1. Introduction
Approximately 1.39 billion people in the world have hypertension, the leading preventable risk factor for cardiovascular disease and all-cause mortality worldwide [1]. Hypertension can contribute to and cause both heart disease and stroke, the first and fifth leading causes of death in the United States as of 2017 [2]. Given these statistics, the importance of blood pressure (BP) control is evident. Currently, the American College of Cardiology/American Heart Association (ACC/AHA) defines normal BP as systolic < 120 mm Hg and diastolic < 80 mm Hg, with stage 1 hypertension starting at systolic BP of 130-139 mm Hg or diastolic BP of 80-89 mm Hg [3]. However, prior literature suggests that adverse effects on health can be seen even within the normal BP range. In a meta-analysis of nearly one million people without known vascular disease, a positive correlation was seen between vascular mortality and BPs above 115/75 [4]. This study also suggested that, for the general normotensive population, even consistent reductions of 2 mm Hg in systolic BP could result in large reductions of disabling strokes and premature deaths from vascular causes [4]. Another meta-analysis of 147 randomized controlled trials (RCTs) found that BPs above 110/70 were correlated with increased deaths from coronary heart disease (CHD) and stroke [5]. The authors suggested that some patients, although considered normotensive by conventional definitions, may benefit from treatment with antihypertensives to reduce this increased mortality risk [5].
Aside from prescription antihypertensives, there is ample literature regarding the BP-lowering ability of various nutraceuticals [6,7]. These nutraceuticals include vitamins (C, D, and E) and minerals (calcium, magnesium, and potassium). Studies have addressed both the mechanisms of action and efficacy of these nutraceuticals for BP reduction. Vitamins C and E are thought to mediate BP through antioxidant effects and enhancement of nitric oxide pathways that prevent endothelial dysfunction [8,9,10]. Vitamin D is a regulator of the renin-angiotensin-aldosterone system (RAAS) [11]. The mechanism underlying calcium is not well-understood but is suspected to be regulated by the parathyroid hormone, vitamin D, and RAAS systems [12]. Magnesium can affect BP by inducing vascular changes through the production of nitric oxide, by indirectly affecting intracellular calcium concentrations, and through the alteration of smooth muscle tone [13]. Finally, potassium exhibits a direct effect on BP via two mechanisms: by downregulation of the sodium-chloride cotransporter within the distal tubule of the kidneys leading to reduced reabsorption of sodium and chloride, as well as increasing activation of RAAS in response to high serum potassium levels [14].
The effectiveness of these six nutraceuticals in lowering BP, when taken as dietary supplements, has been the focus of numerous randomized controlled trials (RCTs) and meta-analyses. In fact, the most recently published meta-analyses suggest that all but vitamin D and calcium are capable of achieving a 2 mm Hg systolic BP reduction [15,16,17,18,19,20]. However, the majority of these meta-analyses have included RCTs where the supplements were used as first-line treatments among patients with uncontrolled hypertension. This limits the generalizability of BP reductions for normotensive patients and likely overestimates their true effect.
This study aims to investigate the effects of the above six nutraceuticals (Vitamins: C, D, E; Minerals: Calcium, Magnesium, Potassium) on systolic and diastolic BP in the general, normotensive population using a pairwise meta-analysis for each supplemental compared to placebo. We chose these six based on our prior knowledge of the literature. The overlap of supplements mentioned in the two aforementioned review articles on nutraceuticals with a blood pressure-lowering effect was also used in this decision [6,7]. Further, we used these review articles to confirm the presence of RCTs examining the effect of supplementation on BP to perform our analysis. We hypothesize finding similar efficacy of these nutraceuticals to what is seen in the most recent published meta-analyses of them. However, we also hypothesize our reductions will be lower than what they obtained because of our controlling for this population, thus excluding studies in which these supplements were used in solely hypertensive patients. To our knowledge, this will be the first study to investigate the effect of all six of these nutraceuticals amongst normotensive subjects in the general population within a single paper. We hope the availability of this data will aid clinicians and patients in determining the efficacy of these nutraceuticals and deciding whether any may be of benefit. Furthermore, it seeks to lay the foundation for future studies that may determine the optimal dosages, treatment length, and long-term safety profiles of these nutraceuticals in this population.