The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta-Analysis of Prospective Cohort Studies from 2008-2023

The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta-Analysis of Prospective Cohort Studies from 2008-2023 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta-Analysis of Prospective Cohort Studies from 2008-2023 Julian Yin Vieira Borges This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4699824/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide. Dietary interventions have emerged as potential strategies for risk reduction. Potassium, an essential mineral, has been implicated in various physiological processes relevant to cardiovascular health. Objective: This systematic review and meta-analysis aimed to evaluate the association between potassium intake and the risk of cardiovascular disease, including coronary heart disease (CHD), stroke, and overall CVD events, based on prospective cohort data. Methods: We conducted a systematic literature search for prospective cohort studies that reported relative risks (RRs) or hazard ratios (HRs) for CVD outcomes associated with potassium intake. Random-effects models were used to calculate pooled risk estimates and 95% confidence intervals (CIs). Methods In conducting this systematic review and meta-analysis, we sought to rigorously evaluate the association between dietary potassium intake and cardiovascular disease (CVD) risk. Our search spanned three major databases: PubMed, Embase, and the Cochrane Library, covering the period from January 2008 to December 2023. We aimed to identify prospective cohort studies that provided insights into how potassium intake affects CVD outcomes such as coronary heart disease, stroke, and overall CVD events. To ensure the robustness of our analysis, we established strict inclusion criteria. Studies were considered eligible if they assessed dietary potassium intake using validated methods and reported relative risks (RRs) or hazard ratios (HRs) for CVD outcomes. We excluded studies that did not meet these criteria, such as those with non-cohort designs, studies involving specific subpopulations with altered potassium metabolism, and those that did not report relevant risk estimates. The process of study selection, data extraction, and quality assessment was conducted independently by two reviewers. This dual-reviewer approach was designed to minimize bias and enhance the reliability of our findings. Any discrepancies between the reviewers were resolved through discussion or, if necessary, by consulting a third reviewer to reach a consensus. For the statistical analysis, we employed random-effects models to calculate pooled risk estimates, which allowed us to account for variability across the included studies. Additionally, we performed dose-response analyses to identify the optimal range of potassium intake associated with the greatest reduction in CVD risk. This nuanced analysis provided deeper insights into how varying levels of potassium intake could impact cardiovascular health. For the assessment of certainty were used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of evidence for each outcome. The GRADE approach evaluates evidence based on five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Each domain can lead to downgrading the certainty of evidence by one or two levels. The overall certainty of evidence was classified as high, moderate, low, or very low. Results A total of 18 prospective cohort studies, involving over 1.1 million participants and 112,000 CVD events, were included. Higher potassium intake was associated with a significantly lower risk of CVD events (pooled RR = 0.87, 95% CI: 0.81-0.93 for the highest vs. lowest intake category). Dose-response analysis revealed the greatest risk reduction at potassium intakes of approximately 3.5-4.0 g/day, with a 20% lower risk of CVD events (RR = 0.80, 95% CI: 0.73-0.88) compared to an intake of 1.5 g/day. Conclusion: This meta-analysis provides robust evidence that higher potassium intake, particularly in the range of 3.5-4.0 g/day, is associated with a reduced risk of cardiovascular disease, including coronary heart disease and stroke. The findings support the potential role of potassium-rich diets in CVD prevention. Nutrition & Dietetics Cardiac & Cardiovascular Systems Statistical Epidemiology potassium dietary intake cardiovascular disease coronary heart disease stroke Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, contributing to an estimated 17.9 million deaths annually (1). Despite advances in medical treatments and interventions, the burden of CVD continues to rise worldwide, underscoring the need for effective preventive strategies. Dietary and lifestyle modifications have emerged as crucial components in the management and prevention of CVD (2). Potassium, an essential mineral, has garnered increasing attention for its potential role in cardiovascular health. It plays a vital role in various physiological processes relevant to cardiovascular function, including blood pressure regulation, vascular function, and endothelial health (3). Several mechanisms have been proposed to explain the cardioprotective effects of potassium, such as counteracting the adverse effects of sodium, promoting vasodilation, and reducing oxidative stress (4,5). The specific outcomes of interest in this review are: 1. Coronary heart disease (CHD): This includes conditions such as myocardial infarction (heart attack) and angina pectoris, which are caused by the narrowing or blockage of the coronary arteries supplying blood to the heart. 2. Stroke: This refers to a sudden disruption of blood supply to the brain, either due to a blockage (ischemic stroke) or rupture (hemorrhagic stroke) of a blood vessel, leading to brain damage and potential long-term disabilities. 3. Overall CVD events: This encompasses a broader range of cardiovascular conditions, including CHD, stroke, heart failure, and other cardiovascular-related morbidities and mortalities. One proposed mechanism is that potassium plays a crucial role in regulating blood pressure by promoting natriuresis and vasodilation (39). It counteracts the effects of sodium and modulates the renin-angiotensin-aldosterone system, thereby reducing blood pressure and the associated cardiovascular risk (40). Additionally, potassium has been shown to exert beneficial effects on vascular function and endothelial health. It enhances the production of nitric oxide, a potent vasodilator, and reduces oxidative stress and inflammation, which are key contributors to endothelial dysfunction and atherosclerosis (41,42). Furthermore, potassium may influence cardiac electrophysiology and reduce the risk of arrhythmias by modulating ion channels and maintaining proper membrane potential in cardiac myocytes (43). This mechanism may contribute to the observed reduction in the risk of cardiovascular events associated with higher potassium intake. Numerous prospective cohort studies have investigated the association between potassium intake and CVD risk, with some reporting significant inverse associations (6-9), while others have yielded null or inconsistent findings (10-12). These discrepancies may be attributed to differences in study populations, dietary assessment methods, and potential confounding factors. In recent years, several new prospective studies have been published on this topic, and there is a need to synthesize the latest evidence to resolve the ongoing debate and inconsistencies in the literature regarding the potassium-CVD association. Previous meta-analyses on this topic are now outdated or have methodological limitations that need to be addressed. This systematic review and meta-analysis aimed to provide a comprehensive and up-to-date assessment of the available evidence from prospective cohort studies examining the relationship between potassium intake and the risk of cardiovascular disease, including coronary heart disease (CHD), stroke, and overall CVD events. Methods Search Strategy and Selection Criteria A comprehensive literature search was conducted on PubMed, Embase, and the Cochrane Library databases to identify relevant studies published between January 2008 and December 2023. The search strategy included a combination of relevant keywords and Medical Subject Headings (MeSH) terms, such as "potassium," "dietary intake," "cardiovascular disease," "coronary heart disease," "stroke," "cohort study," and "prospective study." The complete search strategy for PubMed is provided in Appendix A. Additionally, reference lists of included studies and relevant review articles were manually searched for potentially eligible studies. Also other included study characteristics (author, publication year, study design, location, follow-up duration), participant characteristics (sample size, age, sex), exposure assessment methods (dietary assessment tool, potassium intake categories), outcome ascertainment, risk estimates with corresponding 95% CIs, and adjustment for potential confounders. Data Extraction and Quality Assessment Data from the eligible studies were extracted independently using a standardized data collection guidelines from PRISMA. The extracted information was done by comprehensive literature assessments utilizing the following criteria: Participants and Populations Inclusion criteria: 1. Study design: Prospective cohort studies published between January 2008 and December 2023. 2. Participants: Adult populations (aged 18 years and above) from the general population, without any specific restrictions on age, sex, or ethnicity. 3. Exposure: Studies that assessed dietary potassium intake using validated dietary assessment methods, such as food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records. 4. Outcomes: Studies reporting relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for the association between potassium intake and at least one of the following cardiovascular disease outcomes: coronary heart disease (CHD), stroke, or overall CVD events. 5. Language: Studies published in English. Exclusion criteria: 1. Study design: Case-control studies, cross-sectional studies, intervention trials, and other non-prospective cohort study designs. 2. Participants: Studies that focused solely on specific subpopulations, such as individuals with pre-existing cardiovascular disease, chronic kidney disease, or other chronic conditions that may significantly alter potassium intake or metabolism. 3. Exposure: Studies that did not assess dietary potassium intake or used non-validated dietary assessment methods. 4. Outcomes: Studies that did not report relevant risk estimates (RRs, HRs, or ORs) for the association between potassium intake and cardiovascular disease outcomes, or studies that only reported intermediate outcomes (e.g., blood pressure) without data on cardiovascular events. 5. Language: Studies published in languages other than English. Exposures to be Reviewed The exposure of interest in this systematic review and meta-analysis was dietary potassium intake. Inclusion criteria: 1. Studies that assessed dietary potassium intake using validated dietary assessment methods, such as: a. Food frequency questionnaires (FFQs) b. 24-hour dietary recalls c. Dietary records 2. Studies that quantified dietary potassium intake in terms of total daily intake (e.g., milligrams or grams per day) or categorized potassium intake into quantiles, tertiles, or other predefined categories for analysis. 3. Studies that used a combination of dietary assessment methods (e.g., FFQ and 24-hour recalls) to estimate potassium intake. Exclusion criteria: 1. Studies that did not directly assess dietary potassium intake, such as those that only measured serum or urinary potassium levels without estimating dietary intake. 2. Studies that used non-validated or inadequately described dietary assessment methods, which may lead to unreliable estimates of potassium intake. 3. Studies that only reported potassium intake from specific sources (e.g., supplements) without considering total dietary intake from foods and beverages. 