The Impact of Dietary Copper Intake on Cardiovascular Morbidity and Mortality among Hypertensive Patients: A Longitudinal Analysis from NHANES (2001-2018)

The Impact of Dietary Copper Intake on Cardiovascular Morbidity and Mortality among Hypertensive Patients: A Longitudinal Analysis from NHANES (2001-2018) | 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 Article The Impact of Dietary Copper Intake on Cardiovascular Morbidity and Mortality among Hypertensive Patients: A Longitudinal Analysis from NHANES (2001-2018) Haibin Xu, Zhou Liu, Baohong Yao, Ziqi XU This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4414611/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 While the impact of macronutrients on health is well-understood, the influence of micronutrients such as copper on cardiovascular health remains less explored. Copper, vital for heart function and antioxidant defense, may affect cardiovascular health through its role in enzymatic activities that reduce oxidative stress. This study evaluates the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients using data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. Findings reveal that higher dietary copper intake is associated with significantly lower cardiovascular disease (CVD) prevalence and mortality rates. A non-linear relationship was identified, indicating an optimal copper intake threshold of approximately 2.85 mg/day. Notably, the protective effects of copper were more pronounced in men, non-diabetic individuals, and those with higher educational levels. These results underscore copper’s potential role in preventing cardiovascular complications in hypertensive patients and support the inclusion of copper intake in dietary recommendations to improve cardiovascular health. This study enhances our understanding of how micronutrients influence cardiovascular disease management and aids in developing targeted nutritional interventions. Dietary Copper Intake Cardiovascular Diseases Mortality NHANES Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION Hypertension is a predominant risk factor for cardiovascular diseases (CVDs), which are the leading cause of mortality worldwide 1 . The global burden of these diseases continues to rise, influencing public health policies and healthcare practices across diverse populations 2 . Epidemiologically, hypertension affects over a billion people globally and is directly linked to approximately half of all heart disease and stroke cases 3 . Alongside genetic, environmental, and lifestyle factors, dietary components play a crucial role in the modulation of blood pressure and overall cardiovascular risk. While the impact of macronutrients has been extensively studied, the influence of micronutrients, particularly trace minerals like copper, is not as well-documented but is increasingly recognized as significant in maintaining cardiovascular health 4 . Copper, a trace mineral found in foods such as shellfish, nuts, seeds, and whole grains, is essential for numerous bodily functions, including angiogenesis, heart muscle contraction, and antioxidant defense 5 . Despite its critical roles, the specific mechanisms by which copper intake influences cardiovascular health remain under-explored 6 . Copper contributes to the function of important enzymes like superoxide dismutase, which protects cells from oxidative damage, and plays a role in maintaining endothelial and myocardial health 7 . Preliminary studies suggest that copper deficiency may be associated with increased heart disease risk due to its role in maintaining myocardial tissue integrity and vascular elasticity 6 . However, gaps remain in understanding the optimal intake levels and the direct effects of copper on cardiovascular morbidity and mortality, particularly among those already at risk, such as hypertensive patients 8 . Previous studies exploring the association between copper and CVDs often suffer from limitations like small sample sizes and cross-sectional designs 7 . The primary objective of this study is to explore the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients 9 . We aim to quantify copper intake among hypertensive individuals and investigate its association with the incidence of major cardiovascular events, including myocardial infarctions and strokes 7 . Additionally, the study will adjust for confounders like age and gender to delineate any dose-response relationships 10 . The results are expected to inform dietary recommendations and potentially influence public health guidelines for reducing cardiovascular risk in this population by incorporating copper intake considerations into nutritional recommendations and hypertension management strategies 11 . 2. METHODS 2.1 Data collection We utilized cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), which is specifically designed to reflect the health and nutritional status of the entire U.S. population. NHANES is distinctive in its methodology, combining both interviews and physical examinations to gather comprehensive data. The survey covers a wide range of information, including demographic, socioeconomic, dietary, and health-related questions. Our research exclusively uses data that is publicly available and does not require additional ethical approval, adhering to the standards set by the NCHS Ethics Review Board (ERB). For more information on ERB approval, please visit https://www.cdc.gov/nchs/nhanes/irba98.htm . The dataset can be accessed freely at the Centers for Disease Control and Prevention (CDC) website: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx . This study analyzed data from nine NHANES cycles (2001–2002, 2003–2004, 2005–2006, 2007–2008, 2009–2010, 2011–2012, 2013–2014, 2015–2016, and 2017–2018), which contain information about demographics, medical history, and copper intake. Copper intake data (in milligrams) are available on the NHANES portal. Initially, a total of 91,351 participants were identified across these nine cycles. The inclusion criteria for this study were as follows: ( 1 ) Age between 18 and 80 years; ( 2 ) Hypertension diagnosis criteria: systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, self-reported hypertension, or currently taking antihypertensive medication 12 . These standards align with the guidelines of the International Society of Hypertension 13 . Exclusion criteria included: ( 1 ) Lack of copper intake data; ( 2 ) Incomplete covariate data. In the end, 14,677 participants were included in our study. The flowchart is shown in Fig. 1 . 2.2 Exposure measurement methods In the NHANES database,participants were required to recall their copper intake twice within 24 hours. In the first recall interview, respondents completed it at the NHANES Mobile Examination Center, while they were asked to complete the second recall interview through a telephone interview 3–10 days later. In our study, to calculate dietary copper intake, we averaged the two dietary recall data; otherwise, single dietary data would be excluded. dietary copper intake is primarily calculated through nutrition questionnaires and dietary recall surveys, where researchers inquire about all food and beverage consumption over the past one to two days 14 . These data are then matched with the USDA food composition database to determine the copper content of the foods consumed 15 . To accurately assess dietary copper intake, researchers typically average several days' dietary data while also considering individual differences and the use of supplements, ensuring accuracy and representativeness 16 . 