Modifiable Health Behaviors and Mitochondrial Oxidative Stress: A Dual Approach to Addressing Obesity and Cardiovascular Wellness

Abstract

Cardiovascular diseases (CVDs) remain one of the leading causes of mortality in the United States and worldwide[1, 2]. Elevated blood pressure (BP), or hypertension (HTN), is a significant risk factor and contributor to CVD[2, 3]. Additional risk factors for the development of HTN and CVD include excessive dietary sodium (Na+)[4, 5] and obesity[6]. High dietary Na+ is also associated with obesity, which may mediate some of the long-term consequences of high Na+ intake and the corresponding development of CVD[7, 8] HTN, obesity, and excessive dietary Na+ are considered modifiable risk factors in CVD development, and mediating these risk factors can subsequently decrease CVD risk. Unfortunately, there is an alarming trend in the United States indicating HTN, excess dietary Na+, and obesity prevalence have not improved in recent decades[2, 9]. In fact, nine out of ten American adults consume more than the 2300mg/day recommendation for daily intake of Na+, and four out of ten American adults are classified as obese[7]. Thus, there is a critical need for strategies to counteract and prevent HTN, reduce excess dietary Na+, and decrease obesity rates to reduce the burden of CVD in the United States. Dietary fiber intake impacts CVD development via several mechanisms. Increased dietary fiber is associated with reduced HTN risk and improved cardiovascular health[2]. Higher fiber intake is also inversely associated with obesity[10, 11]. Most Americans do not consume adequate amounts of daily fiber[12]. The standard American diet is comprised of a lot of ultra-processed foods containing excess Na+ and little to no fiber[13]. The manufacturing process includes adding excess Na+ for taste and shelf-life and typically removes the fiber from grain during the food processing[14, 15]. The mechanisms through which high Na+[16, 17] and obesity contribute to high BP and decreased vascular health include oxidative stress[18, 19], inflammation[20, 21] and reduced nitric oxide (NO) bioavailability[22, 23]. Dietary fiber impacts these mechanisms through the conversion by gut microbiota into short-chain fatty acids (SCFAs), which have antioxidant[24, 25] and anti-inflammatory properties[26]. Recent preclinical data indicate high dietary fiber or SCFAs can improve BP and cardiovascular health in the context of heart failure and HTN[27]. In humans, there is promising evidence of a SCFA-boosting prebiotic starch intake leading to an improvement in BP in patients with HTN[28]. These data suggest a potentially important interplay between Na+ and fiber for cardiometabolic health. There is also preclinical data demonstrating high Na+ intake impairs mitochondrial function by increasing BP, decreases ATP production, and increases oxidative stress, apoptosis, and calcium uptake[28]. Several studies also demonstrate mitochondrial-targeted antioxidants improving vascular health in older adults and patient populations[29-31]. While obesity is associated with higher oxidative stress[19], there is less information on the importance of mitochondrial-derived oxidative stress on vascular health in the context of obesity. Collectively, these data inform our two central hypotheses that 1) dietary Na+ indexed to fiber (i.e., Na+/Fiber) is associated with body composition and cardiovascular health, and 2) that mitochondrial oxidative stress contributes to poorer cardiovascular health in the context of obesity. We will test the hypotheses using two specific aims:

Specific Aim One: To determine whether Na+/Fiber is associated with body composition and cardiovascular health in apparently healthy adults. Hypothesis One: Higher Na+/Fiber from 3-day food and fluid records will be associated with higher body mass index (BMI), waist:hip, peripheral and central BP, increased (i.e., worse) arterial stiffening assessed via carotid-femoral pulse wave velocity (cfPWV), and reduced vascular function assessed via brachial artery flow-mediated dilation (FMD). Specific Aim Two: To determine whether mitochondrial oxidative stress contributes to impaired cardiovascular health in individuals with obesity. Hypothesis Two: An acute high dose of the mitochondrial antioxidant MitoQ will reduce peripheral BP, central BP, and cfPWV, and will improve FMD, in participants who are overweight and obese. This study identified distinct hemodynamic alterations in individuals with obesity, including elevated blood pressure and signs of vascular strain. Due to the relatively healthy nature of the cohort, MitoQ supplementation showed limited efficacy in improving vascular function. However, a novel contribution of this work is the identification of the dietary sodium-to-fiber (Na⁺/Fiber) ratio as a potential risk marker for cardiovascular health. These findings contribute to the growing body of literature highlighting the importance of early risk identification and targeted prevention strategies for improving cardiovascular outcomes.