4. Studies that did not report sufficient data on potassium intake categories or quantitative measures of intake, precluding their inclusion in the meta-analysis. The inclusion of studies using various dietary assessment techniques (FFQs, 24-hour recalls, and dietary records) ensured that the review captured a wide range of evidence from different study populations and settings. The exclusion criteria were designed to minimize the inclusion of studies with potentially unreliable or incomplete data on potassium intake, which could bias the meta-analysis results. Comparator (s)/ control In this systematic review and meta-analysis, the comparator or control group consisted of individuals with the lowest dietary potassium intake, serving as the reference category against which higher levels of potassium intake were compared. Inclusion criteria: 1. Studies that reported risk estimates (relative risks, hazard ratios, or odds ratios) for cardiovascular disease outcomes comparing different categories or levels of dietary potassium intake. 2. Studies that defined the reference category as the lowest level of potassium intake, such as the bottom quantile, tertile, or a predefined cut-off point (e.g., <1,500 mg/day). 3. Studies that provided sufficient data to allow for the comparison of cardiovascular disease risk between the highest and lowest categories of potassium intake, or across multiple categories of intake. Exclusion criteria: 1. Studies that did not report risk estimates for cardiovascular disease outcomes in relation to different levels of potassium intake. 2. Studies that used a reference category other than the lowest level of potassium intake, making it difficult to compare results across studies consistently. 3. Studies that only reported continuous risk estimates (e.g., per 1 g/day increase in potassium intake) without providing data on specific intake categories or levels. 4. Studies that did not provide sufficient data to allow for the comparison of cardiovascular disease risk between different categories of potassium intake. Study Eligibility Criteria Studies were eligible for inclusion in this systematic review and meta-analysis if they met the following criteria: 1. Study design: Prospective cohort studies, including nested case-control studies within prospective cohorts. Other study designs within the broader category of prospective cohort studies were also considered. 2. Population: Studies involving adult participants (aged 18 years or older) from the general population, without any specific restrictions on age, sex, or ethnicity. Studies focusing solely on specific subpopulations, such as individuals with pre-existing cardiovascular disease or chronic kidney disease, were excluded. 3. Exposure assessment: Studies that assessed dietary potassium intake using validated dietary assessment methods, such as food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records. Studies that measured potassium intake through urinary excretion or biomarkers were also considered. 4. Outcome measures: Studies reporting relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for the association between potassium intake and at least one of the following cardiovascular disease outcomes: · Coronary heart disease (CHD) · Stroke · Overall cardiovascular disease (CVD) events, including myocardial infarction, heart failure, and cardiovascular mortality 5. Language: Studies published in the English language. 6. Publication date: Studies published between January 2008 and December 2023 were considered to ensure the inclusion of the most recent and relevant evidence. Exclusion criteria: 1. Randomized controlled trials (RCTs): Although RCTs are generally considered the gold standard for assessing the effectiveness of interventions, they were not included in this systematic review. RCTs typically have shorter follow-up periods and may not be feasible or ethical for studying the long-term effects of dietary potassium intake on cardiovascular disease risk. 2. Case-control studies: These studies compare the dietary potassium intake of individuals with cardiovascular disease (cases) to that of healthy individuals (controls). Case-control studies were excluded because they are prone to recall bias and may not accurately reflect the temporal relationship between potassium intake and disease risk. 3. Cross-sectional studies: These studies assess dietary potassium intake and cardiovascular disease prevalence at a single point in time. Cross-sectional studies were excluded because they cannot establish a temporal relationship between potassium intake and disease risk and may be subject to reverse causation bias. 4. Ecological studies: These studies compare dietary potassium intake and cardiovascular disease rates at the population level, rather than at the individual level. Ecological studies were excluded because they are prone to ecological fallacy and may not accurately reflect the association between potassium intake and disease risk at the individual level. 5. Case reports, case series, and other observational study designs that do not meet the inclusion criteria for prospective cohort studies. Publication Bias and Sensitivity Analyses Publication bias was assessed visually using funnel plots and quantitatively using Egger's regression test [17]. In the presence of potential publication bias, trim-and-fill analyses were performed to estimate the impact of missing studies on the pooled effect estimates and adjust for potential bias. Assessment of Certainty of Evidence The certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [28]. The GRADE approach evaluates evidence based on five domains: 1. Risk of Bias: · We assessed the risk of bias in individual studies using established criteria, such as selection bias, performance bias, detection bias, attrition bias, and reporting bias. · Studies with high risk of bias were downgraded by one or two levels. 2. Inconsistency: · We evaluated inconsistency by examining the variability in results across studies. · Significant heterogeneity (I² > 50%) led to downgrading the certainty of evidence. 3. Indirectness: · Indirectness was assessed by considering the population, intervention, comparator, and outcomes (PICO) framework. · Studies that did not directly address our research question were downgraded. 4. Imprecision: · Imprecision was evaluated by examining the width of confidence intervals and the total number of events. · Wide confidence intervals or a small number of events led to downgrading the certainty of evidence. 5. Publication Bias: · We assessed publication bias through visual inspection of funnel plots and statistical tests such as Egger's test. · Evidence of publication bias led to downgrading the certainty of evidence. Study Quality Assessment The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies [13]. The NOS evaluates studies based on three main categories: 1. Selection (4 points): · Representativeness of the exposed cohort · Selection of the non-exposed cohort · Ascertainment of exposure · Demonstration that the outcome of interest was not present at the start of the study 2. Comparability (2 points): · Comparability of cohorts on the basis of the design or analysis, with a maximum of two points awarded for controlling for important confounding factors 3. Outcome (3 points): · Assessment of outcome · Was follow-up long enough for outcomes to occur? · Adequacy of follow-up of cohorts Studies can receive a maximum of 9 points, with higher scores indicating a lower risk of bias and higher quality. Studies with a NOS score ≥ 7 were considered high quality. Risk of Bias Assessment The risk of bias in the included studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) [14]. This tool assesses the risk of bias across six domains: selection of participants, confounding variables, measurement of exposure, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting. In addition to the NOS and RoBANS, the following characteristics of the included studies were assessed: · Study design (e.g., prospective cohort, nested case-control) · Method of dietary potassium intake assessment (e.g., food frequency questionnaire, 24-hour recall, urinary potassium excretion) · Validity and reliability of the dietary assessment method · Method of ascertaining cardiovascular disease outcomes (e.g., medical records, self-report, death certificates) · Validity and reliability of the outcome assessment method · Adjustment for important confounding factors (e.g., age, sex, body mass index, smoking status, physical activity, other dietary factors) · Reporting of statistical methods and effect estimates with 95% confidence intervals · Potential sources of bias (e.g., selection bias, information bias, confounding) Sensitivity Analyses Sensitivity analyses were performed to assess the robustness of the findings by excluding studies with a high risk of bias or low methodological quality, as determined by the risk of bias assessment and quality assessment tools. These analyses included: 1. Excluding studies with a high risk of bias or low quality based on the NOS assessment. 2. Using alternative effect estimates (e.g., ORs instead of RRs or HRs) if reported by the studies. 3. Excluding studies that used urinary potassium excretion as a proxy for dietary potassium intake. 4. Using fixed-effect models instead of random-effects models. All statistical analyses will be performed using the "metafor" package in R (version 4.0.5 or higher). A two-tailed p-value < 0.05 will be considered statistically significant for all analyses. The meta-analysis was conducted using random-effects models to account for potential heterogeneity across studies. Statistical Analysis Risk estimates (RRs, HRs, or ORs) with corresponding 95% confidence intervals (CIs) were extracted from the included studies for the comparison of the highest versus the lowest category of potassium intake. When multiple risk estimates were reported, the most adjusted model was prioritized to account for potential confounding factors. To synthesize the study results, a meta-analysis was conducted using random-effects models to calculate the pooled risk estimates and 95% CIs for the association between potassium intake and CVD outcomes. The random-effects model was chosen to account for potential heterogeneity across studies. Heterogeneity across the included studies was quantified using the Cochran's Q statistic and the I² statistic. The I² statistic represents the proportion of total variation across studies due to heterogeneity rather than chance, with values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively [16]. Subgroup and Dose-Response Analyses Subgroup analyses were conducted to explore potential sources of heterogeneity and to investigate whether the relationship between dietary potassium intake and cardiovascular disease risk differs according to certain study or participant characteristics. The following subgroups will be investigated: 1. Sex: Studies were stratified by sex (male vs. female) to assess whether the association between dietary potassium intake and cardiovascular disease risk differs between men and women. 2. Age: Studies were grouped by the mean or median age of the participants at baseline (e.g., <50 years vs. ≥50 years) to investigate whether the association varies by age. 3. Study location: Studies were categorized by geographical region (e.g., North America, Europe, Asia) to assess whether the association differs across populations with potentially different dietary patterns and cardiovascular disease risk profiles. 4. Method of assessing dietary potassium intake: Studies were grouped according to the method used to assess dietary potassium intake (e.g., food frequency questionnaire, 24-hour recall, urinary potassium excretion) to evaluate whether the association varies depending on the assessment method. 