2.3 Outcome variable selections In this study, the primary outcomes were cardiovascular diseases (CVDs) and mortality. CVDs were identified through either reported or self-admitted physician diagnoses. We assessed self-reported CVD by asking participants whether a doctor or other health professional had ever informed them that they had suffered from heart-related conditions such as a heart attack, coronary heart disease, angina, congestive heart failure, or stroke. The response options provided were "Yes," "No," or "Don't know," with "Yes" indicating a diagnosis of CVD. Participants who responded "Don't know" were excluded from the analysis.For mortality data, we utilized the NHANES Public-Use Linked Mortality Files available up to December 31, 2019, which can be found at CDC's website. These files are linked to the National Death Index (NDI) data using probabilistic matching algorithms to ascertain mortality status. Mortality outcomes were classified according to the International Classification of Diseases, 10th Revision (ICD-10). In ICD-10, cardiovascular-related deaths are identified by specific codes, such as I50 for congestive heart failure and I60-I69 for stroke or cerebrovascular accidents. The follow-up period for each participant extended from the baseline examination date to the date of last known alive status or the date of removal from the mortality archive due to death. 2.4 Covariates extraction Covariates that could influence the relationship between dietary copper intake and the risk of cardiovascular disease (CVD) or CVD-related mortality in hypertensive patients were collected through interviews and medical examinations. These include sociodemographic and lifestyle factors like age, gender, race/ethnicity, education level, and body mass index (BMI). Demographic data on age, gender, race (Non-Hispanic White, Non-Hispanic Black, Mexican American, and other races), and education level (below high school, high school, university, or higher) were gathered through interviews. 3. Data Analysis Data analysis was performed using R software (version 4.3.0). We adopted NHANES-specific weighting procedures to ensure that our estimates are representative of the U.S. population, accounting for selection biases and non-response. Each participant sampled from the 2001–2018 datasets was assigned a weight appropriate for the combined survey cycles.For the association between dietary copper intake and the prevalence of cardiovascular diseases (CVD) among hypertensive patients, we used weighted multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Dietary copper intake was divided into quartiles, with the lowest quartile (Q1) serving as the reference group. Three models were implemented to refine our understanding of this relationship: Model 1 remained unadjusted; Model 2 was adjusted for demographic factors such as age, sex, race, and education level; and Model 3 was further adjusted for clinical and lifestyle factors including body mass index (BMI), smoking and drinking status, and diabetes.We also employed Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD-specific mortality. These models accounted for censoring and the time-dependent nature of risk, structured similarly across three models: an unadjusted Model 1, a demographically adjusted Model 2, and a fully adjusted Model 3 incorporating both demographic and clinical variables.To explore potential nonlinear relationships between dietary copper intake and health outcomes, a restricted cubic spline (RCS) model was applied. This analysis helped to identify any thresholds beyond which the benefits of copper intake on mortality rates may plateau or alter significantly.All statistical analyses were two-sided, and a significance level was maintained at p < 0.05. This rigorous statistical approach enabled us to draw robust conclusions about the dose-response relationship between copper intake and cardiovascular outcomes, informing subsequent clinical and dietary recommendations . 4. RESULTS 4.1 Characteristics of the Study Population The table presents the general characteristics of a population analyzed for the impact of dietary copper intake on cardiovascular morbidity and mortality. Individuals with cardiovascular disease (CVD) are, on average, older (62.46 years vs. 53.29 years) and have a lower mean copper intake (1.17 mg/day vs. 1.27 mg/day) compared to those without CVD. The data also show that individuals with CVD have a higher BMI (31.75 vs. 31.10) and are more likely to be male. Ethnicity-wise, White individuals have the highest prevalence of CVD (71.52%), followed by Black (14.94%), Mexican (7.19%), and other ethnic groups (9.42%). Those with higher education levels, such as college graduates, have a lower prevalence of CVD than those with less education. Diabetes mellitus (DM) is associated with a significantly higher CVD prevalence, affecting 42.01% of the DM group. Smoking status is also influential, with 39.91% of former smokers and 24.52% of current smokers having CVD. Heavy alcohol consumption correlates with higher CVD prevalence (13.01%), while other cardiovascular conditions like stroke, angina, coronary heart disease, congestive heart failure, and heart attack are more prevalent among individuals with CVD. Across copper intake quintiles, a higher intake is linked to lower CVD prevalence, with the highest copper intake group (Q4) having the lowest CVD prevalence. This data emphasizes the significant associations between copper intake, demographic factors, and CVD morbidity(See Table 1 ). 4.2 Association between dietary copper intake and the prevalence of cardiovascular disease in the hypertensive population. The table presents the association between dietary copper intake and the prevalence of cardiovascular disease (CVD) in the hypertensive population, evaluated through three different models using multivariable logistic regression. In Model 1 (unadjusted), higher quartiles of copper intake (Q2, Q3, Q4) were significantly associated with reduced CVD prevalence compared to the reference group, Q1. For instance, Q4 exhibited a markedly lower prevalence of CVD with a coefficient of -0.49 (95% CI: 0.53 to 0.71, P < 0.0001), indicating a protective association. Model 2, adjusted for age, sex, race, and education level, confirmed this trend, with Q4 showing a coefficient of -0.34 (95% CI: 0.61 to 0.84, P < 0.0001). Finally, Model 3, which further accounted for BMI, smoking and drinking status, and diabetes, consistently demonstrated that Q4 maintained a significantly lower CVD prevalence than Q1, with a coefficient of -0.27 (95% CI: 0.65 to 0.91, P = 0.002). This trend across the models, with all P values for trend below 0.01, reveals a robust and dose-responsive association between increasing dietary copper intake and decreased CVD prevalence in hypertensive individuals, even after adjusting for various confounding factors(See Table 2 ). Model 1 was unadjusted; Model 2 was adjusted for age, sex, race, and education level; Model 3 was further adjusted for BMI, smoking and drinking status, and diabetes. 4.3 Establish Cox proportional hazard model The table shows the relationship between different dietary copper intake quartiles (Q1-Q4) and all-cause mortality. Q1 (the lowest quartile of copper intake) serves as the reference group. In Model 1 (unadjusted), the hazard ratios (HRs) for Q2, Q3, and Q4 are 0.82 (P = 0.01), 0.65 (P < 0.0001), and 0.53 (P < 0.0001), respectively, indicating a progressive decline in all-cause mortality risk with increased copper intake. Model 2, adjusted for age, sex, race, and education level, provides HRs of 0.86 (P = 0.05), 0.71 (P < 0.0001), and 0.68 (P < 0.0001) for Q2, Q3, and Q4. In Model 3, further adjusted for BMI, smoking, drinking status, and diabetes, the HRs for Q2, Q3, and Q4 are 0.90, 0.77, and 0.76, respectively. This consistent trend across models shows that individuals with higher dietary copper intake have a significantly lower risk of all-cause mortality than those with lower intake(See Table 3 ). For cardiovascular disease (CVD) mortality, Model 1 (unadjusted) shows that the HR for Q2 is 0.84 (P = 0.14), which is not statistically significant. However, Q3 and Q4 show significantly reduced CVD mortality risks, with HRs of 0.69 (P < 0.001) and 0.48 (P = 0.004), respectively. In Model 2, adjusted for age, sex, race, and education, the HRs for Q2, Q3, and Q4 are 0.88, 0.75 (P = 0.02), and 0.66 (P < 0.001). After further adjustments in Model 3 for BMI, smoking, drinking status, and diabetes, Q3 and Q4 still show HRs of 0.81 (P = 0.08) and 0.75 (P = 0.02). These results indicate a correlation between higher dietary copper intake and reduced CVD mortality, suggesting that higher copper intake may offer protective benefits against cardiovascular mortality(See Table 3 ). Model 1 was unadjusted; Model 2 was adjusted for age, sex, race, and education level; Model 3 was further adjusted for BMI, smoking and drinking status, and diabetes. 