneous adipose.¹⁸⁰ For example, in young male adults, those with high overall and visceral fat mass have lower (i.e., worse) cardiac vagal baroreflex gain¹⁸¹ and higher resting MSNA¹⁸² than their age-matched counterparts. Middle-aged adults with obesity have greater resting MSNA compared to lean adults, even after controlling for the presence of obstructive sleep apnea.¹⁸³ Consistent with animal work,¹⁷⁸ multiple experimental trials in humans have demonstrated that weight loss reduces resting MSNA.^184–186 For example, a 12-week weight loss study in middle-aged adults demonstrated reduced resting BP, plasma norepinephrine concentration, and MSNA, as well as increased (i.e., improved) cardiac vagal baroreflex gain.¹⁸⁷ However, data from a 16-week weight loss study demonstrated reductions in resting MSNA in female but not male adults. Interestingly, the male, but not female, adults had exhibited reductions in 24-h BP but not MSNA. These findings occurred despite both males and females groups losing a large amount of their overall body mass and visceral adiposity.¹⁸⁸

Unsurprisingly, obesity also seems to modulate MSNA and BP responses to various physiological stressors. For example, one trial in female adults demonstrated those with obesity, versus a healthy BMI, have higher resting MSNA but blunted MSNA responses during handgrip exercise.¹⁷⁹ However, females with obesity also exhibited augmented BP responses during handgrip exercise, indicating heightened time–averaged sympathetic vascular transduction.¹⁷⁹ Similarly, others have reported augmented BP responses during exercise in individuals with obesity.^189–192 Studies in participants with obesity who underwent weight loss through diet and/or exercise also exhibit attenuated MSNA during stressors. Following weight loss, absolute MSNA was significantly lower throughout low- and moderate-intensity handgrip exercise compared with a control group of participants with obesity.¹⁸⁴ There are several proposed mechanisms for increased MSNA at rest and during exercise in the context of obesity.

In humans, there is evidence that hyperinsulinemia, dyslipidemia, higher levels of inflammatory adipokines, hyperleptinemia, RAAS stimulation, and mitochondrial dysfunction contribute to an association between obesity and altered autonomic CV regulation.¹⁸⁶ In rodents, afferent signaling from white adipose tissue increases circulating norepinephrine concentration¹⁹³ and renal sympathetic outflow.¹⁹⁴ Additionally, white adipose tissue sensory denervation elicits the greatest reductions in renal sympathetic outflow and BP in rats with obesity and hypertension.¹⁹³ These alterations in BP regulation are thought to be mediated via signaling within the paraventricular nucleus.^195,196 For more information related to these mechanisms, we direct the reader to recent a review on the adipose afferent reflex¹⁹⁷ in obesity-related hypertension.

5.2 |. Dietary salt

High salt feeding can increase blood sodium concentration and expand plasma volume. It is less appreciated that salt loading also increases cerebrospinal fluid sodium concentration in rodents¹⁹⁸ and humans.¹⁹⁹ Central blood sodium concentration is sensed by circumventricular organs including the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ, both of which lack a complete blood–brain barrier (Figure 5).^201,202 Specifically, Na_x-positive glial cells in the OVLT may be activated by high blood sodium concentrations, enhancing hydrogen and lactate through a monocarboxylate transporter to activate ASIC1a-positive OVLT neurons.²⁰³ These signals are communicated through neuronal projections to the median preoptic nucleus before activating neurons in the paraventricular nucleus of the hypothalamus.²⁰³ Importantly, these signals of high central sodium concentrations are relayed to the RVLM. The RVLM consequently changes BP by modulating efferent sympathetic outflow.^{198,204–209} Alterations in efferent sympathetic outflow and BP associated with central hyperosmolality are specific to NaCl concentrations because osmotically balanced sorbitol or mannitol does not produce the same OVLT neuronal discharge frequency changes.²¹⁰ Notably, blocking the autonomic nervous system abolishes the increases in BP induced by raising cerebrospinal fluid sodium concentrations in rodents.¹⁹⁸

FIGURE 5.

