Abstract
Purpose of Review
In this review, we discuss the evidence that vitamin D affects cardiovascular disease through interventional and observational studies and their corresponding association mechanisms. We also highlight the need for further research to definitively conclude clinical recommendations based on preliminary data and determine the extent to which vitamin D levels may impact the incidence and prognosis of major cardiovascular diseases in the future.
Recent Findings
Cardiovascular disease has long been recognized as the leading cause of morbidity and mortality worldwide, with many risk factors implicated in its pathogenesis. Vitamin D is a risk factor that, despite being known to be crucial for its role in maintaining bone health, also has several extra-skeletal effects due to vitamin D receptors in vascular smooth muscle and cardiomyocytes. Recent studies have documented a significant association between higher vitamin D levels and lower risk of each cardiovascular disease entity; 11 studies between serum vitamin D and heart failure, 7 studies between serum vitamin D and hypertension, 8 studies between serum vitamin D and coronary artery disease, and 5 studies between serum vitamin D and atrial fibrillation.
Summary
More studies documenting a significant association between increased serum vitamin D and cardiovascular disease are in the context of heart failure compared to hypertension, coronary artery disease, and atrial fibrillation. Conversely, a significant association between increased serum vitamin D and a lower risk of atrial fibrillation is reported in fewer studies compared to the association of vitamin D with other cardiovascular disease entities. Although there is evidence documenting a clear significant association of vitamin D under each category, further research is still needed to definitively conclude the role of vitamin D in cardiovascular disease management.
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Introduction
Cardiovascular disorders (CVD) are the leading cause of morbidity and mortality globally, despite advancements in preventive and therapeutic measures, thus burdening the global healthcare system [1]. Along with known risk factors such as smoking, diabetes, and dyslipidemia [2], new risk factors with possible implications for the prognosis and treatment of CVD are being studied, leading to a new focus on serum vitamin D levels and their impact on CVD. Low vitamin D levels are prevalent across all age groups and countries, especially in the Middle East [3]. Vitamin D has a pleiotropic role in the human body. While it is crucial for maintaining bone health, recent studies have discovered that it has extra-skeletal effects, especially a significant role in cardiovascular (CV) health [4]. Vitamin D deficiency (VDD) is an independent risk factor and predictor of major CV pathologies [5]. A meta-analysis of observational studies including 849,412 subjects suggested a significant association between low serum 25-hydroxyvitamin D (25(OH)D) levels and the CVD risk [6].
The vitamin D receptor (VDR) is in vascular smooth muscles and cardiomyocytes. Vitamin D binding to the VDR allows retinoid X receptor binding and further, resulting in a complex that binds to vitamin D response elements. This process aids in regulating vitamin D response genes [7]. Studies have indicated that the combination of the active form of vitamin D [1,25-dihydroxyvitamin D; 1,25(OH)2D] with the VDR has a wide range of possible CV advantages, including decreased synthesis of renin, promotion of relaxation of vascular smooth muscle cells, and decreasing the production of atherosclerotic plaque-forming foam cells [8]. Wong et al. demonstrated a reduction in endothelium-dependent aortic contraction, thereby causing a reduction in blood pressure (BP) after the vitamin D3 prescription [9].
Observational studies have suggested an inverse association between low serum vitamin D levels and an increased risk of Myocardial infarction (MI) and CVD mortality [10]. To date, CVDs in which the role of vitamin D has been mostly investigated include coronary artery disease (CAD), heart failure (HF), hypertension (HTN), and atrial fibrillation (AF) [11, 12]. VDD is a highly prevalent comorbidity in these conditions and is associated with worse short-term and long-term prognoses [13, 14]. An analysis of previous data demonstrated that the relationship between 25(OH)D and the risk of CVD might not be linear and may plateau between 50 and 75 mol/L. Others have proposed a U-shaped relationship, with a modest increase in CVD risk at both low (< 50 nmol/L) and high (> 125 mol/L) 25(OH)D levels. The shape of the association between vitamin D and CVD over a wide spectrum of 25(OH)D levels is yet to be determined [15]. The hypothesis that vitamin supplements "improve" or "maintain" overall health and lower the risk of diseases, including CVD, has previously been formulated but never been fully established [16, 17].