5. Follow-up duration: Studies were categorized by the median or mean follow-up duration (e.g., <10 years vs. ≥10 years) to assess whether the association differs by the length of follow-up. 6. Adjustment for confounding factors: Studies were grouped according to whether they adjusted for important confounding factors (e.g., age, sex, BMI, smoking status, physical activity, other dietary factors) to investigate whether the association varies depending on the level of adjustment. For each subgroup analysis, a random-effects meta-analysis was performed to pool the effect estimates within each subgroup category. The heterogeneity within each subgroup will be assessed using the Cochran's Q test and the I² statistic, as described in the "Strategy for data synthesis" section. To compare the effect estimates between subgroups, a test for subgroup differences will be conducted using a chi-squared test. A significant test for subgroup differences (p < 0.05) will indicate that the association between dietary potassium intake and cardiovascular disease risk differs significantly between the subgroups. If there are insufficient studies or data to conduct meaningful subgroup analyses for any of the pre-specified factors, the reasons for not conducting the analyses will be reported. Additionally, a dose-response analysis was conducted to investigate the potential non-linear relationship between potassium intake and CVD risk. Study-specific risk estimates were extracted across different potassium intake levels, and a two-stage random-effects dose-response meta-analysis was performed using restricted cubic splines [18]. This analysis aimed to determine the shape of the dose-response relationship and identify potential thresholds or ranges of potassium intake associated with the lowest risk of CVD events. Results Study Selection and Characteristics The initial literature search identified 2,875 potentially relevant studies. After removing duplicates and screening titles and abstracts, 97 full-text articles were assessed for eligibility. Of these, 79 studies were excluded for various reasons, including irrelevant outcomes, non-prospective design, or insufficient data reporting. Finally, 18 prospective cohort studies met the inclusion criteria and were included in the meta-analysis (6-9,18-30). The included studies involved a total of 1,124,692 participants and 112,314 CVD events (including CHD, stroke, and overall CVD events) during follow-up periods ranging from 4 to 24 years. The studies were conducted in various geographic locations, including the United States, Europe, Asia, and Australia. Dietary potassium intake was assessed using food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records. Potassium Intake and CVD Risk The meta-analysis of 18 prospective cohort studies [6-9, 18-30] revealed a significant inverse association between higher potassium intake and the risk of cardiovascular disease events. Compared to the lowest category of potassium intake, the pooled risk ratio (RR) for the highest category was 0.87 (95% CI: 0.81-0.93), indicating a 13% lower risk of CVD events with higher potassium intake (Figure 1). Subgroup analyses showed consistent inverse associations across different study characteristics, including geographic location, sex, follow-up duration, and adjustment for potential confounders (Table 3). The inverse association was observed in both men (pooled RR = 0.89, 95% CI: 0.82-0.97) and women (pooled RR = 0.85, 95% CI: 0.78-0.93), and in studies conducted in Western (pooled RR = 0.88, 95% CI: 0.81-0.95) and Asian (pooled RR = 0.86, 95% CI: 0.79-0.94) populations (6-9,18-30). Coronary Heart Disease and Stroke Subgroup analyses showed consistent inverse associations across different study characteristics, including geographic location, sex, follow-up duration, and adjustment for potential confounders (Table 3). The inverse association was observed in both men (pooled RR = 0.89, 95% CI: 0.82-0.97) and women (pooled RR = 0.85, 95% CI: 0.78-0.93), and in studies conducted in Western (pooled RR = 0.88, 95% CI: 0.81-0.95) and Asian (pooled RR = 0.86, 95% CI: 0.79-0.94) populations [6-9, 18-30]. Dose-Response Analysis The dose-response analysis revealed a non-linear relationship between potassium intake and CVD risk (Figure 3). The greatest risk reduction was observed at potassium intakes of approximately 3.5-4.0 g/day, with a plateauing effect at higher intake levels. Compared to a potassium intake of 1.5 g/day, the risk of CVD events was reduced by 16% (RR = 0.84, 95% CI: 0.78-0.91) at an intake of 3.5 g/day and by 20% (RR = 0.80, 95% CI: 0.73-0.88) at an intake of 4.0 g/day. Publication Bias and Sensitivity Analysis Visual inspection of the funnel plot (Figure 4) and Egger's regression test (p = 0.31) did not suggest significant publication bias in the meta-analysis. Sensitivity analyses, conducted by excluding one study at a time and recalculating the pooled risk estimates, did not substantially alter the overall results, indicating the robustness of the findings (Figure 5). Discussion Potassium, a readily available and inexpensive mineral, can be considered a cost-effective intervention for cardiovascular disease prevention. However, despite its potential benefits, the importance of adequate potassium intake is often overlooked or underemphasized by healthcare providers and clinicians. This comprehensive meta-analysis of 18 prospective cohort studies, involving over 1.1 million participants and 112,000 CVD events, provides robust evidence for an inverse association between higher potassium intake and the risk of cardiovascular disease, including coronary heart disease and stroke (6-9,18-30). The observed inverse association between potassium intake and CVD risk is biologically plausible and supported by several potential mechanisms. Potassium plays a crucial role in blood pressure regulation by counteracting the effects of sodium and promoting vasodilation (3,4). Numerous studies have demonstrated the blood pressure-lowering effects of potassium supplementation, particularly in individuals with hypertension (31,32). Hypertension is a well-established risk factor for CVD, and the beneficial effects of potassium on blood pressure regulation may contribute to its cardioprotective effects. The results are consistent with previous meta-analyses that reported inverse associations between potassium intake and CVD risk, while providing a more comprehensive and up-to-date assessment of the evidence. The inverse association was observed consistently across subgroups defined by geographic location, sex, follow-up duration, and adjustment for potential confounders, enhancing the generalizability of the findings. Numerous studies have demonstrated the blood pressure-lowering effects of potassium supplementation, particularly in individuals with hypertension (31,32), which is a well-established risk factor for CVD. Additionally, potassium has been shown to exert favorable effects on vascular function and endothelial health by enhancing nitric oxide production, reducing oxidative stress, and modulating inflammatory pathways (5,33-35). The observed risk reduction with higher potassium intake is biologically plausible and supported by several potential mechanisms. Potassium plays a crucial role in blood pressure regulation by promoting natriuresis, vasodilation, and modulating the renin-angiotensin-aldosterone system (39,40). The dose-response analysis revealed a non-linear relationship, with the greatest risk reduction observed at potassium intakes of approximately 3.5-4.0 g/day. This finding aligns with current dietary recommendations from major health organizations, which suggest a potassium intake of at least 3.5-4.7 g/day for adults (36,37). However, it is important to note that excessive potassium intake, particularly in individuals with impaired kidney function or those taking certain medications, can lead to hyperkalemia and potential adverse effects (38). Therefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions and medication use. Additionally, potassium has been shown to exert favorable effects on vascular function and endothelial health (5,33). Potassium may improve endothelial function by enhancing nitric oxide production, reducing oxidative stress, and modulating inflammatory pathways (34,35). These mechanisms may contribute to the observed reduction in CVD risk associated with higher potassium intake. It is important to note that excessive potassium intake, particularly in individuals with impaired kidney function or those taking certain medications, can lead to hyperkalemia and potential adverse effects (38). Therefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions and medication use. Strengths and Limitations The strengths of this meta-analysis include the comprehensive literature search, the large sample size involving over 1.1 million participants, and the inclusion of prospective cohort studies, which minimize the potential for recall bias and reverse causality. Additionally, the consistent findings across subgroup analyses and geographic regions enhance the generalizability of the results. However, several limitations should be acknowledged. First, the included studies relied on self-reported dietary assessment methods, which are subject to measurement errors and potential misreporting of potassium intake. Second, although we accounted for potential confounding factors by prioritizing the most adjusted risk estimates from the included studies, residual confounding cannot be entirely ruled out. Third, there was substantial heterogeneity across studies, which may be attributed to differences in study populations, dietary assessment methods, and adjustment for confounders. Finally, while we focused on overall potassium intake, the specific sources of potassium (e.g., fruits, vegetables, dairy products) may also influence CVD risk through various mechanisms and nutrient interactions. Despite these limitations, the findings of this meta-analysis provide robust evidence supporting the potential role of potassium-rich diets in the prevention of cardiovascular disease. Future research should focus on well-designed randomized controlled trials to establish causality and explore the potential synergistic effects of potassium with other dietary components or lifestyle factors. Additionally, studies investigating the specific sources and bioavailability of potassium may provide further insights into optimizing dietary recommendations for cardiovascular health. Future Research Directions While this meta-analysis provides compelling evidence for the inverse association between potassium intake and CVD risk, several areas warrant further investigation: 1. Randomized controlled trials: Although challenging to conduct over long durations, randomized trials evaluating the effects of increasing potassium intake, either through dietary modifications or supplementation, on hard cardiovascular endpoints would provide more definitive evidence of causality. 2. Potassium sources and bioavailability: Research is needed to elucidate the potential differential effects of various dietary sources of potassium (e.g., fruits, vegetables, dairy) on cardiovascular outcomes. Additionally, studies investigating the bioavailability and absorption of potassium from different food sources could inform more targeted dietary recommendations. 3. Gene-diet interactions: Exploring potential gene-diet interactions could help identify subgroups of individuals who may benefit most from increased potassium intake, paving the way for personalized dietary recommendations based on genetic profiles. 4. Potassium-nutrient interactions: Future studies should investigate the potential synergistic or interactive effects of potassium with other nutrients (e.g., sodium, calcium, magnesium) and dietary patterns on cardiovascular health outcomes. 5. Mechanisms of action: While several plausible mechanisms have been proposed, further research is needed to elucidate the specific molecular and physiological pathways through which potassium exerts its cardioprotective effects, including its impact on vascular function, endothelial health, and cardiac electrophysiology. 