Republished with permissions.²⁰⁰ Dietary salt alters autonomic function by excitation of NaCl-sensing neurons in the lamina terminalis or increasing gain/excitability of bulbospinal neurons in the rostral ventrolateral medulla. Salt-sensitive hypertension is associated with increased sympathetic outflow to the splanchnic or hindlimb vasculature. A midsagittal section of the rodent brain illustrates key autonomic centers involved in salt-sensitive hypertension. (i) Neurons in the organum vasculosum of the lamina terminalis and subfornical organ sense changes in extracellular NaCl to increase sympathetic nerve activity. Potential NaCl-sensing mechanisms include an N-terminal variant of the transient receptor potential cation channel subfamily V member 1 (TRPV1), the epithelial sodium channel (ENaC), and the Nax channel. (ii) Dietary salt also increases the excitability or gain of bulbospinal sympathetic neurons of the rostral ventrolateral medulla. Thus, glutamatergic (or GABAergic) input onto RVLM neurons results in an exaggerated discharge and change in sympathetic nerve activity. BP, blood pressure; RVLM, rostral ventrolateral medulla; SNA, sympathetic nerve activity. Adapted from Servier Medical Art by Servier licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com).

Dietary salt may also influence the transduction of MSNA to vasoconstriction and, consequently, BP.^175,176 Specifically, plasma volume expansion with salt loading is associated with reduced MSNA, which may sensitize α-adrenergic receptors and heighten the vasoconstrictor response to a given MSNA input.^173,175,211 Other work details that dietary salt restriction attenuates BP during isometric handgrip and dynamic lower body exercise^212,213 and that high salt augments BP during dynamic lower body exercise.¹⁵⁷ Importantly, exaggerated BP responses during physical stressors (e.g., acute exercise) are prognostic of hypertension risk, CV events, and CV mortality.^214–221 In summary, obesity and salt impair autonomic control of BP. However, it is unclear whether those with obesity are more susceptible to high salt-induced alterations in autonomic control of BP. Thus, future studies in this area are needed.

6 |. ADDITIONAL PHYSIOLOGICAL AND ENVIRONMENTAL FACTORS RELATED TO OBESITY AND HIGH SALT INTAKE

6.1 |. Renal function and insulin resistance

As highlighted above, the vasculature and autonomic nervous system contribute to many of the effects of obesity and dietary salt on BP and CV health. However, the kidneys and metabolism are also implicated in BP regulation and CV health and are influenced by obesity and high dietary salt. In this subsection, we will discuss the role of obesity and high salt intake on kidney function and metabolism, specifically insulin and leptin resistance. The kidneys are critical for regulating BP by manipulating extracellular fluid volume via water and salt retention and excretion. Kidney dysfunction is characterized by impaired pressure natriuresis and is a hallmark of experimental models of salt-sensitive BP (i.e., resting BP changes from dietary salt manipulation) and human salt-sensitive hypertension.²²² We will also briefly discuss the influence of salt loading on the kidney and how this influences fluid volume regulation, with an emphasis on the RAAS. We will then discuss the role of insulin in salt retention and how obesity, as a result of energy overconsumption, is associated with insulin resistance and enhanced salt reabsorption.⁴⁵ Lastly, we will discuss the interplay between adipose, RAAS, and downstream regulation of autonomic control.

The classic view of the kidneys and salt sensitivity contends that BP is mathematically the product of cardiac output and total peripheral resistance. Short-term high salt intake increases thirst to promote fluid intake,^223,224 although long-term studies do not support increased thirst.^225,226 High salt-induced extracellular fluid volume expansion is thought to culminate in decreased RAAS (i.e., circulating angiotensin II and aldosterone) to counteract increased blood salt concentration and promote water excretion.²²⁷ Studies demonstrating that high salt diets elicit peripheral endothelial dysfunction support the idea of insufficient reductions in total peripheral resistance or vascular dysfunction.^{150–154,156,158,160,161,228}

The hormone insulin is secreted by the pancreatic beta cells in response to consuming a variety of nutrients. Under normal conditions, insulin has an essential role in metabolism by inhibiting hepatic glucose output and increasing glucose uptake in muscle and adipose tissue (Figure 6). The term “insulin resistance” refers to a decrease in a target organ’s (e.g., skeletal muscle) response to the metabolic actions of insulin.^45,229 Functionally, insulin resistance represents inadequate actions of circulating insulin to lower blood glucose concentration via multiple organ systems including skeletal muscle, the liver, adipose tissue, and the pancreas (eventual β-cell dysfunction).^45,230 Mechanistically, insulin resistance is mediated by enhanced oxidative stress and inflammation, with the mitochondria being at least partially involved in this pathology.^{45,228,231,232}

FIGURE 6.