This review highlights scientific evidence from recent studies focusing solely on patients with CVDs, specifically HF, HTN, CAD, and AF. Our review included interventional studies with vitamin D supplementation and observational studies measuring vitamin D status. This review of recent research attempts to ascertain the association between vitamin D levels and the incidence and prognosis of major CVDs.
Association of Vitamin D with HF
Definition and Prevalence of HF
HF is a challenging health condition frequently resulting from dysfunctional cardiac activity, leading to reduced ventricular filling or blood ejection [18]. Despite ongoing advances in therapy, diagnosis, and prevention, this illness is growing at an alarming rate globally and is linked to higher patient morbidity and mortality [19, 20]. Globally, HF affects over 64.3 million people, and its incidence is increasing daily [18, 21]. It affects approximately 1–2% of adults in developed nations and can affect up to 10% of adults over 70. At age 55, men have a 33% lifetime risk of HF, and women have a lifetime risk of 28%. The mortality risk from HF within the first five years was very high, at over 50%. According to a significant meta-analysis, the 1, 2, 5, and 10-year survival rates of HF patients were 87, 73, 57, and 35%, respectively, leading to a huge burden [22].
Role of Vitamin D in HF
Hypovitaminosis D is observed to be quite widespread in patients with HF, with rates ranging from 80 to 95%, even in sunny climates. According to some studies, it is attributed to the progression of HF and may be a standalone predictor of mortality in patients with HF. Although prospective vitamin D supplementation trials have produced conflicting results, vitamin D treatment may benefit patients with HF positively. The small number of high-risk patients and insufficient sample sizes in these trials are significant drawbacks [23, 24].
Mechanisms of Association Between Vitamin D and HF
Vitamin D has pleiotropic effects on chronic HF [25••]. It negatively influences natriuretic peptides, augmented collagen synthesis, oxidative stress, endothelial dysfunction, and fibrosis, which are likely mechanisms underlying CVDs, such as cardiac hypertrophy and HF [26]. It is a significant regulator of the renin–angiotensin–aldosterone system (RAAS). Therefore, VDD can lead to uninhibited RAAS activation and contribute to the worsening of HF by retaining salt and water [20]. Additionally, it controls the metabolism of Parathyroid hormone (PTH) and calcium, which are crucial for cardiac remodeling and contractility. Low amounts of vitamin D cause calcium levels to decrease, which affects contractility and causes systolic dysfunction. Inadequate PTH production can also impair LV systolic function by causing myocardial fibrosis and hypertrophy [23, 27].
Vitamin D has immunomodulatory properties, as immune cells express 1-α-hydroxylase to control the concentration of calcitriol. By activating anti-inflammatory T-helper cells such as Th2 cells and suppressing Th1 and Th17 cells, it reduces the symptoms of inflammation. Increased levels of the anti-inflammatory cytokines IL-4 and 10, tumor necrosis factor-alpha, and decreased levels of the proinflammatory cytokines IL-1 and IL-6 have all been linked to adequate serum 25(OH)D levels. Conversely, a lack of vitamin D has been linked to proinflammatory cytokine profiles and chronic inflammatory conditions. In a 2019 study, Roffe-Vazquez et al. discovered that the cluster with the lowest levels of 25(OH)D had the lowest levels of vitamin D intake, IL-10, and IL-12p70, but the highest levels of TNF-a, IL-8, and IL-17A [20].
There is evidence from numerous studies that HF is related to low vitamin D levels. A recent study found that higher serum 25(OH)D levels were associated with a lower risk of HF when using the inverse-variance weighted technique. Additionally, they performed a reverse Mendelian randomization analysis, in which the amount of serum 25(OH)D was adversely associated with genetic susceptibility to HF [25••].