4.4 Nonlinear Relationship Detection The Restricted Cubic Spline (RCS) analysis of dietary copper intake and its impact on all-cause mortality among hypertensive patients provides insightful data on the non-linear relationship between copper intake and mortality risks. The RCS curve, derived from a comprehensive R language analysis incorporating adjustments for age, sex, race, education level, BMI, smoking, and drinking status, as well as diabetes, illustrates key points in the effect of copper intake on mortality.From the RCS curve, we observe an initial sharp decrease in the log hazard of all-cause mortality as copper intake increases from the lowest levels up to about 2.85 mg/day, indicating a strong protective effect of moderate copper intake against mortality. This decrease levels off and the curve stabilizes beyond this intake amount, suggesting diminishing returns in mortality reduction with higher levels of copper intake. The plot shows that increasing copper intake beyond approximately 5 mg/day does not provide additional benefits and might even potentially increase mortality risk slightly, although the curve remains relatively stable in this higher intake range.The analysis identifies a critical inflection point at a copper intake of 2.85 mg/day, where the log hazard of mortality begins to stabilize. This point is statistically significant and is crucial for understanding the optimal range of dietary copper intake that could confer the most significant health benefit.(see Fig. 2 ). It is evident that while increasing copper intake is generally beneficial up to a certain point, excessively high intakes do not confer additional protective effects and could be unnecessary or potentially harmful. This RCS analysis thus emphasizes the importance of balancing copper intake within a specific range to optimize health outcomes for hypertensive individuals. The findings strongly support the inclusion of copper intake considerations in dietary guidelines for this population, aiming to harness its benefits while avoiding potential risks associated with excessive consumption. The RCS curve(see Fig. 3 ) analysis presented here examines the relationship between dietary copper intake and cardiovascular mortality rates. The curve reveals that as copper intake increases from the lowest level, the log hazard of cardiovascular mortality initially decreases rapidly, stabilizing around 5 mg. Beyond this point, even as copper intake continues to increase, the reduction in mortality risk is no longer pronounced, indicating that increasing copper intake is most effective in reducing mortality risk within a low to moderate range, but the marginal benefits diminish once a certain threshold is exceeded. Additionally, the analysis did not detect any significant change points, suggesting that changes in cardiovascular mortality risk across the entire range of intake studied are relatively smooth, without abrupt shifts. These findings suggest that appropriately increasing dietary copper intake may help reduce cardiovascular mortality risk within a certain range but also emphasize the importance of controlling copper intake to avoid excess. This provides crucial scientific support for nutritional recommendations for patients with hypertension. 4.5 subgroup analysis In analyzing the relationship between dietary copper intake and cardiovascular mortality among hypertensive patients, significant influences from factors such as gender, ethnicity, and education level were observed. Both males and females exhibited a reduction in cardiovascular mortality with increased copper intake, particularly more pronounced in males, potentially due to higher baseline cardiovascular risks in men. Among ethnic groups, Whites and Mexicans showed significant decreases in cardiovascular risk, while the effects were not significant in Blacks and other ethnicities. Education level also played a critical role, with individuals holding higher education degrees (college and above) demonstrating stronger protective effects, likely reflecting healthier lifestyles and nutritional habits associated with higher educational attainment. Additionally, the analysis on diabetes status indicated that individuals without diabetes experienced a significant decrease in cardiovascular mortality upon increasing their copper intake, with similar trends observed among those with prediabetes conditions (DM and IFG)(see Table 4 ). For all-cause mortality, gender and ethnicity were also key factors affecting the efficacy of copper intake. Both men and women benefited from increased copper intake in reducing all-cause mortality, with effects more prominently seen in men. Ethnically, Whites and other races saw significant reductions in all-cause mortality with increased copper intake, while the results for Blacks and Mexicans did not show significance. Higher education levels were correlated with more pronounced protective effects against all-cause mortality, suggesting that educational attainment may be linked to better health awareness and access to resources. Regarding diabetes status, individuals without diabetes gained the most benefit from increased copper intake, while those with prediabetes conditions showed protective effects, though not as significant as those without diabetes(see Table 5 ). These findings underscore the importance of considering individual characteristics such as gender, ethnicity, education, and health status when developing nutritional guidelines for hypertensive patients, aiming to optimize recommendations for copper intake to maximize its potential benefits in reducing mortality risks. Moreover, these insights suggest that nutritional interventions should take these factors into account to achieve the best health outcomes. 5. DISCUSSION This study underscores the importance of dietary copper in reducing cardiovascular disease (CVD) incidence and mortality among hypertensive patients, adding to the body of evidence on micronutrients' crucial role in cardiovascular health. The findings align with recent research that highlights the beneficial effects of trace minerals such as copper 19 . Our analysis demonstrates a clear dose-response relationship, with increased copper intake associated with reduced risks of CVD incidence and mortality. This relationship holds even after adjusting for confounders such as age, sex, BMI, and lifestyle factors, indicating copper's intrinsic protective properties against cardiovascular stress. These results support and extend the findings of earlier studies which have suggested that essential micronutrients, including copper, play significant roles in mitigating cardiovascular risks 22 . Further, the nonlinear effects of copper intake were explored through Restricted Cubic Spline (RCS) models, revealing an optimal intake threshold. Beyond this point, additional copper does not seem to confer further benefits and could potentially be harmful, suggesting the necessity of moderation in supplementation practices. This observation of a plateau effect at approximately 2.85 mg/day of copper intake where benefits stabilize is consistent with other recent findings but contrasts with studies suggesting continuous benefits at higher intake levels, such as the PURE-China Study 20 . Our findings are crucial for public health recommendations, particularly in formulating dietary guidelines for hypertensive individuals where micronutrient intake must be carefully balanced. While increasing dietary copper can be beneficial up to a certain point, our study highlights the importance of not exceeding this level to avoid potential negative effects. Health professionals should carefully consider these results when recommending copper intake levels, ensuring they align with individual patient needs and the latest clinical evidence 21 . Overall, our study contributes to the understanding of the complex interactions between dietary copper and cardiovascular health outcomes in hypertensive patients, emphasizing the need for well-defined dietary copper recommendations based on robust epidemiological evidence and clinical trials.Despite these insights, significant gaps remain in the literature, particularly concerning the optimal copper intake for different populations and the long-term effects of slightly elevated copper levels. and the potential biases inherent in self-reported dietary data and the generalizability of findings to non-U.S. populations.Future research should focus on longitudinal studies and randomized controlled trials to establish causality and clarify the mechanisms by which copper interacts with cardiovascular health determinants. 