Mechanisms of obesity and excess dietary salt affecting kidney function and insulin sensitivity.

A less appreciated role of insulin and insulin resistance in the context of obesity and hypertension is the role of insulin on kidney function.^233,234 Indeed, insulin stimulates sodium transport in the kidney.²³³ This is mediated by insulin receptors throughout the nephron segments including the proximal tubule, thick ascending limb, and distal tubule/collecting duct.^229,233,235 Further, there is a notable role in the antinatriuretic actions of insulin (Figure 6).^236,237 For example, in chronically instrumented dogs with type 1 diabetes, a 6-day uncontrolled diabetes challenge (removal of insulin therapy) elicited both hyperglycemia and increased natriuresis. However, hyperglycemia in the context of continued insulin treatment largely prevented an increase in natriuresis and renal plasma flow after the initial 24 h, demonstrating a sustained antinatriuretic effect of insulin.²³⁸ Moreover, salt-sensitive rodent models are insulin resistant compared to their salt-resistant counterparts.^232,239 Specifically, compared to salt-sensitive rodents, salt-resistant rodents exhibit increased fasting plasma insulin even before salt loading and develop insulin resistance even on normal salt diets.²³⁹ While there is a relatively large amount of literature on hyperinsulinemia being associated with hypertension, there is not substantial evidence that this relation is mediated by salt retention in the absence of obesity and/or metabolic syndrome.^240,241 For example, lean hyperinsulinemic rats do not necessarily experience elevations in BP but still have a heightened salt sensitivity to acute saline loading. Interestingly, they do not exhibit an associated increase in sodium retention.²⁴² In contrast, hyperinsulinemia is associated with salt retention and hypertension in the context of obesity and metabolic syndrome.²⁴³

Hyperinsulinemia in the context of metabolic syndrome and obesity may also contribute to sodium retention in humans.^236,240,241 Studies as early as the 1930s demonstrated that stopping insulin therapy in individuals with type 1 diabetes increases sodium excretion that could be reversed when insulin administration resumed.^237,244 It is important to note that these data were confounded by concomitant changes in extracellular fluid volume, glomerular filtration rate, and renal plasma flow.²³⁷ Nonetheless, carbohydrate refeeding after fasting elicits postprandial sodium retention in humans, irrespective of obesity,^245,246 although this supposedly causal relation between insulin and sodium excretion can be confounded by concomitant postprandial glycemia, which also influences natriuresis. Notably, intravenous insulin administration acutely reduces urinary sodium excretion despite no changes in blood glucose, glomerular filtration rate, or renal blood flow in male participants with a healthy BMI.²⁴⁶ Furthermore, observational data demonstrate insulin resistance and long-term sodium retention in adolescents with obesity²⁴¹ as well as patients with type 2 diabetes²⁴⁰ and hyperlipidemia²⁴² who exhibit excess skin sodium storage relative to lean individuals. Thus, it is plausible that adults with obesity store excess sodium in the skin because of insulin resistance and chronic excess sodium consumption. However, prospective dietary salt studies are needed to determine whether individuals with obesity are more prone to store excess sodium in the skin following high dietary salt.