Vitamin D Effects on Physical Activity, BP, and Quality of Life in HF Patients
An 8-week study on the effects of short-term vitamin D supplementation in patients with HF was conducted by Hosseinzadeh et al. in 2019 [28]. They investigated how it was related to both physical activity and BP. Only a minor positive correlation between the 25(OH)D level and the 6-Minute Walk Test was observed in their results. After vitamin D-3 treatment, no appreciable changes in BP or 6-Minute Walk Test were seen. Another study by Woo et al. [29] in 2022 assessed the 6-Minute Walk Test and quality of life six months after receiving therapy for vitamin D insufficiency. Patients in the vitamin D group showed statistically significant improvements with the 6-Minute Walk Test distance and quality of life at six months. Moretti et al. [30] concluded in a study that the quality of life scores, including composite overall and clinical summary, significantly improved in vitamin D treatment compared to placebo. Further evidence is needed to prove that vitamin D insufficiency impacts physical activity, BP, and quality of life in individuals with HF.
Role of Vitamin D as a Predictor for Risk of Hospitalization Due to HF
A prospective study of approximately 19000 individuals in 2017 demonstrated that patients with VDD had an increased risk of hospitalization for HF compared with patients with normal levels, reporting a hazard ratio (HR) of 1.61 [24]. Another significant 2019 study examined the relationship between vitamin D status and the pattern of fatality rates and hospitalization risk in HF patients. The results of this investigation showed that the CV hospitalization rates, as well as the 5-year mortality rates, were significantly increased (p = 0.023, HR = 1.74) and that the 5-year mortality rate had increased (p = 0.05, HR = 1.55) in patients with VDD [31].
The prevalence of VDD in elderly patients is high; hence, Porto et al. conducted a novel randomized clinical trial to assess the risk of HF in the elderly owing to the high frequency of vitamin D insufficiency in geriatric individuals. Low levels of 25(OH)D were found to be significantly correlated with the occurrence of HF, particularly in males and obese individuals [27]. In another key study on the geriatric population in the United States, patients with 25(OH)D deficiency had a significantly greater likelihood of being admitted to the hospital (HR = 1.8). Hospitalization risk was also statistically higher in frail elderly than in non-frail elderly people (HR = 1.7) [32]. As most studies suggest a positive correlation between low vitamin D levels and higher rates of HF hospitalization, a definitive causal association must be established in future clinical trials.
Role of Vitamin D as a Predictor of Mortality Rates Due to HF
A randomized control trial conducted on 10,974 individuals reported that vitamin D supplementation decreased overall in-hospital mortality in patients (6.5 vs. 9.4%, Odds ratio (OR): 0.67, p < 0.001) as well as in-hospital mortality within seven days and 30 days (0.9 vs. 2.5%, OR: 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001) [29]. Another observational study followed up for five years suggested that vitamin D levels less than 24.13 ng/mL predicted higher 5-year mortality (p = 0.045) and suboptimal clinical outcomes (p = 0.03) [19]. Cubbon et al. [33] conducted a study on patients receiving CHF therapy. They reported that each 2.72-fold increase in 25(OH)D concentration was related to a 14% decrease in all-cause mortality (95% Cl = 1, 26%; p = 0.04) over a mean follow-up period of 4 years.
In contrast, a randomized control trial conducted on 5110 patients concluded that a daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. These data indicate caution regarding long-term supplementation with moderately high vitamin D doses [34]. Most of these have suggested that VDD is associated with higher mortality rates in patients with HF. However, a few studies also suggest caution regarding high doses of vitamin D; this needs to be explored in future studies for conclusive results. The studies documenting the association between vitamin D and HF have been shown in Table 1.