6. CONCLUSIONS This longitudinal study from the NHANES database (2001-2018) has significantly enhanced our understanding of the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients. We observed that higher copper intake is associated with reduced rates of cardiovascular morbidity and mortality. Specifically, patients with higher copper intake showed lower prevalence and better prognostic outcomes in cardiovascular health compared to those with lower intake levels.These findings suggest that dietary copper may play a crucial role in cardiovascular protection among hypertensive individuals. Therefore, incorporating copper into dietary recommendations could potentially improve cardiovascular health outcomes in this high-risk population. This study supports the need for further research to refine our understanding of copper's benefits and to guide public health strategies aimed at reducing cardiovascular risks through nutrition. Declarations Data Availability Statement The data that support the findings of this study are available from the National Health and Nutrition Examination Survey (NHANES), which is publicly accessible through the Centers for Disease Control and Prevention (CDC). These data can be accessed at https://www.cdc.gov/nchs/nhanes/. Author contributions B.Y. and H.X. designed the research. H.X., Z.L., B.Y., and Z.X. collected, analyzed the data, and drafted the manuscript. H.X., Z.L., B.Y., and Z.X. revised the manuscript. All authors contributed to the article and approved the submitted version. Competing interests The authors declare no competing interests. References World Health Organization. (2021, June 11). Cardiovascular diseases (CVDs). Sun, J., Qiao, Y., Zhao, M., Magnussen, C. G., & Xi, B. (2023). 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Li, X., Dehghan, M., Tse, L. A., Lang, X., Rangarajan, S., Liu, W., ... & Li, W. (2023). Associations of dietary copper intake with cardiovascular disease and mortality: findings from the Chinese Perspective Urban and Rural Epidemiology (PURE-China) Study. BMC Public Health, 23(1), 2525. Collins, J. F. (2021). New roles for copper metabolism in cell proliferation, signaling, and disease. Journal of Biological Chemistry, 295(2), 464-478. DiNicolantonio, J. J., Mangan, D., & O’Keefe, J. H. (2018). Copper deficiency may be a leading cause of ischaemic heart disease. Open heart, 5(2), e000784. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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of Lin'an District","correspondingAuthor":false,"prefix":"","firstName":"Ziqi","middleName":"","lastName":"XU","suffix":""}],"badges":[],"createdAt":"2024-05-13 17:09:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4414611/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4414611/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57444655,"identity":"04a64d60-7b9f-4b58-8be3-c3a6ed467907","added_by":"auto","created_at":"2024-05-30 19:00:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":551877,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe flowchart of study sample selection form NHANES 2001–2018\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4414611/v1/afc3f18efaeb0c6ff01c532f.png"},{"id":57444017,"identity":"e4eac8e8-1695-40a6-8b01-2c8b47190c3a","added_by":"auto","created_at":"2024-05-30 18:52:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27004,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImpact of Dietary Copper Intake on All-Cause Mortality Risk in Hypertensive Patients: A Restricted Cubic Spline Analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-4414611/v1/d34934ae66a39b1fe0c6769c.png"},{"id":57444020,"identity":"61177555-d46a-493b-9626-cf9f7c653ffe","added_by":"auto","created_at":"2024-05-30 18:52:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":133152,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImpact of Dietary Copper Intake on Cardiovascular Mortality Risk in Hypertensive Patients: A Restricted Cubic Spline Analysis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-4414611/v1/b435e1d9083e24ce00d4dec7.png"},{"id":61102883,"identity":"7837b812-16f0-4000-843f-7a74608ae219","added_by":"auto","created_at":"2024-07-25 15:24:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1214144,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4414611/v1/a75b9435-60b7-4311-abfb-71a61fa2218a.pdf"},{"id":57444019,"identity":"9476ce0c-5802-4045-a306-e0a46ee2cbb5","added_by":"auto","created_at":"2024-05-30 18:52:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15210,"visible":true,"origin":"","legend":"","description":"","filename":"table23.docx","url":"https://assets-eu.researchsquare.com/files/rs-4414611/v1/6afadfdf557f3ff120f2c74b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Impact of Dietary Copper Intake on Cardiovascular Morbidity and Mortality among Hypertensive Patients: A Longitudinal Analysis from NHANES (2001-2018)","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eHypertension is a predominant risk factor for cardiovascular diseases (CVDs), which are the leading cause of mortality worldwide\u003csup\u003e1\u003c/sup\u003e. The global burden of these diseases continues to rise, influencing public health policies and healthcare practices across diverse populations\u003csup\u003e2\u003c/sup\u003e. Epidemiologically, hypertension affects over a billion people globally and is directly linked to approximately half of all heart disease and stroke cases\u003csup\u003e3\u003c/sup\u003e. Alongside genetic, environmental, and lifestyle factors, dietary components play a crucial role in the modulation of blood pressure and overall cardiovascular risk. While the impact of macronutrients has been extensively studied, the influence of micronutrients, particularly trace minerals like copper, is not as well-documented but is increasingly recognized as significant in maintaining cardiovascular health\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCopper, a trace mineral found in foods such as shellfish, nuts, seeds, and whole grains, is essential for numerous bodily functions, including angiogenesis, heart muscle contraction, and antioxidant defense\u003csup\u003e5\u003c/sup\u003e. Despite its critical roles, the specific mechanisms by which copper intake influences cardiovascular health remain under-explored\u003csup\u003e6\u003c/sup\u003e. Copper contributes to the function of important enzymes like superoxide dismutase, which protects cells from oxidative damage, and plays a role in maintaining endothelial and myocardial health\u003csup\u003e7\u003c/sup\u003e. Preliminary studies suggest that copper deficiency may be associated with increased heart disease risk due to its role in maintaining myocardial tissue integrity and vascular elasticity\u003csup\u003e6\u003c/sup\u003e. However, gaps remain in understanding the optimal intake levels and the direct effects of copper on cardiovascular morbidity and mortality, particularly among those already at risk, such as hypertensive patients\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePrevious studies exploring the association between copper and CVDs often suffer from limitations like small sample sizes and cross-sectional designs\u003csup\u003e7\u003c/sup\u003e. The primary objective of this study is to explore the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients\u003csup\u003e9\u003c/sup\u003e. We aim to quantify copper intake among hypertensive individuals and investigate its association with the incidence of major cardiovascular events, including myocardial infarctions and strokes\u003csup\u003e7\u003c/sup\u003e. Additionally, the study will adjust for confounders like age and gender to delineate any dose-response relationships\u003csup\u003e10\u003c/sup\u003e. The results are expected to inform dietary recommendations and potentially influence