As previously summarized,²⁴³ it is important to highlight that high salt may increase the risk of obesity and metabolic syndrome due to endogenous fructose generation (through the polyol pathway), vasopressin stimulation, and interactions with the vasopressin 1b receptor.²⁴⁷ Moreover, high salt intake may elicit T-cell infiltration in the kidney, resulting in renal vasoconstriction.^248,249 Thus, understanding the role of sodium storage, as mediated by the kidney, and sodium’s role in inflammation is key factors to be explored. Another potential mechanism suggested to mediate obesity-induced autonomic CV dysregulation is RAAS stimulation, more specifically adipocyte secretion of angiotensin. In rodents, afferent signaling from white adipose tissue raises circulating renin and angiotensin II.¹⁹³ Increased angiotensin II mediates insulin infusion-induced increases in lumbar sympathetic outflow following dietary salt loading.²⁵⁰ Additionally, dietary salt restriction reduces pro-inflammatory cytokines, RAAS gene expression, and BP in a rat model of metabolic syndrome, independent of weight loss.²⁵¹ Together, these studies suggest a role for the RAAS in mediating white adipose tissue-induced autonomic dysfunction, which may be exacerbated with high dietary salt. In humans, circulating angiotensinogen concentration is elevated in individuals with obesity.²⁵² Elevated circulating angiotensin II increases MSNA, demonstrating a potential interplay between inadequate RAAS suppression and altered sympathetic outflow, a contributor to BP.²⁵³ Further, angiotensinogen mRNA concentrations are higher in visceral compared to subcutaneous adipocytes,²⁵⁴ suggesting a potential mechanism that explains augmented autonomic CV dysfunction with central (i.e., visceral) obesity.^182,255,256 Indeed, angiotensin II receptor blockade lowers MSNA in adults with obesity and hypertension,²⁵⁷ suggesting a potential treatment strategy. Together, there appears to be strong evidence for the RAAS contributing to obesity-related hypertension. Thus, future investigations should elucidate the potential prevention and treatment strategies for excess body fat, specifically excess visceral fat, to limit autonomic CV dysregulation. A key challenge for research in this area is disentangling the complex interplay between obesity, type 2 diabetes, dyslipidemia, and hypertension, which commonly present together.

One proposed mechanism underlying obesity and increased CV disease risk is increased leptin production. Interestingly, dietary-salt-induced increases in circulating leptin seem to precede weight gain. Increased leptin production is associated with autonomic CV dysfunction.^258,259 Specifically, leptin may act on the PVN to stimulate autonomic preganglionic neurons.²⁶⁰ Conversely, leptin increases lumbar and renal sympathetic outflow as well as BP in rats.^261–265 Separate from obesity, high dietary salt also increases plasma leptin concentrations in rats.²⁶⁶ There is conflicting evidence for the role of dietary salt and leptin in raising BP, with one study in rats reporting that dietary salt does not modulate the BP-raising effect of chronic leptin infusions,²⁶¹ whereas another study in rabbits demonstrated that a high salt diet raised resting BP but abolished leptin infusion-induced increases in BP compared to a low salt diet.²⁶⁷ Because cerebrospinal and plasma leptin concentrations are highly correlated in humans,²⁶⁸ it is tempting to speculate leptin may act similarly to affect autonomic CV control in humans.²⁶⁹ However, circulating leptin concentrations in humans are not associated with higher resting MSNA,²⁷⁰ despite being associated with total²⁷¹ and renal norepinephrine spillover.^271,272 Further, leptin appears to be more dependent on subcutaneous compared with visceral fat stores in most,^180,270,273 but not all,²⁷⁴ studies. Taken together, it appears additional human data are needed regarding leptin and obesity-related autonomic CV dysfunction.²⁷⁵

6.2 |. Ultra-processed foods can contribute to the overconsumption of calories and dietary salt

Regarding associations between obesity and high dietary salt, rodent data indicate that high-salt diets increase white adipose tissue.^266,276 In humans, observational data demonstrate that high salt intake^{141,143,144,277} and salt density (i.e., grams of sodium per calorie consumed)¹⁴² are independently associated with obesity and metabolic syndrome. Conversely, obesity is associated with a preference for salty food.²⁷⁸ Accordingly, in this section, we discuss the relation between obesity and salt while highlighting that high dietary salt from ultra-processed food contributes to both overconsumption of calories and dietary salt. We are taking this approach because most dietary salt comes from pre-prepared foods (i.e., ultra-processed foods and restaurant foods).²⁷⁹