Association of Vitamin D with HTN
Prevalence of HTN
One of the most prevalent diseases family physicians observe in primary care is HTN [35]. Essential HTN is a major risk factor for CVD and stroke. It is one of the leading causes of mortality and disability [36, 41••]. It affects approximately a billion people worldwide (approximately 25%); by 2025, this number could rise by 29% [35]. In studies conducted on children across the globe, the prevalence was 3–12.6% [36].
Vitamin D and HTN
Numerous studies have demonstrated an inverse relationship between 25(OH)D levels and BP in healthy and hypertensive subjects [4]. Studies have also reported that Vitamin D supplementation exerts a clinically significant antihypertensive effect in VDD patients in the general population and patients with comorbidities [36]. The extensive expression of VDRs and 1, α-hydroxylase enzymes throughout the body may be responsible for the paracrine actions of vitamin D on tissues that regulate BP, glucose, and lipids. This concept supports the correlation between hypovitaminosis D and cardio-metabolic changes, causing CV morbidity and mortality [37]. The United States and Canada have established Complementary and alternative medicine, antihypertensive therapies, an area of study for treatments not frequently offered in hospitals. This therapy provides evidence that vitamin D supplementation lowers BP [35].
Mechanisms of Association
Several pathophysiological mechanisms exist between VDD and arterial HTN. First, studies on mice have revealed that mice without VDRs produce more renin and angiotensin II, which causes HTN. According to another study, renin and angiotensin II plasma concentrations are inversely related to 25(OH)D and 1,25(OH)2D levels. Second, research has demonstrated that PTH is an independent risk factor for HTN and CV events since PTH receptors are found in the cardiovascular system, and PTH infusions increase BP. Additionally, studies have shown that VDD can cause hyperparathyroidism, leading to HTN [35].
Third, changes in the inflammatory activity in the vasculature are key mechanisms in the development and progression of arterial HTN. Most studies have indicated that VDR activation is important for regulating the innate immune response. It has been demonstrated that 1,25(OH)2D3 influences the differentiation of dendritic cells, macrophages, and CD4 + and CD25 + regulatory cells. Vitamin D reduces inflammation by suppressing nuclear factor‐κB and pro-inflammatory cytokine production [38]. Fourth, studies have shown that VDRs are expressed in endothelial cells, vascular smooth muscle cells, and cardiac myocytes, and 1,25(OH)2D reduces the harmful effects of advanced glycation end products on the endothelium, due to which vitamin D has antihypertensive, vasculoprotective, and nephroprotective effects [4]. Finally, vitamin D decreases inflammatory and atherosclerotic factors and enhances the function of the nitric oxide system, thereby decreasing the risk of HTN [35].
Studies Based on the Association Between Vitamin D and HTN
Panahi et al. [39] observed that eight weeks of vitamin D supplementation (50,000 IU/week, and 1000 IU/day) for patients with HTN resulted in significant decreases in mean systolic blood pressure and mean arterial pressure of 5.5 ± 16.16 (p = 0.01) and 3.7 ± 9.24 (p = 0.004) mmHg, respectively. Similar conclusions have also been made in a longer study of 1 year in which an improved systolic blood pressure (− 13.4% ± 8.5 vs. − 2.4% ± 12.6) in patients supplemented with and without vitamin D, respectively, was found. Systolic blood pressure and diastolic blood pressure levels were lower in the patients supplemented with vitamin D(p < 0.05) [37]. Likewise, an investigation conducted by Sheikh et al. [4] showed that in the first and second months following the intervention, the impact of vitamin D supplementation (50,000 units weekly for two months for patients whose serum vitamin D level was less than 20 ng/ml, and 1,000 units weekly for two months for patients whose serum vitamin D level was between 20 and 30 ng/ml) on systolic blood pressure was statistically significant (p = 0.004 and p = 0.024, respectively). In the first month following the intervention, the effect of vitamin D supplementation on diastolic blood pressure was statistically significant (p = 0.046), but not in the second month (p = 0.885). Studies conducted in India, a country with a high prevalence of HTN, found that the prevalence of severe and mild-moderate VDD in hypertensive patients was 77% and 8.7%, respectively. In non-hypertensive patients, the frequencies were 22.2% and 13.9%, respectively [35].