public health guidelines for reducing cardiovascular risk in this population by incorporating copper intake considerations into nutritional recommendations and hypertension management strategies\u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e\n"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e2.1 Data collection\u003c/h2\u003eWe utilized cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), which is specifically designed to reflect the health and nutritional status of the entire U.S. population. NHANES is distinctive in its methodology, combining both interviews and physical examinations to gather comprehensive data. The survey covers a wide range of information, including demographic, socioeconomic, dietary, and health-related questions. Our research exclusively uses data that is publicly available and does not require additional ethical approval, adhering to the standards set by the NCHS Ethics Review Board (ERB). For more information on ERB approval, please visit \u003cspan\u003e\u003cspan\u003ehttps://www.cdc.gov/nchs/nhanes/irba98.htm\u003c/span\u003e\u003c/span\u003e. The dataset can be accessed freely at the Centers for Disease Control and Prevention (CDC) website: \u003cspan\u003e\u003cspan\u003ehttps://wwwn.cdc.gov/nchs/nhanes/Default.aspx\u003c/span\u003e\u003c/span\u003e.\u003cp\u003eThis study analyzed data from nine NHANES cycles (2001\u0026ndash;2002, 2003\u0026ndash;2004, 2005\u0026ndash;2006, 2007\u0026ndash;2008, 2009\u0026ndash;2010, 2011\u0026ndash;2012, 2013\u0026ndash;2014, 2015\u0026ndash;2016, and 2017\u0026ndash;2018), which contain information about demographics, medical history, and copper intake. Copper intake data (in milligrams) are available on the NHANES portal. Initially, a total of 91,351 participants were identified across these nine cycles. The inclusion criteria for this study were as follows: (\u003cspan\u003e1\u003c/span\u003e) Age between 18 and 80 years; (\u003cspan\u003e2\u003c/span\u003e) Hypertension diagnosis criteria: systolic blood pressure (SBP)\u0026thinsp;\u0026ge;\u0026thinsp;140 mmHg or diastolic blood pressure (DBP)\u0026thinsp;\u0026ge;\u0026thinsp;90 mmHg, self-reported hypertension, or currently taking antihypertensive medication\u003csup\u003e12\u003c/sup\u003e. These standards align with the guidelines of the International Society of Hypertension\u003csup\u003e13\u003c/sup\u003e. Exclusion criteria included: (\u003cspan\u003e1\u003c/span\u003e) Lack of copper intake data; (\u003cspan\u003e2\u003c/span\u003e) Incomplete covariate data. In the end, 14,677 participants were included in our study. The flowchart is shown in Fig. \u003cspan\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e2.2 Exposure measurement methods\u003c/h2\u003e\n \u003cp\u003eIn the NHANES database,participants were required to recall their copper intake twice within 24 hours. In the first recall interview, respondents completed it at the NHANES Mobile Examination Center, while they were asked to complete the second recall interview through a telephone interview 3\u0026ndash;10 days later. In our study, to calculate dietary copper intake, we averaged the two dietary recall data; otherwise, single dietary data would be excluded. dietary copper intake is primarily calculated through nutrition questionnaires and dietary recall surveys, where researchers inquire about all food and beverage consumption over the past one to two days\u003csup\u003e14\u003c/sup\u003e. These data are then matched with the USDA food composition database to determine the copper content of the foods consumed\u003csup\u003e15\u003c/sup\u003e. To accurately assess dietary copper intake, researchers typically average several days\u0026apos; dietary data while also considering individual differences and the use of supplements, ensuring accuracy and representativeness\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e2.3 Outcome variable selections\u003c/h2\u003e\n \u003cp\u003eIn this study, the primary outcomes were cardiovascular diseases (CVDs) and mortality. CVDs were identified through either reported or self-admitted physician diagnoses. We assessed self-reported CVD by asking participants whether a doctor or other health professional had ever informed them that they had suffered from heart-related conditions such as a heart attack, coronary heart disease, angina, congestive heart failure, or stroke. The response options provided were \u0026quot;Yes,\u0026quot; \u0026quot;No,\u0026quot; or \u0026quot;Don\u0026apos;t know,\u0026quot; with \u0026quot;Yes\u0026quot; indicating a diagnosis of CVD. Participants who responded \u0026quot;Don\u0026apos;t know\u0026quot; were excluded from the analysis.For mortality data, we utilized the NHANES Public-Use Linked Mortality Files available up to December 31, 2019, which can be found at CDC\u0026apos;s website. These files are linked to the National Death Index (NDI) data using probabilistic matching algorithms to ascertain mortality status. Mortality outcomes were classified according to the International Classification of Diseases, 10th Revision (ICD-10). In ICD-10, cardiovascular-related deaths are identified by specific codes, such as I50 for congestive heart failure and I60-I69 for stroke or cerebrovascular accidents. The follow-up period for each participant extended from the baseline examination date to the date of last known alive status or the date of removal from the mortality archive due to death.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003e2.4 Covariates extraction\u003c/h2\u003e\n \u003cp\u003eCovariates that could influence the relationship between dietary copper intake and the risk of cardiovascular disease (CVD) or CVD-related mortality in hypertensive patients were collected through interviews and medical examinations. These include sociodemographic and lifestyle factors like age, gender, race/ethnicity, education level, and body mass index (BMI). Demographic data on age, gender, race (Non-Hispanic White, Non-Hispanic Black, Mexican American, and other races), and education level (below high school, high school, university, or higher) were gathered through interviews.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Data Analysis","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eData analysis was performed using R software (version 4.3.0). We adopted NHANES-specific weighting procedures to ensure that our estimates are representative of the U.S. population, accounting for selection biases and non-response. Each participant sampled from the 2001\u0026ndash;2018 datasets was assigned a weight appropriate for the combined survey cycles.For the association between dietary copper intake and the prevalence of cardiovascular diseases (CVD) among hypertensive patients, we used weighted multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Dietary copper intake was divided into quartiles, with the lowest quartile (Q1) serving as the reference group. Three models were implemented to refine our understanding of this relationship: Model 1 remained unadjusted; Model 2 was adjusted for demographic factors such as age, sex, race, and education level; and Model 3 was further adjusted for clinical and lifestyle factors including body mass index (BMI), smoking and drinking status, and diabetes.We also employed Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD-specific mortality. These models accounted for censoring and the time-dependent nature of risk, structured similarly across three models: an unadjusted Model 1, a demographically adjusted Model 2, and a fully adjusted Model 3 incorporating both demographic and clinical variables.To explore potential nonlinear relationships between dietary copper intake and health outcomes, a restricted cubic spline (RCS) model was applied. This analysis helped to identify any thresholds beyond which the benefits of copper intake on mortality rates may plateau or alter significantly.All statistical analyses were two-sided, and a significance level was maintained at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. This rigorous statistical approach enabled us to draw robust conclusions about the dose-response relationship between copper intake and cardiovascular outcomes, informing subsequent clinical and dietary recommendations .