Ultra-processed food production and availability have likely contributed to the obesity epidemic along with several other factors noted above.²⁸⁰ Notably, ~60% of energy intake in the American diet is estimated to come from ultra-processed foods,²⁸¹ defined as foods with added salt, oil, or sugar with high energy density and low micronutrient density. Examples of ultra-processed foods include soft drinks, sweet or savory packaged snacks, reconstituted meat products, fast food meals, and pre-prepared frozen dishes (Figures 7 and 8).²⁸² Ultraprocessed foods contribute ~70% of dietary sodium for Americans relative to only 10% sodium added at the table or during food preparation at home.²⁷⁹ Interestingly, despite this, a higher frequency of adding salt to food at the table is associated with a higher risk of CV disease.²⁸³

FIGURE 7.

Sample menu for an entire day with sodium contents.

FIGURE 8.

Caloric contents of popular foods in the United States. We obtained nutritional information on each company’s website in November 2022. Ice cream−peanut butter cup; 2 servings; Ben & Jerry’s^®. Pizza−XL ultimate pepperoni; 2 slices; Domino’s^®. Cheeseburger & fries−double double; In-N-Out^®. Chicken burrito−with white rice, black beans, pinto beans, guacamole, sour cream, and cheese; Chiptole^®.

A recent metabolic ward study demonstrated that ad libitum consumption of total calories, calories from carbohydrates and fats, and dietary sodium was higher during the 14-day ultra-processed diet compared to the 14-day unprocessed diet (Figure 9). Participants were ~2 kg heavier on the final day of the ultra-processed compared with the unprocessed diet.²⁸⁴ Additionally, higher ultra-processed food consumption is associated with an increased risk of developing obesity,²⁸⁵ hypertension,²⁸⁶ and certain types of cancer.²⁸⁷ Alarmingly, ultra-processed foods are also associated with increased all-cause mortality.^288–290 Taken together, these findings demonstrate that ultra-processed foods may facilitate the development of cardiometabolic diseases and premature mortality. As we have previously reviewed,²⁹¹ the socioeconomic environments many Americans live in make reducing ultra-processed food consumption challenging.

FIGURE 9.

Comparing caloric, sodium, and macronutrient intake between ultra-processed food and unprocessed food diets in a metabolic ward, controlled feeding trial.²⁸⁴

In America, many people in lower socioeconomic positions and people living in predominately racially/ethnically minoritized neighborhoods reside in “food swamps,” areas with low access to fresh foods relative to ultra-processed food.²⁹² These areas present inadequate opportunities to consume minimally processed foods. Indeed, lower-income and predominantly minority neighborhoods have a lower density of supermarkets, and the supermarkets that are present are further away (i.e., “food deserts”).²⁹³ Additionally, the overall quality and variety of foods available at local convenience stores are lower than that of supermarkets.²⁹³ Part of the reason for the less healthful food available in lower-income neighborhoods may be due to food costs. A 2019 NIH inpatient feeding study reported that the average weekly cost to prepare a 2,000 kcal/day diet was $106 for an ultraprocessed food diet compared to $151 for an unprocessed food diet.²⁸⁴ Together, these reasons likely contribute to the higher prevalence of obesity for groups within the lowest socioeconomic positions.^294,295 Thus, there is an overwhelming rationale to prioritize efforts to address the issue of inequitable access to healthful food that is ultimately an upstream mediator of CV disease risk.

6.3 |. The influence of obesity on salt sensitivity

Both salt sensitivity and excess adiposity are associated with greater mortality. Importantly, salt sensitivity is a predictor of mortality independent of resting BP.^296,297 To date, there is limited evidence on the effects of excess body mass on salt sensitivity of BP, but there is strong plausibility of an association. As noted above, high absolute salt intake^141,143,144 and salt density¹⁴² are independently associated with obesity. Additionally, individuals with obesity are at increased risk for inadequate micronutrient intake (e.g., iron, calcium, magnesium, zinc, copper, folate, vitamin A, and vitamin B12) from high-energy density, nutrient-poor, ultra-processed foods.²⁹⁸ Therefore, an overall poorer diet (i.e., high in salt and deficient in many healthful vitamins and minerals) may contribute to a greater prevalence of salt sensitivity in many individuals with obesity. Obesity is also associated with several risk factors that may augment the negative CV effects of salt. Specifically, obesity is associated with elevated resting BP,^{193,299–301} reduced (i.e., worse) baroreflex sensitivity,^50,182,185 left-ventricular hypertrophy,³⁰⁰ and higher resting MSNA.^182,302,303 In fact, obesity explains a large portion of the relation between high dietary salt and elevated BP,^304,305 independent of total energy intake.³⁰⁶ Nonetheless, while the available data are sparse, there have been some experimental studies addressing the potential role of obesity on salt sensitivity.