Serum 25(OH)D and its receptor VDR were shown to be lower in children with HTN than in the control group in a specific investigation conducted on children. The findings revealed that abdominal obesity was linked to an increased risk of HTN in multivariable logistic regression models and that longer breastfeeding and higher high-density lipoprotein cholesterol were protective factors against HTN [36]. In patients with elevated BP, C-reactive protein level and neutrophil-to-lymphocyte ratio are known risk factors for morbidity and mortality. A study on the general population found that serum 25(OH)D deficiency in HTN subjects was associated with significantly low levels of C-reactive protein CRP, mean serum calcium and phosphorus, and high levels of total alkaline phosphatase. Vitamin D deficiency is associated with a 1.5-times higher risk for HTN; whereas elevated-reactive protein and alanine transaminase associate with 1.4 and 1.2-times higher risk, respectively, for HTN [40].
Another study found that ten weeks of vitamin D supplementation (50,000 IU weekly) resulted in higher 25(OH)D levels and lower PTH, total cholesterol, and low-density lipoprotein cholesterol levels, thereby causing an overall reduction in CV risk [41••]. In contrast, Theiler-Schwetz et al. [42] examined the effects of vitamin D supplementation on 24-h BP in individuals with VDD and found no significant treatment effects on 24-h BP (all p-values > 0.30). However, there was a significant tendency for the 25(OH)D level to be adversely linked with 24-h systolic blood pressure (-0.196 per ng/mL 25(OH)D, 95% Confidence Interval = –0.325 to –0.067; p = 0.003).
The use of vitamin D supplements to prevent or treat HTN has recently been in contention due to differences in the findings of randomized trials addressing the relationship between vitamin D supplementation and HTN. Although preliminary evidence is available (Table 2), additional clinical trials are required to reach a definitive conclusion.
Association of Vitamin D with CAD
Definition and Prevalence of CAD
CAD causes the myocardium to receive insufficient oxygen and blood supply. This results in an imbalance between the supply and demand of oxygen and is caused by coronary artery blockage. Typically, it involves the development of blood flow-impairing plaques in the coronary artery lumen [43]. Globally, it is the primary cause of death. Deaths from CAD peaked in the 1960s and then began to decline, although they are still the biggest cause of mortality globally [44].
According to one study, CAD was estimated to account for 32.7% of CVDs and 2.2% of the world's overall disease burden [45]. The following categories are generally used to categorize coronary artery disease: stable ischemic heart disease, acute coronary syndrome (ACS), ST-elevation MI, non-ST elevation MI and unstable angina [43].
Overview of the Association Between Vitamin D and CAD
A significant amount of research is being conducted on CVD risk factors and treatments due to the increased death rates associated with CVD. Due to this improvement, the death rate from CVD has decreased by 20% over the past several decades. Nevertheless, 18 billion fatalities occur annually, with MI being the major cause. A recent risk factor for CVD in the human population is VDD [46••].
The direct effect of VDD on CV mortality has been established in various investigations and meta-analyses by demonstrating an increase in CV mortality for every 10 ng/ml reduction in 25(OH)D [47•].
Mechanism of Association Between Vitamin D and CAD
According to research, vitamin D influences endothelial function, cardiomyocyte proliferation, endothelial cell growth, and inflammatory processes that lead to atherosclerosis and associated thrombotic consequences [47•]. Several theories have been proposed, but the precise mechanism underlying the elevated CV risk in patients with vitamin D insufficiency remains unknown [48]. Cardiovascular cells having VDR can produce autocrine calcitriol because they contain the enzyme 1-α-hydroxylase. Calcitriol negatively regulates RAAS, whose excessive activity leads to arterial HTN and cardiac hypertrophy. Evidence links VDD to specific plaque development phases and coronary artery disease destabilization [46••].