\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"4. RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1 Characteristics of the Study Population\u003c/h2\u003e\n \u003cp\u003eThe table presents the general characteristics of a population analyzed for the impact of dietary copper intake on cardiovascular morbidity and mortality. Individuals with cardiovascular disease (CVD) are, on average, older (62.46 years vs. 53.29 years) and have a lower mean copper intake (1.17 mg/day vs. 1.27 mg/day) compared to those without CVD. The data also show that individuals with CVD have a higher BMI (31.75 vs. 31.10) and are more likely to be male. Ethnicity-wise, White individuals have the highest prevalence of CVD (71.52%), followed by Black (14.94%), Mexican (7.19%), and other ethnic groups (9.42%). Those with higher education levels, such as college graduates, have a lower prevalence of CVD than those with less education. Diabetes mellitus (DM) is associated with a significantly higher CVD prevalence, affecting 42.01% of the DM group. Smoking status is also influential, with 39.91% of former smokers and 24.52% of current smokers having CVD. Heavy alcohol consumption correlates with higher CVD prevalence (13.01%), while other cardiovascular conditions like stroke, angina, coronary heart disease, congestive heart failure, and heart attack are more prevalent among individuals with CVD. Across copper intake quintiles, a higher intake is linked to lower CVD prevalence, with the highest copper intake group (Q4) having the lowest CVD prevalence. This data emphasizes the significant associations between copper intake, demographic factors, and CVD morbidity(See Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\u003cbr\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2 Association between dietary copper intake and the prevalence of cardiovascular disease in the hypertensive population.\u003c/h2\u003e\n \u003cp\u003eThe table presents the association between dietary copper intake and the prevalence of cardiovascular disease (CVD) in the hypertensive population, evaluated through three different models using multivariable logistic regression. In Model 1 (unadjusted), higher quartiles of copper intake (Q2, Q3, Q4) were significantly associated with reduced CVD prevalence compared to the reference group, Q1. For instance, Q4 exhibited a markedly lower prevalence of CVD with a coefficient of -0.49 (95% CI: 0.53 to 0.71, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), indicating a protective association. Model 2, adjusted for age, sex, race, and education level, confirmed this trend, with Q4 showing a coefficient of -0.34 (95% CI: 0.61 to 0.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Finally, Model 3, which further accounted for BMI, smoking and drinking status, and diabetes, consistently demonstrated that Q4 maintained a significantly lower CVD prevalence than Q1, with a coefficient of -0.27 (95% CI: 0.65 to 0.91, P\u0026thinsp;=\u0026thinsp;0.002). This trend across the models, with all P values for trend below 0.01, reveals a robust and dose-responsive association between increasing dietary copper intake and decreased CVD prevalence in hypertensive individuals, even after adjusting for various confounding factors(See Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1 was unadjusted;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2 was adjusted for age, sex, race, and education level;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3 was further adjusted for BMI, smoking and drinking status, and diabetes.\u003c/strong\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\u003c/table\u003e\n \u003c/div\u003e\u003cbr\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e4.3 Establish Cox proportional hazard model\u003c/h2\u003e\n \u003cp\u003eThe table shows the relationship between different dietary copper intake quartiles (Q1-Q4) and all-cause mortality. Q1 (the lowest quartile of copper intake) serves as the reference group. In Model 1 (unadjusted), the hazard ratios (HRs) for Q2, Q3, and Q4 are 0.82 (P\u0026thinsp;=\u0026thinsp;0.01), 0.65 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and 0.53 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), respectively, indicating a progressive decline in all-cause mortality risk with increased copper intake. Model 2, adjusted for age, sex, race, and education level, provides HRs of 0.86 (P\u0026thinsp;=\u0026thinsp;0.05), 0.71 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and 0.68 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) for Q2, Q3, and Q4. In Model 3, further adjusted for BMI, smoking, drinking status, and diabetes, the HRs for Q2, Q3, and Q4 are 0.90, 0.77, and 0.76, respectively. This consistent trend across models shows that individuals with higher dietary copper intake have a significantly lower risk of all-cause mortality than those with lower intake(See Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eFor cardiovascular disease (CVD) mortality, Model 1 (unadjusted) shows that the HR for Q2 is 0.84 (P\u0026thinsp;=\u0026thinsp;0.14), which is not statistically significant. However, Q3 and Q4 show significantly reduced CVD mortality risks, with HRs of 0.69 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 0.48 (P\u0026thinsp;=\u0026thinsp;0.004), respectively. In Model 2, adjusted for age, sex, race, and education, the HRs for Q2, Q3, and Q4 are 0.88, 0.75 (P\u0026thinsp;=\u0026thinsp;0.02), and 0.66 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). After further adjustments in Model 3 for BMI, smoking, drinking status, and diabetes, Q3 and Q4 still show HRs of 0.81 (P\u0026thinsp;=\u0026thinsp;0.08) and 0.75 (P\u0026thinsp;=\u0026thinsp;0.02). These results indicate a correlation between higher dietary copper intake and reduced CVD mortality, suggesting that higher copper intake may offer protective benefits against cardiovascular mortality(See Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1 was unadjusted;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2 was adjusted for age, sex, race, and education level;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3 was further adjusted for BMI, smoking and drinking status, and diabetes.\u003c/strong\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e4.4 Nonlinear Relationship Detection\u003c/h2\u003e\n \u003cp\u003eThe Restricted Cubic Spline (RCS) analysis of dietary copper intake and its impact on all-cause mortality among hypertensive patients provides insightful data on the non-linear relationship between copper intake and mortality risks. The RCS curve, derived from a comprehensive R language analysis incorporating adjustments for age, sex, race, education level, BMI, smoking, and drinking status, as well as diabetes, illustrates key points in the effect of copper intake on mortality.From the RCS curve, we observe an initial sharp decrease in the log hazard of all-cause mortality as copper intake increases from the lowest levels up to about 2.85 mg/day, indicating a strong protective effect of moderate copper intake against mortality. This decrease levels off and the curve stabilizes beyond this intake amount, suggesting diminishing returns in mortality reduction with higher levels of copper intake. The plot shows that increasing copper intake beyond approximately 5 mg/day does not provide additional benefits and might even potentially increase mortality risk slightly, although the curve remains relatively stable in this higher intake range.The analysis identifies a critical inflection point at a copper intake of 2.85 mg/day, where the log hazard of mortality begins to stabilize. This point is statistically significant and is crucial for understanding the optimal range of dietary copper intake that could confer the most significant health benefit.(see Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eIt is evident that while increasing copper intake is generally beneficial up to a certain point, excessively high intakes do not confer additional protective effects and could be unnecessary or potentially harmful. This RCS analysis thus emphasizes the importance of balancing copper intake within a specific range to optimize health outcomes for hypertensive individuals. The findings strongly support the inclusion of copper intake considerations in dietary guidelines for this population, aiming to harness its benefits while avoiding potential risks associated with excessive consumption.