Most of the limited published data suggest that salt sensitivity is associated with a higher BMI in adults without hypertension.^307–309 Central obesity is also associated with salt sensitivity in adults with essential hypertension.³¹⁰ In contrast, a study manipulating salt consumption did not find differences in salt sensitivity between individuals with combined obesity and hypertension, individuals with obesity but not hypertension, and lean adults without hypertension. However, the diets were hypocaloric (1,800 kcal/day) and potassium-rich (>3,600 mg/day).³⁰⁸ Given that hypocaloric diets and high potassium consumption³¹¹ likely offset some of the adverse effects of salt (i.e., NaCl), it is difficult to determine the role of obesity on salt sensitivity from these data. Future studies are warranted to address this knowledge gap given the mixed and sparse information in this area. There is also limited data on the relation between obesity and BP-independent effects of dietary salt (e.g., endothelial dysfunction and alterations in autonomic regulation) that should be addressed. Physiological outcomes of interest include endothelial function, arterial stiffness, resting/reflex sympathetic outflow, and renal function. Additionally, salt density is relatively stable across a range of energy intake amounts.³¹² Thus, individuals with higher caloric requirements likely consume more salt. Therefore, prospective studies should consider salt density as an additional independent variable to be examined. Lastly, prospective trials will be differentiating classes of obesity (i.e., class 1 vs. class 3 obesity), which have a stepwise association with comorbidities. Future trials will also disentangle the confounding influence of obstructive sleep apnea, metabolic syndrome, and type 2 diabetes mellitus.

7 |. CONCLUSION

In this review, we focused on two of the most critical public health challenges in most of the post-industrial world−obesity and excess dietary salt (Figure 10). Nearly 4 in 10 American adults have obesity, which independently contributes to the development of hypertension and CV-related mortality. Additionally, nearly 9 in 10 American adults overconsume dietary salt, which independently contributes to the development of hypertension and CV-related mortality. Here, we discussed both the independent and combined effects of obesity and excess dietary salt given their contributions to vascular dysfunction, autonomic CV dysregulation, renal dysfunction, and insulin resistance. Together, this information will provide a strong rationale for targets to prevent, manage, and treat BP dysregulation associated with obesity and high dietary salt that can contribute to elevated CV disease risk. In closing, obesity and high dietary salt have several potentially interactive deleterious effects on CV function. This review should provoke future mechanistic studies and randomized clinical trials to fill these high-priority knowledge gaps for high BP and CV disease, the leading cause of death worldwide.

FIGURE 10.

Summary. A proposed positive feedback loop relation between obesity and excess dietary salt intake on risk factors (e.g., blood pressure) for CVD. CVD, cardiovascular disease.

Abbreviations:

ADMA

asymmetric dimethylarginine

AHA

American Heart Association

BMI

body mass index

BP

blood pressure

CV

cardiovascular

DGA

Dietary Guidelines for Americans

eNOS

endothelial NO· synthase

HDL

high-density lipoprotein

H₂O₂

hydrogen peroxide

MSNA

muscle sympathetic nerve activity

NaCl

sodium chloride or salt

NO

nitric oxide

NOX

NADPH oxidase

O2−

superoxide

ONOO⁻

peroxynitrite

OVLT

organum vasculosum of the lamina terminalis

PVAT

periventricular adipose tissue

RAAS

renin angiotensin aldosterone system

ROS

reactive oxygen species

RVLM

rostral ventrolateral medulla

SOD

superoxide dismutase

TNFα

tumor necrosis factor α

WHO

World Health Organization