Vitamin D protects thrombosis and inflammation by reducing cardiac ischemia–reperfusion injury and reactive oxygen species [48]. Atherosclerosis is greatly influenced by inflammation, also caused by a VDD. Chen et al. [49] used pigs as a model and revealed an intriguing relationship between vitamin D and the nuclear factor‐κB pathway, which inhibits the development of CAD. KPNA4 is a membrane transporter that moves NF‐κB from the cytosol to the nucleus of epicardial adipose tissue cells. Nuclear factor‐κB promotes the transcription of proinflammatory cytokines like IL-6, IL-8, and tumor necrosis factor-alpha, which play a role in atherogenesis in the coronary arteries. Vitamin D-3 inhibits the transcription and translation of KPNA4 in epicardial adipose tissue cells. The shuttling of nuclear factor‐κB into the nucleus is impaired due to decreased KPNA4 expression. Therefore, this paper outlines the inflammatory response, which may be reduced by sufficient intracellular 1,25(OH)2-vitamin D3 levels. Additionally, this provides a mechanistic insight into the relationship between vitamin D insufficiency and CAD.
Studies Based on the Association Between Vitamin D and CAD
Dziedzic et al. [46••] conducted a study and found that patients with single, double, or triple vessel disease had significantly lower 25(OH)D levels than patients without such lesions (median, 17 vs. 15 ng/ml; p < 0.01). Another study conducted by Verdoia et al. [47•] demonstrated that lower levels of vitamin D were statistically associated with more severe coronary disease (p = 0.001), Major adverse cardiovascular events (p = 0.01), and MI (p = 0.03). Lower vitamin D levels are associated with a threefold increased mortality risk among patients undergoing percutaneous coronary procedures. One study demonstrated that Acute Coronary Syndrome was predicted by low vitamin 25(OH)D and 1,25(OH)2D and not by vitamin D2 or D3(p > 0.05) [48].
Xu et al. [50] analyzed that vitamin D shortage increased the risk of CAD (OR = 2.891; p = 0.001, confidence range = 1.459–7.139). Another study by Norouzi et al. [51] demonstrated that lower vitamin D levels are linked to a high risk of coronary artery involvement severity. Furthermore, Navarro-Valverde et al. [52] conducted a randomized control trial in which they demonstrated that only 1 had major adverse cardiovascular event in the group who received 25(OH)D3 compared to 5 in the control group (p = 0.66) and 28.6% of patients with 25(OH)D levels ≤ 50 nmol/L experienced major adverse cardiovascular events compared to 0% of patients with level > 50 nmol/L (p = 0.037).
Lee et al. [53] have also demonstrated that 106 out of the 339 individuals who had plaque also had lower levels of 25(OH)D (p = 0.0316). On the contrary, the study by Aslanabadi et al. [54] indicated that vitamin D did not significantly affect the cardiac biomarker (p = 0.417). Still, the mean change in Creatine Kinase-Myoglobin Binding between 8 and 24 h (p = 0.048) and hs- C-reactive protein (p = 0.045) was significantly in favor of the vitamin D group. In addition, Sajjadieh et al. [55] did not find any association between vitamin D serum levels and coronary artery calcification, and the study by López-Bautista et al. [56] did not find any independent relationship between VDD and CAD occurrence among the Mexican Population. A study by Rokni et al. [57] suggested that 25(OH)D may be a risk factor for CAD but needs further investigation.
Most studies cited above in Table 3 supported that lower vitamin D levels is associated with an increased risk of CAD, and supplementation with vitamin D may help reduce major adverse cardiovascular events. However, this needs to be explored further in a larger clinical trial.