\u003c/p\u003e\u003cbr\u003eThe RCS curve(see Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) analysis presented here examines the relationship between dietary copper intake and cardiovascular mortality rates. The curve reveals that as copper intake increases from the lowest level, the log hazard of cardiovascular mortality initially decreases rapidly, stabilizing around 5 mg. Beyond this point, even as copper intake continues to increase, the reduction in mortality risk is no longer pronounced, indicating that increasing copper intake is most effective in reducing mortality risk within a low to moderate range, but the marginal benefits diminish once a certain threshold is exceeded. Additionally, the analysis did not detect any significant change points, suggesting that changes in cardiovascular mortality risk across the entire range of intake studied are relatively smooth, without abrupt shifts. These findings suggest that appropriately increasing dietary copper intake may help reduce cardiovascular mortality risk within a certain range but also emphasize the importance of controlling copper intake to avoid excess. This provides crucial scientific support for nutritional recommendations for patients with hypertension.\u003cbr\u003e\u003cbr\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e4.5 subgroup analysis\u003c/h2\u003e\n \u003cp\u003eIn analyzing the relationship between dietary copper intake and cardiovascular mortality among hypertensive patients, significant influences from factors such as gender, ethnicity, and education level were observed. Both males and females exhibited a reduction in cardiovascular mortality with increased copper intake, particularly more pronounced in males, potentially due to higher baseline cardiovascular risks in men. Among ethnic groups, Whites and Mexicans showed significant decreases in cardiovascular risk, while the effects were not significant in Blacks and other ethnicities. Education level also played a critical role, with individuals holding higher education degrees (college and above) demonstrating stronger protective effects, likely reflecting healthier lifestyles and nutritional habits associated with higher educational attainment. Additionally, the analysis on diabetes status indicated that individuals without diabetes experienced a significant decrease in cardiovascular mortality upon increasing their copper intake, with similar trends observed among those with prediabetes conditions (DM and IFG)(see Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eFor all-cause mortality, gender and ethnicity were also key factors affecting the efficacy of copper intake. Both men and women benefited from increased copper intake in reducing all-cause mortality, with effects more prominently seen in men. Ethnically, Whites and other races saw significant reductions in all-cause mortality with increased copper intake, while the results for Blacks and Mexicans did not show significance. Higher education levels were correlated with more pronounced protective effects against all-cause mortality, suggesting that educational attainment may be linked to better health awareness and access to resources. Regarding diabetes status, individuals without diabetes gained the most benefit from increased copper intake, while those with prediabetes conditions showed protective effects, though not as significant as those without diabetes(see Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThese findings underscore the importance of considering individual characteristics such as gender, ethnicity, education, and health status when developing nutritional guidelines for hypertensive patients, aiming to optimize recommendations for copper intake to maximize its potential benefits in reducing mortality risks. Moreover, these insights suggest that nutritional interventions should take these factors into account to achieve the best health outcomes.\u003c/p\u003e\n"},{"header":"5. DISCUSSION","content":"\u003cp\u003eThis study underscores the importance of dietary copper in reducing cardiovascular disease (CVD) incidence and mortality among hypertensive patients, adding to the body of evidence on micronutrients\u0026apos; crucial role in cardiovascular health. The findings align with recent research that highlights the beneficial effects of trace minerals such as copper\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur analysis demonstrates a clear dose-response relationship, with increased copper intake associated with reduced risks of CVD incidence and mortality. This relationship holds even after adjusting for confounders such as age, sex, BMI, and lifestyle factors, indicating copper\u0026apos;s intrinsic protective properties against cardiovascular stress. These results support and extend the findings of earlier studies which have suggested that essential micronutrients, including copper, play significant roles in mitigating cardiovascular risks \u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFurther, the nonlinear effects of copper intake were explored through Restricted Cubic Spline (RCS) models, revealing an optimal intake threshold. Beyond this point, additional copper does not seem to confer further benefits and could potentially be harmful, suggesting the necessity of moderation in supplementation practices. This observation of a plateau effect at approximately 2.85 mg/day of copper intake where benefits stabilize is consistent with other recent findings but contrasts with studies suggesting continuous benefits at higher intake levels, such as the PURE-China Study\u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur findings are crucial for public health recommendations, particularly in formulating dietary guidelines for hypertensive individuals where micronutrient intake must be carefully balanced. While increasing dietary copper can be beneficial up to a certain point, our study highlights the importance of not exceeding this level to avoid potential negative effects. Health professionals should carefully consider these results when recommending copper intake levels, ensuring they align with individual patient needs and the latest clinical evidence\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOverall, our study contributes to the understanding of the complex interactions between dietary copper and cardiovascular health outcomes in hypertensive patients, emphasizing the need for well-defined dietary copper recommendations based on robust epidemiological evidence and clinical trials.Despite these insights, significant gaps remain in the literature, particularly concerning the optimal copper intake for different populations and the long-term effects of slightly elevated copper levels. and the potential biases inherent in self-reported dietary data and the generalizability of findings to non-U.S. populations.Future research should focus on longitudinal studies and randomized controlled trials to establish causality and clarify the mechanisms by which copper interacts with cardiovascular health determinants.\u003c/p\u003e\n"},{"header":"6. CONCLUSIONS","content":"\u003cp\u003eThis longitudinal study from the NHANES database (2001-2018) has significantly enhanced our understanding of the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients. We observed that higher copper intake is associated with reduced rates of cardiovascular morbidity and mortality. Specifically, patients with higher copper intake showed lower prevalence and better prognostic outcomes in cardiovascular health compared to those with lower intake levels.These findings suggest that dietary copper may play a crucial role in cardiovascular protection among hypertensive individuals. Therefore, incorporating copper into dietary recommendations could potentially improve cardiovascular health outcomes in this high-risk population. This study supports the need for further research to refine our understanding of copper\u0026apos;s benefits and to guide public health strategies aimed at reducing cardiovascular risks through nutrition.