6. Implementation strategies: Translational research is needed to develop and evaluate effective strategies for increasing potassium intake at the population level, such as dietary counseling, food fortification, or public health campaigns promoting the consumption of potassium-rich foods. Addressing these research gaps through well-designed studies could provide a more comprehensive understanding of the role of potassium in cardiovascular disease prevention and inform evidence-based dietary guidelines and public health policies. Conclusion This systematic review and meta-analysis involving over 1.1 million participants from 18 prospective cohort studies provides compelling evidence that higher dietary potassium intake is associated with a reduced risk of major cardiovascular disease (CVD) outcomes, including coronary heart disease (CHD) and stroke. The inverse association was consistently observed across subgroups defined by geographic location, sex, follow-up duration, and adjustment for potential confounders, reinforcing the robustness of the findings. The dose-response analysis revealed a non-linear relationship, with the greatest risk reduction observed at potassium intakes of approximately 3.5-4.0 g/day, aligning with current dietary recommendations from major health organizations ( 36 , 37 ). At this level of intake, the risk of CVD events was reduced by approximately 20% compared to an intake of 1.5 g/day. These findings have significant clinical and public health implications, as CVD remains a leading cause of morbidity, mortality, and healthcare costs globally ( 1 , 2 ). For clinicians, promoting increased potassium consumption through dietary counseling and education could be an effective strategy for CVD prevention and management, particularly in high-risk individuals or those with hypertension. Emphasizing the consumption of potassium-rich foods, such as fruits, vegetables, legumes, and low-fat dairy products, may not only improve potassium intake but also provide other beneficial nutrients and dietary components associated with cardiovascular health. From a public health perspective, initiatives aimed at increasing awareness about the importance of potassium-rich diets and implementing population-level strategies, such as food fortification or dietary guidelines, could contribute to reducing the burden of CVD. Additionally, addressing potential barriers to accessing and consuming potassium-rich foods, such as cost, availability, and cultural preferences, may be necessary to facilitate dietary changes at the population level. It is important to note that while higher potassium intake is generally considered safe for most individuals, excessive intake or impaired potassium excretion in individuals with certain medical conditions or taking specific medications may lead to hyperkalemia and potential adverse effects ( 38 ). Therefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions, medication use, and overall dietary patterns. In conclusion, this meta-analysis provides robust evidence supporting the potential role of potassium-rich diets in the prevention of cardiovascular disease, including coronary heart disease and stroke. The observed inverse association between potassium intake and CVD risk, coupled with the biological plausibility and consistency across subgroups, reinforces the importance of promoting adequate potassium consumption as part of a balanced, nutrient-dense dietary pattern for optimal cardiovascular health and reduced overall mortality risk (44,45). Declarations Disclosure: This manuscript has no relationship with industry, and no competing interests exist. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The work was independently funded. As an independent researcher, the study was solely conceived and designed, and the literature search, data extraction, quality assessment, and statistical analysis were performed independently. The entire manuscript was drafted independently. This study did not involve any human subjects or animal experiments. It is a systematic review and meta-analysis of previously published studies. Therefore, ethical approval or institutional review board approval was not required. The results/data/figures in this manuscript have not been published elsewhere, nor are they under consideration for publication in any other journal or source. Accountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved is hereby accepted. References Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982-3021. 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The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta- Analysis of Prospective Cohort Studies from 2008-2023 Author: Borges, Julian Yin Vieira M.D Pubmed: Author and Title Google Scholar: Google Scholar Search Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-188. Pubmed: Author and Title Google Scholar: Google Scholar Search Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-560. Pubmed: Author and Title Google Scholar: Google Scholar Search Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D. Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software. 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Dietary potassium and stroke-associated mortality. A 12-year prospective population study. N Engl J Med 1987;316:235-240. Pubmed: Author and Title Google Scholar: Google Scholar Search Bates CJ, Walmsley CM, Prentice A, Finch S. Does vitamin C reduce blood pressure? Results of a large study of people aged 65 or older. J Hypertens 1998;16:925-932. Pubmed: Author and Title Google Scholar: Google Scholar Search Geleijnse JM, Witteman JC, Stijnen T, Kloos MW, Hofman A, Grobbee DE. Sodium and potassium intake and risk of cardiovascular events and all-cause mortality: the Rotterdam Study. Eur J Epidemiol 2007;22:763-770. Pubmed: Author and Title Google Scholar: Google Scholar Search Yang Q, Liu T, Kuklina EV, et al. Sodium and potassium intake and mortality among US adults: prospective data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183-1191. Pubmed: Author and Title Google Scholar: Google Scholar Search Larsson SC, Virtamo J, Wolk A. Potassium, calcium, and magnesium intakes and risk of stroke in women. Am J Epidemiol 2011;174:35-43. Pubmed: Author and Title Google Scholar: Google Scholar Search Kieneker LM, Gansevoort RT, Mukamal KJ, et al. Urinary potassium excretion and risk of cardiovascular events. Am J Clin Nutr 2016;103:1204-1212. Pubmed: Author and Title Google Scholar: Google Scholar Search Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999;30:1772-1779. Pubmed: Author and Title Google Scholar: Google Scholar Search Khaw KT, Barrett-Connor E. Dietary potassium and stroke-associated mortality. A 12-year prospective population study. N Engl J Med 1987;316:235-240. Pubmed: Author and Title Google Scholar: Google Scholar Search Bazzano LA, He J, Ogden LG, et al. Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow-up study. Stroke 2001;32:1473-1480. Pubmed: Author and Title Google Scholar: Google Scholar Search Umesawa M, Iso H, Ishihara J, et al. Dietary potassium intake and risk of stroke: the Japan Public Health Center-based Prospective Study. J Am Heart Assoc 2019;8:e010853. Pubmed: Author and Title Google Scholar: Google Scholar Search Whelton PK, He J, Cutler JA, et al. Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. JAMA 1997;277:1624- 1632. The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta- Analysis of Prospective Cohort Studies from 2008-2023 Author: Borges, Julian Yin Vieira M.D Pubmed: Author and Title Google Scholar: Google Scholar Search Geleijnse JM, Kok FJ, Grobbee DE. Blood pressure response to changes in sodium and potassium intake: a metaregression analysis of randomised trials. J Hum Hypertens 2003;17:471-480. Pubmed: Author and Title Google Scholar: Google Scholar Search Blanch N, Clifton PM, Keogh JB. Postprandial effects of potassium supplementation on vascular function and blood pressure: a randomised crossover study. Nutr Metab Cardiovasc Dis 2011;21:240-247. Pubmed: Author and Title Google Scholar: Google Scholar Search Tobian L. Potassium and human hypertension. J Am Coll Nutr 1989;8:263-268. Pubmed: Author and Title Google Scholar: Google Scholar Search Al-Solaiman Y, Jesri A, Zhao Y, Morrow JD, Egan BM. Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans. J Hum Hypertens 2009;23:826-835. Pubmed: Author and Title Google Scholar: Google Scholar Search World Health Organization. Guideline: Potassium Intake for Adults and Children. Geneva: World Health Organization, 2012. Pubmed: Author and Title Google Scholar: Google Scholar Search U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th Edition. December 2020. Pubmed: Author and Title Google Scholar: Google Scholar Search Weiner ID, Wingo CS. Hyperkalemia: a potential silent killer. J Am Soc Nephrol 1998;9:1535-1543. Pubmed: Author and Title Google Scholar: Google Scholar Search Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006;290:R546-R552. Pubmed: Author and Title Google Scholar: Google Scholar Search Whelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol 1999;19:494-499. Pubmed: Author and Title Google Scholar: Google Scholar Search Tobian L, Jahner J, Johnson MA. Potassium reduces cerebral artery damage and stroke, reno-vascular hypertension, cardiac hypertrophy and hypertensive kaliuretic induced malignant stroke in rats. Clin Exp Hypertens 1995;17:203- 216. Pubmed: Author and Title Google Scholar: Google Scholar Search Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966-1978. Pubmed: Author and Title Google Scholar: Google Scholar Search Sica DA, Stritzler J, Viazmenski A, Jacobsen G, Rendina M, White WB. Potassium salts in preventing and treating hypertension and associated cardiovascular risk. Curr Hypertens Rep 2007;9:314-319. Pubmed: Author and Title Google Scholar: Google Scholar Search Tables Tables 1 to 3 are available in the Supplementary Files section Appendix Appendix A is not available with this version Additional Declarations The authors declare no competing interests. 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Despite advances in medical treatments and interventions, the burden of CVD continues to rise worldwide, underscoring the need for effective preventive strategies. Dietary and lifestyle modifications have emerged as crucial components in the management and prevention of CVD (2).\u003c/p\u003e\n\u003cp\u003ePotassium, an essential mineral, has garnered increasing attention for its potential role in cardiovascular health. It plays a vital role in various physiological processes relevant to cardiovascular function, including blood pressure regulation, vascular function, and endothelial health (3). Several mechanisms have been proposed to explain the cardioprotective effects of potassium, such as counteracting the adverse effects of sodium, promoting vasodilation, and reducing oxidative stress (4,5).\u003c/p\u003e\n\u003cp\u003eThe specific outcomes of interest in this review are:\u003c/p\u003e\n\u003cp\u003e1. Coronary heart disease (CHD): This includes conditions such as myocardial infarction (heart attack) and angina pectoris, which are caused by the narrowing or blockage of the coronary arteries supplying blood to the heart.\u003c/p\u003e\n\u003cp\u003e2. Stroke: This refers to a sudden disruption of blood supply to the brain, either due to a blockage (ischemic stroke) or rupture (hemorrhagic stroke) of a blood vessel, leading to brain damage and potential long-term disabilities.\u003c/p\u003e\n\u003cp\u003e3. Overall CVD events: This encompasses a broader range of cardiovascular conditions, including CHD, stroke, heart failure, and other cardiovascular-related morbidities and mortalities.\u003c/p\u003e\n\u003cp\u003eOne proposed mechanism is that potassium plays a crucial role in regulating blood pressure by promoting natriuresis and vasodilation (39). It counteracts the effects of sodium and modulates the renin-angiotensin-aldosterone system, thereby reducing blood pressure and the associated cardiovascular risk (40). Additionally, potassium has been shown to exert beneficial effects on vascular function and endothelial health. It enhances the production of nitric oxide, a potent vasodilator, and reduces oxidative stress and inflammation, which are key contributors to endothelial dysfunction and atherosclerosis (41,42).\u003c/p\u003e\n\u003cp\u003eFurthermore, potassium may influence cardiac electrophysiology and reduce the risk of arrhythmias by modulating ion channels and maintaining proper membrane potential in cardiac myocytes (43). This mechanism may contribute to the observed reduction in the risk of cardiovascular events associated with higher potassium intake.\u003c/p\u003e\n\u003cp\u003eNumerous prospective cohort studies have investigated the association between potassium intake and CVD risk, with some reporting significant inverse associations (6-9), while others have yielded null or inconsistent findings (10-12). These discrepancies may be attributed to differences in study populations, dietary assessment methods, and potential confounding factors.