Association of Vitamin D with AF
Prevalence of AF
AF is the most common persistent arrhythmia that significantly impacts overall morbidity and mortality. According to estimates, after age 40, the risk of AF increases by up to 26%, and AF may cause 10% to 15% of all strokes, with a 1.9-fold increase in mortality [58, 59]. Although it is not a lethal arrhythmia, it can lower the quality of life, elevate the likelihood of cardiac mortality, and lead to stroke. Epidemiological research on AF has found that the condition's prevalence is underestimated. The major causes are the failure to diagnose paroxysmal AF and the lack of interest in treating silent AF patients. The prevalence of AF is anticipated to increase over time as the population's age structure changes, the proportion of elderly people rises, and other risk factors, including HTN, diabetes, and CV disease, increase [60].
Relationship Between Vitamin D and AF
It is established that an inflammatory state is closely correlated to AF. IL-10 production can be increased by vitamin D, whereas IL-6, IL-12, interferon, and tumor necrosis factor-alpha production can be decreased. This relationship creates a cytokine spectrum that helps reduce inflammation [60]. It is also hypothesized that cardiac remodeling driven by RAAS axis activation may enhance the risk of AF [61]. The activity of the RAAS is modulated by vitamin D. Oxidative stress and inflammation brought on by activated RAAS may both result in AF [58].
Low plasma 25(OH)D3 levels may cause the RAAS to become more active, whereas RAAS suppression can delay the development of AF. Vitamin D is a negative endocrine modulator of RAAS. Patients with Vitamin D insufficiency fail to suppress RAAS, making preventing AF more challenging [61]. High fibroblast growth factor 23 levels prevent 1-α hydroxylase activity and reduce vitamin D3 synthesis [60]. Chen et al. [62] demonstrated a consistent association between high circulating fibroblast growth factor 23concentrations and AF. Another pathophysiology attempt at an explanation focuses on how parathyroid hormones interact with vitamin D to affect electrolytes, particularly calcium but phosphate and magnesium. Unbalanced electrolytes may be causative in the onset of AF [63••].
Relationship Between Genetically Predisposed VDD and AF
Chan et al. [64] attempted to establish a relationship between low levels of vitamin D and AF in a case–control study on subjects recruited from a Chinese clinical cohort of patients with stable coronary artery disease. A total of 12 Single Nucleotide Polymorphisms involved in the vitamin D mechanistic pathways from prior genome-wide association studies were studied, and a composite Genetic Risk Score (GRS) (linear continuous: 0–8) was constructed based on the summation method described previously in the literature.
The Vitamin D Genetic Risk Score (points 0–8) generated from the 4 Single Nucleotide Polymorphisms involved in the Vitamin D-binding protein)/group-specific component was strongly predictive of serum 25(OH)D [p = 0.52, 95% CI: 0.294–0.742; p < 0.001], and this relationship persisted even after adjustment for confounders (age, gender, BMI, smoking, HTN, diabetes mellitus, systolic/diastolic BP, triglycerides, low-density lipoprotein / high-density lipoprotein cholesterol, creatinine, etc.) [64].
Genetic exposure to vitamin D was independently associated with a reduced risk of AF. Categorically, those with genetically deprived vitamin D status, as denoted by a low Genetic Risk Score (0–3), had an excess AF risk of 85% compared to those with a high Genetic Risk Score (4–8). This evidence suggests that VDD might have an important role in AF development [64].
Relationship Between Vitamin D Status and 1-α-hydroxylase in AF
Nikolova et al. [65], in a prospective observational study, evaluated the vitamin D status and the expression of 1-α-hydroxylase (CYP27B1) in peripheral blood mononuclear cells in patients with CVD (HF and AF specifically) in an attempt to reveal possible relationships with CVD risk factors. A significant decrease in 25(OH)D levels was found in the AF-group (29–56 ± 11.76 ng/ml, P = 0.044) vs. controls (37.36 ± 15.10 ng/ml), with an increase in coronary artery calcium score. In addition, a significant decrease was also seen in BMI, abdominal obesity, and duration of HTN for both controls and cases (HF and AF patients).