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the National Health and Nutrition Examination Survey (NHANES), which is publicly accessible through the Centers for Disease Control and Prevention (CDC). These data can be accessed at https://www.cdc.gov/nchs/nhanes/.\u003cbr\u003e \u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eB.Y. and H.X. designed the research. H.X., Z.L., B.Y., and Z.X. collected, analyzed the data, and drafted the manuscript. H.X., Z.L., B.Y., and Z.X. revised the manuscript. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Health Organization. (2021, June 11). Cardiovascular diseases (CVDs).\u003c/li\u003e\n\u003cli\u003eSun, J., Qiao, Y., Zhao, M., Magnussen, C. G., \u0026amp; Xi, B. (2023). Global, regional, and national burden of cardiovascular diseases in youths and young adults aged 15\u0026ndash;39 years in 204 countries/territories, 1990\u0026ndash;2019: a systematic analysis of Global Burden of Disease Study 2019. BMC medicine, 21(1), 222.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. (2023, March 16). Hypertension.\u003c/li\u003e\n\u003cli\u003eTong, Z., Xie, Y., Li, K., Yuan, R., \u0026amp; Zhang, L. (2024). The global burden and risk factors of cardiovascular diseases in adolescent and young adults, 1990\u0026ndash;2019. BMC Public Health, 24(1), 1-12.\u003c/li\u003e\n\u003cli\u003eMunoz-Bravo, C., Soler-Iborte, E., Lozano-Lorca, M., Kouiti, M., Gonz\u0026aacute;lez-Palacios Torres, C., Barrios-Rodriguez, R., \u0026amp; Jimenez-Moleon, J. J. (2023). Serum copper levels and risk of major adverse cardiovascular events: a systematic review and meta-analysis. Frontiers in Cardiovascular Medicine, 10, 1217748.\u003c/li\u003e\n\u003cli\u003eLi, X., Dehghan, M., Tse, L. A., Lang, X., Rangarajan, S., Liu, W., ... \u0026amp; Li, W. (2023). Associations of dietary copper intake with cardiovascular disease and mortality: findings from the Chinese Perspective Urban and Rural Epidemiology (PURE-China) Study. BMC Public Health, 23(1), 2525.\u003c/li\u003e\n\u003cli\u003eLi, X., Ling, J., Hu, Q., Fang, C., Mei, K., Wu, Y., ... \u0026amp; Li, J. (2023). Association of serum copper (Cu) with cardiovascular mortality and all-cause mortality in a general population: a prospective cohort study. BMC Public Health, 23(1), 2138.\u003c/li\u003e\n\u003cli\u003eWang, L., \u0026amp; Zhao, Y. T. (2023). Association of the dietary copper intake with all-cause and cardiovascular mortality: A prospective cohort study. Plos one, 18(10), e0292759.\u003c/li\u003e\n\u003cli\u003eWang, D., Tian, Z., Zhang, P., Zhen, L., Meng, Q., Sun, B., ... \u0026amp; Li, S. (2023). The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease. Biomedicine \u0026amp; Pharmacotherapy, 163, 114830.\u003c/li\u003e\n\u003cli\u003eParsanathan, R. (2024). Copper\u0026rsquo;s dual role: unravelling the link between copper homeostasis, cuproptosis, and cardiovascular diseases. Hypertension Research, 1-3.\u003c/li\u003e\n\u003cli\u003eIsiozor, N. M., Kunutsor, S. K., Vogelsang, D., Isiozor, I., Kauhanen, J., \u0026amp; Laukkanen, J. A. (2023). Serum copper and the risk of cardiovascular disease death in Finnish men. Nutrition, Metabolism and Cardiovascular Diseases, 33(1), 151-157.\u003c/li\u003e\n\u003cli\u003eAnonymous (2019) Chinese Elderly Hypertension Management Guidelines 2019. People\u0026apos;s Health Publishing House.\u003c/li\u003e\n\u003cli\u003eLee, J. (2019). Associations between handgrip strength and disease-specific mortality including cancer, cardiovascular, and respiratory diseases in older adults: a meta-analysis. Journal of Aging and Physical Activity, 28(2), 320-331.\u003c/li\u003e\n\u003cli\u003eYang, L., Chen, X., Cheng, H., \u0026amp; Zhang, L. (2022). Dietary copper intake and risk of stroke in adults: a case-control study based on national health and nutrition examination survey 2013\u0026ndash;2018. Nutrients, 14(3), 409.\u003c/li\u003e\n\u003cli\u003eZeng, Z., Cen, Y., **ong, L., Hong, G., Luo, Y., \u0026amp; Luo, X. (2024). Dietary copper intake and risk of Parkinson\u0026rsquo;s disease: a cross-sectional study. Biological Trace Element Research, 202(3), 955-964.\u003c/li\u003e\n\u003cli\u003eYao, J., Hu, P., \u0026amp; Zhang, D. (2018). Associations between copper and zinc and risk of hypertension in US adults. Biological Trace Element Research, 186(2), 346-353.\u003c/li\u003e\n\u003cli\u003eKodama, S., Saito, K., Tanaka, S., Maki, M., Yachi, Y., Asumi, M., ... \u0026amp; Sone, H. (2009). Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. Jama, 301(19), 2024-2035\u003c/li\u003e\n\u003cli\u003eChen, Y., Lin, W., Fu, L., Liu, H., Jin, S., Ye, X., Pu, S., \u0026amp; Xue, Y. (2023). Muscle quality index and cardiovascular disease among US population-findings from NHANES 2011-2014. BMC public health, 23(1), 2388.\u003c/li\u003e\n\u003cli\u003eMunoz-Bravo, C., Soler-Iborte, E., Lozano-Lorca, M., Kouiti, M., Gonz\u0026aacute;lez-Palacios Torres, C., Barrios-Rodriguez, R., \u0026amp; Jimenez-Moleon, J. J. (2023). Serum copper levels and risk of major adverse cardiovascular events: a systematic review and meta-analysis. Frontiers in Cardiovascular Medicine, 10, 1217748.\u003c/li\u003e\n\u003cli\u003eLi, X., Dehghan, M., Tse, L. A., Lang, X., Rangarajan, S., Liu, W., ... \u0026amp; Li, W. (2023). Associations of dietary copper intake with cardiovascular disease and mortality: findings from the Chinese Perspective Urban and Rural Epidemiology (PURE-China) Study. BMC Public Health, 23(1), 2525.\u003c/li\u003e\n\u003cli\u003eCollins, J. F. (2021). New roles for copper metabolism in cell proliferation, signaling, and disease. Journal of Biological Chemistry, 295(2), 464-478.\u003c/li\u003e\n\u003cli\u003eDiNicolantonio, J. J., Mangan, D., \u0026amp; O\u0026rsquo;Keefe, J. H. (2018). Copper deficiency may be a leading cause of ischaemic heart disease. Open heart, 5(2), e000784.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","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":"Dietary Copper Intake, Cardiovascular Diseases, Mortality, NHANES","lastPublishedDoi":"10.21203/rs.3.rs-4414611/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4414611/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile the impact of macronutrients on health is well-understood, the influence of micronutrients such as copper on cardiovascular health remains less explored. Copper, vital for heart function and antioxidant defense, may affect cardiovascular health through its role in enzymatic activities that reduce oxidative stress. This study evaluates the relationship between dietary copper intake and cardiovascular outcomes in hypertensive patients using data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. Findings reveal that higher dietary copper intake is associated with significantly lower cardiovascular disease (CVD) prevalence and mortality rates. A non-linear relationship was identified, indicating an optimal copper intake threshold of approximately 2.85 mg/day. Notably, the protective effects of copper were more pronounced in men, non-diabetic individuals, and those with higher educational levels. These results underscore copper\u0026rsquo;s potential role in preventing cardiovascular complications in hypertensive patients and support the inclusion of copper intake in dietary recommendations to improve cardiovascular health. This study enhances our understanding of how micronutrients influence cardiovascular disease management and aids in developing targeted nutritional interventions.\u003c/p\u003e","manuscriptTitle":"The Impact of Dietary Copper Intake on Cardiovascular Morbidity and Mortality among Hypertensive Patients: A Longitudinal Analysis from NHANES (2001-2018)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 18:52:49","doi":"10.21203/rs.3.rs-4414611/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":"d4778f9d-9568-40dc-a6c1-acde939a1401","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-25T15:16:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-30 18:52:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4414611","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4414611","identity":"rs-4414611","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}