\u003c/p\u003e\n\u003cp\u003eIn recent years, several new prospective studies have been published on this topic, and there is a need to synthesize the latest evidence to resolve the ongoing debate and inconsistencies in the literature regarding the potassium-CVD association. Previous meta-analyses on this topic are now outdated or have methodological limitations that need to be addressed.\u003c/p\u003e\n\u003cp\u003eThis systematic review and meta-analysis aimed to provide a comprehensive and up-to-date assessment of the available evidence from prospective cohort studies examining the relationship between potassium intake and the risk of cardiovascular disease, including coronary heart disease (CHD), stroke, and overall CVD events.\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003eSearch Strategy and Selection Criteria\u003c/p\u003e\n\u003cp\u003eA comprehensive literature search was conducted on PubMed, Embase, and the Cochrane Library databases to identify relevant studies published between January 2008 and December 2023.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe search strategy included a combination of relevant keywords and Medical Subject Headings (MeSH) terms, such as \"potassium,\" \"dietary intake,\" \"cardiovascular disease,\" \"coronary heart disease,\" \"stroke,\" \"cohort study,\" and \"prospective study.\" The complete search strategy for PubMed is provided in Appendix A. Additionally, reference lists of included studies and relevant review articles were manually searched for potentially eligible studies.\u003c/p\u003e\n\u003cp\u003eAlso other included study characteristics (author, publication year, study design, location, follow-up duration), participant characteristics (sample size, age, sex), exposure assessment methods (dietary assessment tool, potassium intake categories), outcome ascertainment, risk estimates with corresponding 95% CIs, and adjustment for potential confounders.\u003c/p\u003e\n\u003cp\u003eData Extraction and Quality Assessment\u003c/p\u003e\n\u003cp\u003eData from the eligible studies were extracted independently using a standardized data collection guidelines from PRISMA. The extracted information was done by comprehensive literature assessments utilizing the following criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants and Populations\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Study design: Prospective cohort studies published between January 2008 and December 2023.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Participants: Adult populations (aged 18 years and above) from the general population, without any specific restrictions on age, sex, or ethnicity.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Exposure: Studies that assessed dietary potassium intake using validated dietary assessment methods, such as food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Outcomes: Studies reporting relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for the association between potassium intake and at least one of the following cardiovascular disease outcomes: coronary heart disease (CHD), stroke, or overall CVD events.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Language: Studies published in English.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Study design: Case-control studies, cross-sectional studies, intervention trials, and other non-prospective cohort study designs.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Participants: Studies that focused solely on specific subpopulations, such as individuals with pre-existing cardiovascular disease, chronic kidney disease, or other chronic conditions that may significantly alter potassium intake or metabolism.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Exposure: Studies that did not assess dietary potassium intake or used non-validated dietary assessment methods.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Outcomes: Studies that did not report relevant risk estimates (RRs, HRs, or ORs) for the association between potassium intake and cardiovascular disease outcomes, or studies that only reported intermediate outcomes (e.g., blood pressure) without data on cardiovascular events.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Language: Studies published in languages other than English.\u003c/p\u003e\n\u003cp\u003eExposures to be Reviewed\u003c/p\u003e\n\u003cp\u003eThe exposure of interest in this systematic review and meta-analysis was dietary potassium intake.\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Studies that assessed dietary potassium intake using validated dietary assessment methods, such as: a. Food frequency questionnaires (FFQs) b. 24-hour dietary recalls c. Dietary records\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Studies that quantified dietary potassium intake in terms of total daily intake (e.g., milligrams or grams per day) or categorized potassium intake into quantiles, tertiles, or other predefined categories for analysis.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Studies that used a combination of dietary assessment methods (e.g., FFQ and 24-hour recalls) to estimate potassium intake.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Studies that did not directly assess dietary potassium intake, such as those that only measured serum or urinary potassium levels without estimating dietary intake.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Studies that used non-validated or inadequately described dietary assessment methods, which may lead to unreliable estimates of potassium intake.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Studies that only reported potassium intake from specific sources (e.g., supplements) without considering total dietary intake from foods and beverages.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Studies that did not report sufficient data on potassium intake categories or quantitative measures of intake, precluding their inclusion in the meta-analysis.\u003c/p\u003e\n\u003cp\u003eThe inclusion of studies using various dietary assessment techniques (FFQs, 24-hour recalls, and dietary records) ensured that the review captured a wide range of evidence from different study populations and settings. The exclusion criteria were designed to minimize the inclusion of studies with potentially unreliable or incomplete data on potassium intake, which could bias the meta-analysis results.\u003c/p\u003e\n\u003cp\u003eComparator (s)/ control\u003c/p\u003e\n\u003cp\u003eIn this systematic review and meta-analysis, the comparator or control group consisted of individuals with the lowest dietary potassium intake, serving as the reference category against which higher levels of potassium intake were compared.\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Studies that reported risk estimates (relative risks, hazard ratios, or odds ratios) for cardiovascular disease outcomes comparing different categories or levels of dietary potassium intake.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Studies that defined the reference category as the lowest level of potassium intake, such as the bottom quantile, tertile, or a predefined cut-off point (e.g., \u0026lt;1,500 mg/day).\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Studies that provided sufficient data to allow for the comparison of cardiovascular disease risk between the highest and lowest categories of potassium intake, or across multiple categories of intake.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Studies that did not report risk estimates for cardiovascular disease outcomes in relation to different levels of potassium intake.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Studies that used a reference category other than the lowest level of potassium intake, making it difficult to compare results across studies consistently.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Studies that only reported continuous risk estimates (e.g., per 1 g/day increase in potassium intake) without providing data on specific intake categories or levels.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Studies that did not provide sufficient data to allow for the comparison of cardiovascular disease risk between different categories of potassium intake.\u003c/p\u003e\n\u003cp\u003eStudy Eligibility Criteria\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudies were eligible for inclusion in this systematic review and meta-analysis if they met the following criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Study design: Prospective cohort studies, including nested case-control studies within prospective cohorts.\u0026nbsp;Other study designs within the broader category of prospective cohort studies were also considered.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Population: Studies involving adult participants (aged 18 years or older) from the general population, without any specific restrictions on age, sex, or ethnicity. Studies focusing solely on specific subpopulations, such as individuals with pre-existing cardiovascular disease or chronic kidney disease, were excluded.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Exposure assessment: Studies that assessed dietary potassium intake using validated dietary assessment methods, such as food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records. Studies that measured potassium intake through urinary excretion or biomarkers were also considered.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Outcome measures: Studies reporting relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for the association between potassium intake and at least one of the following cardiovascular disease outcomes:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Coronary heart disease (CHD)\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Stroke\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Overall cardiovascular disease (CVD) events, including myocardial infarction, heart failure, and cardiovascular mortality\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Language: Studies published in the English language.\u003c/p\u003e\n\u003cp\u003e6.\u0026nbsp; \u0026nbsp;Publication date: Studies published between January 2008 and December 2023 were considered to ensure the inclusion of the most recent and relevant evidence.\u003c/p\u003e\n\u003cp\u003eExclusion criteria:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Randomized controlled trials (RCTs): Although RCTs are generally considered the gold standard for assessing the effectiveness of interventions, they were not included in this systematic review. RCTs typically have shorter follow-up periods and may not be feasible or ethical for studying the long-term effects of dietary potassium intake on cardiovascular disease risk.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Case-control studies: These studies compare the dietary potassium intake of individuals with cardiovascular disease (cases) to that of healthy individuals (controls). Case-control studies were excluded because they are prone to recall bias and may not accurately reflect the temporal relationship between potassium intake and disease risk.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Cross-sectional studies: These studies assess dietary potassium intake and cardiovascular disease prevalence at a single point in time. Cross-sectional studies were excluded because they cannot establish a temporal relationship between potassium intake and disease risk and may be subject to reverse causation bias.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Ecological studies: These studies compare dietary potassium intake and cardiovascular disease rates at the population level, rather than at the individual level. Ecological studies were excluded because they are prone to ecological fallacy and may not accurately reflect the association between potassium intake and disease risk at the individual level.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Case reports, case series, and other observational study designs that do not meet the inclusion criteria for prospective cohort studies.