In this study, the analysis of the (CYP27B1) gene expression in peripheral blood mononuclear cells revealed a tendency for downregulation (p = 0.07) in HF and AF patients and increased coronary calcium accumulation. This concept not only implies a significant association between serum 25(OH)D levels and the incidence of AF and HF but also lays the foundation for further studies on 1-α-hydroxylase gene (CYP27B1) expression in peripheral blood mononuclear cells to be used as a reliable biomarker for CV pathology [65].
Relationship Between Vitamin D Levels and Incident AF & Postoperative Atrial Fibrillation (POAF)
Cerit et al. [58] observed subjects who underwent CABG surgery to assess the relationship between Vitamin D and the development of POAF. They noted that although there was a significant negative correlation between Vitamin D and left atrial diameter, Vitamin D level was not an independent predictor for POAF. A succeeding study by Cerit et al. [59] demonstrated that while no significant difference in terms of POAF was noted between patients with taking oral vitamin D supplements and those that did not, i.e. control group; (p = 0.538), those without vitamin D deficiency had a significant advantage from vitamin D supplementation to reduce the incidence of POAF (p = 0.02).
In a large retrospective study by Turin et al. [61], where 47,083 patients were included to establish a relationship between VDD and incident AF in the setting of RAAS inhibition, a significant association between vitamin D levels and the incidence of AF was observed. The major observational finding was that VDD patients in the angiotensin-converting enzyme inhibitor/angiotensin receptor blocker receiving group had an increased rate of AF. An investigation by Kara et al. [66] suggests that vitamin D supplementation reduced the probability of developing POAF by 0.24 times (p = 0.034) in patients with VDD. In contrast, patients who acquired POAF had greater vitamin D concentrations and took vitamin D supplements more frequently, according to research by Ohlrogge et al. [63••], which determined that using vitamin D supplements could increase the incidence of POAF (p = 0.034, OR = 5.03).
(The studies demonstrating an association between vitamin D and AF have been shown in Table 4. Further research is also needed on this topic to conclude because the findings of the various studies conducted in the recent past have needed to be more consistent.
Conclusion
Being the leading cause of morbidity and mortality, cardiovascular disease risk factors such as vitamin D levels have much potential based on recent evidence through interventional and observational studies. A significant association, along with the mechanism of association between vitamin D and cardiovascular disease entities, including heart failure, hypertension, coronary artery disease, and atrial fibrillation, has been documented in the literature. Although most studies have been reported in the context of vitamin D and heart failure, with literature even detailing the effect of vitamin D on the quality of life of heart failure patients and a predictor for risk of hospitalization, a definitive clinical recommendation has yet to be made. Indeed, a conclusive role of vitamin D in impacting overall cardiovascular disease remains to be established through future research.
Data Availability
The authors declare that data supporting the findings of this study are available within the article.
Abbreviations
- CVD:
-
Cardiovascular disorder
- CV:
-
Cardiovascular
- VDD:
-
Vitamin D deficiency
- 25(OH)D:
-
Serum 25-hydroxyvitamin D
- VDR:
-
Vitamin D receptor
- 1,25(OH)2D:
-
1,25-Dihydroxyvitamin D
- BP:
-
Blood pressure
- CAD:
-
Coronary artery disease
- HF:
-
Heart failure
- HTN:
-
Hypertension
- AF:
-
Atrial fibrillation
- RAAS:
-
Renin-angiotensin-aldosterone system
- PTH:
-
Parathyroid hormone
- IL:
-
Interleukin
- HR:
-
Hazard ratio
- OR:
-
Odds ratio
- POAF:
-
Post-operative atrial fibrillation
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Agarwal, P., Agarwal, Y. & Hameed, M. Recent Advances in Association Between Vitamin D Levels and Cardiovascular Disorders. Curr Hypertens Rep 25, 185–209 (2023). https://doi.org/10.1007/s11906-023-01246-4
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DOI: https://doi.org/10.1007/s11906-023-01246-4