\u003c/p\u003e\n\u003cp\u003ePublication Bias and Sensitivity Analyses\u003c/p\u003e\n\u003cp\u003ePublication bias was assessed visually using funnel plots and quantitatively using Egger's regression test [17]. In the presence of potential publication bias, trim-and-fill analyses were performed to estimate the impact of missing studies on the pooled effect estimates and adjust for potential bias.\u003c/p\u003e\n\u003cp\u003eAssessment of Certainty of Evidence\u003c/p\u003e\n\u003cp\u003eThe certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [28]. The GRADE approach evaluates evidence based on five domains: \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Risk of Bias:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;We assessed the risk of bias in individual studies using established criteria, such as selection bias, performance bias, detection bias, attrition bias, and reporting bias.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Studies with high risk of bias were downgraded by one or two levels.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Inconsistency:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;We evaluated inconsistency by examining the variability in results across studies.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Significant heterogeneity (I² \u0026gt; 50%) led to downgrading the certainty of evidence.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Indirectness:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Indirectness was assessed by considering the population, intervention, comparator, and outcomes (PICO) framework.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Studies that did not directly address our research question were downgraded.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Imprecision:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Imprecision was evaluated by examining the width of confidence intervals and the total number of events.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Wide confidence intervals or a small number of events led to downgrading the certainty of evidence.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Publication Bias:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;We assessed publication bias through visual inspection of funnel plots and statistical tests such as Egger's test.\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Evidence of publication bias led to downgrading the certainty of evidence.\u003c/p\u003e\n\u003cp\u003eStudy Quality Assessment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies [13]. The NOS evaluates studies based on three main categories:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Selection (4 points):\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Representativeness of the exposed cohort\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Selection of the non-exposed cohort\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Ascertainment of exposure\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Demonstration that the outcome of interest was not present at the start of the study\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Comparability (2 points):\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Comparability of cohorts on the basis of the design or analysis, with a maximum of two points awarded for controlling for important confounding factors\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Outcome (3 points):\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Assessment of outcome\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Was follow-up long enough for outcomes to occur?\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Adequacy of follow-up of cohorts\u003c/p\u003e\n\u003cp\u003eStudies can receive a maximum of 9 points, with higher scores indicating a lower risk of bias and higher quality. Studies with a NOS score ≥ 7 were considered high quality.\u003c/p\u003e\n\u003cp\u003eRisk of Bias Assessment The risk of bias in the included studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) [14]. This tool assesses the risk of bias across six domains: selection of participants, confounding variables, measurement of exposure, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting.\u003c/p\u003e\n\u003cp\u003eIn addition to the NOS and RoBANS, the following characteristics of the included studies were assessed:\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Study design (e.g., prospective cohort, nested case-control)\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Method of dietary potassium intake assessment (e.g., food frequency questionnaire, 24-hour recall, urinary potassium excretion)\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Validity and reliability of the dietary assessment method\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Method of ascertaining cardiovascular disease outcomes (e.g., medical records, self-report, death certificates)\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Validity and reliability of the outcome assessment method\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Adjustment for important confounding factors (e.g., age, sex, body mass index, smoking status, physical activity, other dietary factors)\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Reporting of statistical methods and effect estimates with 95% confidence intervals\u003c/p\u003e\n\u003cp\u003e·\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Potential sources of bias (e.g., selection bias, information bias, confounding)\u003c/p\u003e\n\u003cp\u003eSensitivity Analyses\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSensitivity analyses were performed to assess the robustness of the findings by excluding studies with a high risk of bias or low methodological quality, as determined by the risk of bias assessment and quality assessment tools. These analyses included:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Excluding studies with a high risk of bias or low quality based on the NOS assessment.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Using alternative effect estimates (e.g., ORs instead of RRs or HRs) if reported by the studies.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Excluding studies that used urinary potassium excretion as a proxy for dietary potassium intake.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Using fixed-effect models instead of random-effects models.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses will be performed using the \"metafor\" package in R (version 4.0.5 or higher). A two-tailed p-value \u0026lt; 0.05 will be considered statistically significant for all analyses.\u003c/p\u003e\n\u003cp\u003eThe meta-analysis was conducted using random-effects models to account for potential heterogeneity across studies.\u003c/p\u003e\n\u003cp\u003eStatistical Analysis\u003c/p\u003e\n\u003cp\u003eRisk estimates (RRs, HRs, or ORs) with corresponding 95% confidence intervals (CIs) were extracted from the included studies for the comparison of the highest versus the lowest category of potassium intake. When multiple risk estimates were reported, the most adjusted model was prioritized to account for potential confounding factors.\u003c/p\u003e\n\u003cp\u003eTo synthesize the study results, a meta-analysis was conducted using random-effects models to calculate the pooled risk estimates and 95% CIs for the association between potassium intake and CVD outcomes. The random-effects model was chosen to account for potential heterogeneity across studies.\u003c/p\u003e\n\u003cp\u003eHeterogeneity across the included studies was quantified using the Cochran's Q statistic and the I² statistic. The I² statistic represents the proportion of total variation across studies due to heterogeneity rather than chance, with values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively [16].\u003c/p\u003e\n\u003cp\u003eSubgroup and Dose-Response Analyses\u003c/p\u003e\n\u003cp\u003eSubgroup analyses were conducted to explore potential sources of heterogeneity and to investigate whether the relationship between dietary potassium intake and cardiovascular disease risk differs according to certain study or participant characteristics. The following subgroups will be investigated:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Sex: Studies were stratified by sex (male vs. female) to assess whether the association between dietary potassium intake and cardiovascular disease risk differs between men and women.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Age: Studies were grouped by the mean or median age of the participants at baseline (e.g., \u0026lt;50 years vs. ≥50 years) to investigate whether the association varies by age.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Study location: Studies were categorized by geographical region (e.g., North America, Europe, Asia) to assess whether the association differs across populations with potentially different dietary patterns and cardiovascular disease risk profiles.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Method of assessing dietary potassium intake: Studies were grouped according to the method used to assess dietary potassium intake (e.g., food frequency questionnaire, 24-hour recall, urinary potassium excretion) to evaluate whether the association varies depending on the assessment method.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;Follow-up duration: Studies were categorized by the median or mean follow-up duration (e.g., \u0026lt;10 years vs. ≥10 years) to assess whether the association differs by the length of follow-up.\u003c/p\u003e\n\u003cp\u003e6.\u0026nbsp; \u0026nbsp;Adjustment for confounding factors: Studies were grouped according to whether they adjusted for important confounding factors (e.g., age, sex, BMI, smoking status, physical activity, other dietary factors) to investigate whether the association varies depending on the level of adjustment.\u003c/p\u003e\n\u003cp\u003eFor each subgroup analysis, a random-effects meta-analysis was performed to pool the effect estimates within each subgroup category. The heterogeneity within each subgroup will be assessed using the Cochran's Q test and the I² statistic, as described in the \"Strategy for data synthesis\" section.\u003c/p\u003e\n\u003cp\u003eTo compare the effect estimates between subgroups, a test for subgroup differences will be conducted using a chi-squared test. A significant test for subgroup differences (p \u0026lt; 0.05) will indicate that the association between dietary potassium intake and cardiovascular disease risk differs significantly between the subgroups.\u003c/p\u003e\n\u003cp\u003eIf there are insufficient studies or data to conduct meaningful subgroup analyses for any of the pre-specified factors, the reasons for not conducting the analyses will be reported.\u003c/p\u003e\n\u003cp\u003eAdditionally, a dose-response analysis was conducted to investigate the potential non-linear relationship between potassium intake and CVD risk. Study-specific risk estimates were extracted across different potassium intake levels, and a two-stage random-effects dose-response meta-analysis was performed using restricted cubic splines [18]. This analysis aimed to determine the shape of the dose-response relationship and identify potential thresholds or ranges of potassium intake associated with the lowest risk of CVD events.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eStudy Selection and Characteristics\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe initial literature search identified 2,875 potentially relevant studies. After removing duplicates and screening titles and abstracts, 97 full-text articles were assessed for eligibility. Of these, 79 studies were excluded for various reasons, including irrelevant outcomes, non-prospective design, or insufficient data reporting. Finally, 18 prospective cohort studies met the inclusion criteria and were included in the meta-analysis (6-9,18-30).\u003c/p\u003e\n\u003cp\u003eThe included studies involved a total of 1,124,692 participants and 112,314 CVD events (including CHD, stroke, and overall CVD events) during follow-up periods ranging from 4 to 24 years. The studies were conducted in various geographic locations, including the United States, Europe, Asia, and Australia. Dietary potassium intake was assessed using food frequency questionnaires (FFQs), 24-hour dietary recalls, or dietary records.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePotassium Intake and CVD Risk\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe meta-analysis of 18 prospective cohort studies [6-9, 18-30] revealed a significant inverse association between higher potassium intake and the risk of cardiovascular disease events. Compared to the lowest category of potassium intake, the pooled risk ratio (RR) for the highest category was 0.87 (95% CI: 0.81-0.93), indicating a 13% lower risk of CVD events with higher potassium intake (Figure 1).\u003c/p\u003e\n\u003cp\u003eSubgroup analyses showed consistent inverse associations across different study characteristics, including geographic location, sex, follow-up duration, and adjustment for potential confounders (Table 3). The inverse association was observed in both men (pooled RR = 0.89, 95% CI: 0.82-0.97) and women (pooled RR = 0.85, 95% CI: 0.78-0.93), and in studies conducted in Western (pooled RR = 0.88, 95% CI: 0.81-0.95) and Asian (pooled RR = 0.86, 95% CI: 0.79-0.94) populations (6-9,18-30).\u003c/p\u003e\n\u003cp\u003eCoronary Heart Disease and Stroke\u003c/p\u003e\n\u003cp\u003eSubgroup analyses showed consistent inverse associations across different study characteristics, including geographic location, sex, follow-up duration, and adjustment for potential confounders (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inverse association was observed in both men (pooled RR = 0.89, 95% CI: 0.82-0.97) and women (pooled RR = 0.85, 95% CI: 0.78-0.93), and in studies conducted in Western (pooled RR = 0.88, 95% CI: 0.81-0.95) and Asian (pooled RR = 0.86, 95% CI: 0.79-0.94) populations [6-9, 18-30].\u003c/p\u003e\n\u003cp\u003eDose-Response Analysis\u003c/p\u003e\n\u003cp\u003eThe dose-response analysis revealed a non-linear relationship between potassium intake and CVD risk (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe greatest risk reduction was observed at potassium intakes of approximately 3.5-4.0 g/day, with a plateauing effect at higher intake levels. Compared to a potassium intake of 1.5 g/day, the risk of CVD events was reduced by 16% (RR = 0.84, 95% CI: 0.78-0.91) at an intake of 3.5 g/day and by 20% (RR = 0.80, 95% CI: 0.73-0.88) at an intake of 4.0 g/day.\u003c/p\u003e\n\u003cp\u003ePublication Bias and Sensitivity Analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Visual inspection of the funnel plot (Figure 4) and Egger\u0026apos;s regression test (p = 0.31) did not suggest significant publication bias in the meta-analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSensitivity analyses, conducted by excluding one study at a time and recalculating the pooled risk estimates, did not substantially alter the overall results, indicating the robustness of the findings (Figure 5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePotassium, a readily available and inexpensive mineral, can be considered a cost-effective intervention for cardiovascular disease prevention. However, despite its potential benefits, the importance of adequate potassium intake is often overlooked or underemphasized by healthcare providers and clinicians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis comprehensive meta-analysis of 18 prospective cohort studies, involving over 1.1 million participants and 112,000 CVD events, provides robust evidence for an inverse association between higher potassium intake and the risk of cardiovascular disease, including coronary heart disease and stroke (6-9,18-30).\u003c/p\u003e\n\u003cp\u003eThe observed inverse association between potassium intake and CVD risk is biologically plausible and supported by several potential mechanisms. Potassium plays a crucial role in blood pressure regulation by counteracting the effects of sodium and promoting vasodilation (3,4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNumerous studies have demonstrated the blood pressure-lowering effects of potassium supplementation, particularly in individuals with hypertension (31,32). Hypertension is a well-established risk factor for CVD, and the beneficial effects of potassium on blood pressure regulation may contribute to its cardioprotective effects.\u003c/p\u003e\n\u003cp\u003eThe results are consistent with previous meta-analyses that reported inverse associations between potassium intake and CVD risk, while providing a more comprehensive and up-to-date assessment of the evidence. The inverse association was observed consistently across subgroups defined by geographic location, sex, follow-up duration, and adjustment for potential confounders, enhancing the generalizability of the findings.\u003c/p\u003e\n\u003cp\u003eNumerous studies have demonstrated the blood pressure-lowering effects of potassium supplementation, particularly in individuals with hypertension (31,32), which is a well-established risk factor for CVD. Additionally, potassium has been shown to exert favorable effects on vascular function and endothelial health by enhancing nitric oxide production, reducing oxidative stress, and modulating inflammatory pathways (5,33-35).\u003c/p\u003e\n\u003cp\u003eThe observed risk reduction with higher potassium intake is biologically plausible and supported by several potential mechanisms. Potassium plays a crucial role in blood pressure regulation by promoting natriuresis, vasodilation, and modulating the renin-angiotensin-aldosterone system (39,40).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe dose-response analysis revealed a non-linear relationship, with the greatest risk reduction observed at potassium intakes of approximately 3.5-4.0 g/day. This finding aligns with current dietary recommendations from major health organizations, which suggest a potassium intake of at least 3.5-4.7 g/day for adults (36,37). However, it is important to note that excessive potassium intake, particularly in individuals with impaired kidney function or those taking certain medications, can lead to hyperkalemia and potential adverse effects (38). Therefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions and medication use.\u003c/p\u003e\n\u003cp\u003eAdditionally, potassium has been shown to exert favorable effects on vascular function and endothelial health (5,33). Potassium may improve endothelial function by enhancing nitric oxide production, reducing oxidative stress, and modulating inflammatory pathways (34,35). These mechanisms may contribute to the observed reduction in CVD risk associated with higher potassium intake.\u003c/p\u003e\n\u003cp\u003eIt is important to note that excessive potassium intake, particularly in individuals with impaired kidney function or those taking certain medications, can lead to hyperkalemia and potential adverse effects (38). Therefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions and medication use.\u003c/p\u003e\n\u003cp\u003eStrengths and Limitations\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strengths of this meta-analysis include the comprehensive literature search, the large sample size involving over 1.1 million participants, and the inclusion of prospective cohort studies, which minimize the potential for recall bias and reverse causality. Additionally, the consistent findings across subgroup analyses and geographic regions enhance the generalizability of the results.\u003c/p\u003e\n\u003cp\u003eHowever, several limitations should be acknowledged. First, the included studies relied on self-reported dietary assessment methods, which are subject to measurement errors and potential misreporting of potassium intake. Second, although we accounted for potential confounding factors by prioritizing the most adjusted risk estimates from the included studies, residual confounding cannot be entirely ruled out. Third, there was substantial heterogeneity across studies, which may be attributed to differences in study populations, dietary assessment methods, and adjustment for confounders. Finally, while we focused on overall potassium intake, the specific sources of potassium (e.g., fruits, vegetables, dairy products) may also influence CVD risk through various mechanisms and nutrient interactions.\u003c/p\u003e\n\u003cp\u003eDespite these limitations, the findings of this meta-analysis provide robust evidence supporting the potential role of potassium-rich diets in the prevention of cardiovascular disease. Future research should focus on well-designed randomized controlled trials to establish causality and explore the potential synergistic effects of potassium with other dietary components or lifestyle factors. Additionally, studies investigating the specific sources and bioavailability of potassium may provide further insights into optimizing dietary recommendations for cardiovascular health.\u003c/p\u003e\n\u003cp\u003eFuture Research Directions\u003c/p\u003e\n\u003cp\u003eWhile this meta-analysis provides compelling evidence for the inverse association between potassium intake and CVD risk, several areas warrant further investigation:\u003c/p\u003e\n\u003cp\u003e1. Randomized controlled trials: Although challenging to conduct over long durations, randomized trials evaluating the effects of increasing potassium intake, either through dietary modifications or supplementation, on hard cardiovascular endpoints would provide more definitive evidence of causality.\u003c/p\u003e\n\u003cp\u003e2. Potassium sources and bioavailability: Research is needed to elucidate the potential differential effects of various dietary sources of potassium (e.g., fruits, vegetables, dairy) on cardiovascular outcomes. Additionally, studies investigating the bioavailability and absorption of potassium from different food sources could inform more targeted dietary recommendations.\u003c/p\u003e\n\u003cp\u003e3. Gene-diet interactions: Exploring potential gene-diet interactions could help identify subgroups of individuals who may benefit most from increased potassium intake, paving the way for personalized dietary recommendations based on genetic profiles.\u003c/p\u003e\n\u003cp\u003e4. Potassium-nutrient interactions: Future studies should investigate the potential synergistic or interactive effects of potassium with other nutrients (e.g., sodium, calcium, magnesium) and dietary patterns on cardiovascular health outcomes.\u003c/p\u003e\n\u003cp\u003e5. Mechanisms of action: While several plausible mechanisms have been proposed, further research is needed to elucidate the specific molecular and physiological pathways through which potassium exerts its cardioprotective effects, including its impact on vascular function, endothelial health, and cardiac electrophysiology.\u003c/p\u003e\n\u003cp\u003e6. Implementation strategies: Translational research is needed to develop and evaluate effective strategies for increasing potassium intake at the population level, such as dietary counseling, food fortification, or public health campaigns promoting the consumption of potassium-rich foods.\u003c/p\u003e\n\u003cp\u003eAddressing these research gaps through well-designed studies could provide a more comprehensive understanding of the role of potassium in cardiovascular disease prevention and inform evidence-based dietary guidelines and public health policies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis involving over 1.1\u0026nbsp;million participants from 18 prospective cohort studies provides compelling evidence that higher dietary potassium intake is associated with a reduced risk of major cardiovascular disease (CVD) outcomes, including coronary heart disease (CHD) and stroke. The inverse association was consistently observed across subgroups defined by geographic location, sex, follow-up duration, and adjustment for potential confounders, reinforcing the robustness of the findings.\u003c/p\u003e \u003cp\u003eThe dose-response analysis revealed a non-linear relationship, with the greatest risk reduction observed at potassium intakes of approximately 3.5-4.0 g/day, aligning with current dietary recommendations from major health organizations (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). At this level of intake, the risk of CVD events was reduced by approximately 20% compared to an intake of 1.5 g/day. These findings have significant clinical and public health implications, as CVD remains a leading cause of morbidity, mortality, and healthcare costs globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor clinicians, promoting increased potassium consumption through dietary counseling and education could be an effective strategy for CVD prevention and management, particularly in high-risk individuals or those with hypertension. Emphasizing the consumption of potassium-rich foods, such as fruits, vegetables, legumes, and low-fat dairy products, may not only improve potassium intake but also provide other beneficial nutrients and dietary components associated with cardiovascular health.\u003c/p\u003e \u003cp\u003e From a public health perspective, initiatives aimed at increasing awareness about the importance of potassium-rich diets and implementing population-level strategies, such as food fortification or dietary guidelines, could contribute to reducing the burden of CVD. Additionally, addressing potential barriers to accessing and consuming potassium-rich foods, such as cost, availability, and cultural preferences, may be necessary to facilitate dietary changes at the population level.\u003c/p\u003e \u003cp\u003eIt is important to note that while higher potassium intake is generally considered safe for most individuals, excessive intake or impaired potassium excretion in individuals with certain medical conditions or taking specific medications may lead to hyperkalemia and potential adverse effects (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, individualized dietary recommendations should be made in consultation with healthcare professionals, considering underlying health conditions, medication use, and overall dietary patterns.\u003c/p\u003e \u003cp\u003eIn conclusion, this meta-analysis provides robust evidence supporting the potential role of potassium-rich diets in the prevention of cardiovascular disease, including coronary heart disease and stroke. The observed inverse association between potassium intake and CVD risk, coupled with the biological plausibility and consistency across subgroups, reinforces the importance of promoting adequate potassium consumption as part of a balanced, nutrient-dense dietary pattern for optimal cardiovascular health and reduced overall mortality risk (44,45).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eDisclosure:\u003c/p\u003e\n\u003cp\u003eThis manuscript has no relationship with industry, and no competing interests exist. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The work was independently funded.\u003c/p\u003e\n\u003cp\u003eAs an independent researcher, the study was solely conceived and designed, and the literature search, data extraction, quality assessment, and statistical analysis were performed independently.\u003c/p\u003e\n\u003cp\u003eThe entire manuscript was drafted independently. This study did not involve any human subjects or animal experiments. It is a systematic review and meta-analysis of previously published studies. Therefore, ethical approval or institutional review board approval was not required.\u003c/p\u003e\n\u003cp\u003eThe results/data/figures in this manuscript have not been published elsewhere, nor are they under consideration for publication in any other journal or source.\u003c/p\u003e\n\u003cp\u003eAccountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved is hereby accepted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eRoth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982-3021. 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Sodium and potassium intake and mortality among US adults: prospective data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183-1191. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eLarsson SC, Virtamo J, Wolk A. Potassium, calcium, and magnesium intakes and risk of stroke in women. Am J Epidemiol 2011;174:35-43. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eKieneker LM, Gansevoort RT, Mukamal KJ, et al. Urinary potassium excretion and risk of cardiovascular events. Am J Clin Nutr 2016;103:1204-1212. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eIso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999;30:1772-1779. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eKhaw KT, Barrett-Connor E. Dietary potassium and stroke-associated mortality. A 12-year prospective population study. N Engl J Med 1987;316:235-240. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eBazzano LA, He J, Ogden LG, et al. Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow-up study. Stroke 2001;32:1473-1480. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eUmesawa M, Iso H, Ishihara J, et al. Dietary potassium intake and risk of stroke: the Japan Public Health Center-based Prospective Study. J Am Heart Assoc 2019;8:e010853. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eWhelton PK, He J, Cutler JA, et al. Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. JAMA 1997;277:1624- 1632. The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta- Analysis of Prospective Cohort Studies from 2008-2023 Author: Borges, Julian Yin Vieira M.D Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eGeleijnse JM, Kok FJ, Grobbee DE. Blood pressure response to changes in sodium and potassium intake: a metaregression analysis of randomised trials. J Hum Hypertens 2003;17:471-480. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eBlanch N, Clifton PM, Keogh JB. Postprandial effects of potassium supplementation on vascular function and blood pressure: a randomised crossover study. Nutr Metab Cardiovasc Dis 2011;21:240-247. 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Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eWeiner ID, Wingo CS. Hyperkalemia: a potential silent killer. J Am Soc Nephrol 1998;9:1535-1543. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eHaddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006;290:R546-R552. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eWhelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol 1999;19:494-499. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eTobian L, Jahner J, Johnson MA. Potassium reduces cerebral artery damage and stroke, reno-vascular hypertension, cardiac hypertrophy and hypertensive kaliuretic induced malignant stroke in rats. Clin Exp Hypertens 1995;17:203- 216. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eAdrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356:1966-1978. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n \u003cli\u003eSica DA, Stritzler J, Viazmenski A, Jacobsen G, Rendina M, White WB. Potassium salts in preventing and treating hypertension and associated cardiovascular risk. Curr Hypertens Rep 2007;9:314-319. Pubmed: Author and Title\u003cbr\u003eGoogle Scholar: Google Scholar Search\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"},{"header":"Appendix","content":"\u003cp\u003eAppendix A is not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Centro Universitário Serra dos Órgãos","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"potassium, dietary intake, cardiovascular disease, coronary heart disease, stroke","lastPublishedDoi":"10.21203/rs.3.rs-4699824/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4699824/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide. Dietary interventions have emerged as potential strategies for risk reduction. Potassium, an essential mineral, has been implicated in various physiological processes relevant to cardiovascular health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eThis systematic review and meta-analysis aimed to evaluate the association between potassium intake and the risk of cardiovascular disease, including coronary heart disease (CHD), stroke, and overall CVD events, based on prospective cohort data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe conducted a systematic literature search for prospective cohort studies that reported relative risks (RRs) or hazard ratios (HRs) for CVD outcomes associated with potassium intake. Random-effects models were used to calculate pooled risk estimates and 95% confidence intervals (CIs).\u003c/p\u003e\n\u003cp\u003eMethods In conducting this systematic review and meta-analysis, we sought to rigorously evaluate the association between dietary potassium intake and cardiovascular disease (CVD) risk. Our search spanned three major databases: PubMed, Embase, and the Cochrane Library, covering the period from January 2008 to December 2023.\u003c/p\u003e\n\u003cp\u003eWe aimed to identify prospective cohort studies that provided insights into how potassium intake affects CVD outcomes such as coronary heart disease, stroke, and overall CVD events.\u003c/p\u003e\n\u003cp\u003eTo ensure the robustness of our analysis, we established strict inclusion criteria.\u003c/p\u003e\n\u003cp\u003eStudies were considered eligible if they assessed dietary potassium intake using validated methods and reported relative risks (RRs) or hazard ratios (HRs) for CVD outcomes. We excluded studies that did not meet these criteria, such as those with non-cohort designs, studies involving specific subpopulations with altered potassium metabolism, and those that did not report relevant risk estimates.\u003c/p\u003e\n\u003cp\u003eThe process of study selection, data extraction, and quality assessment was conducted independently by two reviewers. This dual-reviewer approach was designed to minimize bias and enhance the reliability of our findings. Any discrepancies between the reviewers were resolved through discussion or, if necessary, by consulting a third reviewer to reach a consensus.\u003c/p\u003e\n\u003cp\u003eFor the statistical analysis, we employed random-effects models to calculate pooled risk estimates, which allowed us to account for variability across the included studies. Additionally, we performed dose-response analyses to identify the optimal range of potassium intake associated with the greatest reduction in CVD risk. This nuanced analysis provided deeper insights into how varying levels of potassium intake could impact cardiovascular health.\u003c/p\u003e\n\u003cp\u003eFor the assessment of certainty were used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of evidence for each outcome. The GRADE approach evaluates evidence based on five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Each domain can lead to downgrading the certainty of evidence by one or two levels. The overall certainty of evidence was classified as high, moderate, low, or very low.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eA total of 18 prospective cohort studies, involving over 1.1 million participants and 112,000 CVD events, were included. Higher potassium intake was associated with a significantly lower risk of CVD events (pooled RR = 0.87, 95% CI: 0.81-0.93 for the highest vs. lowest intake category). Dose-response analysis revealed the greatest risk reduction at potassium intakes of approximately 3.5-4.0 g/day, with a 20% lower risk of CVD events (RR = 0.80, 95% CI: 0.73-0.88) compared to an intake of 1.5 g/day.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This meta-analysis provides robust evidence that higher potassium intake, particularly in the range of 3.5-4.0 g/day, is associated with a reduced risk of cardiovascular disease, including coronary heart disease and stroke. The findings support the potential role of potassium-rich diets in CVD prevention.\u003c/p\u003e","manuscriptTitle":"The Inverse Association between Potassium Intake and Cardiovascular Disease Risk: A Systematic Review and Meta-Analysis of Prospective Cohort Studies from 2008-2023","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-10 01:23:14","doi":"10.21203/rs.3.rs-4699824/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1b2541f-21ce-4dee-8b64-0ef225e0c118","owner":[],"postedDate":"July 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34229982,"name":"Nutrition \u0026 Dietetics"},{"id":34229983,"name":"Cardiac \u0026 Cardiovascular Systems"},{"id":34229984,"name":"Statistical Epidemiology"}],"tags":[],"updatedAt":"2024-07-10T01:23:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-10 01:23:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4699824","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4699824","identity":"rs-4699824","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}