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Cardiac & Cardiovascular Systems
Atrial fibrillation (AF) is a severe and most common supraventricular arrhythmia in humans, which, if left untreated or treated ineffectively, can lead to ischemic stroke or heart failure. It has been suggested that serum vitamin D (VitD) deficiency may be one of the critical factors influencing the onset of AF, especially in the period after cardiac surgery, such as coronary artery bypass grafting. Several papers have indicated that VitD supplementation reduces the risk of AF, significantly reducing the proportion of patients between the control and study groups in both the pre- and postoperative periods. Factors that increase the risk of AF from VitD deficiency are also further indicated, and these are age, gender, weight, season or comorbidities.
- atrial fibrillation
- vitamin D deficiency
- vitamin D supplementation
1. Introduction
Vitamin D (1,25(OH)D) deficiency is seen in various populations around the world regardless of ethnicity [1,2,3,4]. Vitamin D (VitD) status is determined by serum testing and can vary widely depending on age, gender, complexion, season or location. VitD can be ingested in the diet as well as synthesized in a complicated metabolic process involving hydroxylation reactions in two stages. The initiation of VitD synthesis takes place in the skin as a result of UVB radiation. Its precursor is 7-dehydrocholesterol, which is an intermediate of cholesterol synthesis, and its activity depends on the concentration of 7-dehydrocholesterol reductase (DHCR7), so the intensity of preVitD synthesis depends on the concentration of DHCR7 and exposure to sunlight. PreVitD is taken up in the blood by vitamin-D-binding protein (DBP) and transported mostly to the liver. Here, through the action of specific CYP450 hydrolases, such as CYP2D11, CYP2D25 and CYP2R1, another form of VitD, 25-hydroxyvitamin Dt, is obtained through hydroxylation of the carbon ring at position 25 [5]. Of these three hydroxylases, CYP2R1 is the most important, and its activity has also been found in the testes [6]. Subsequently, there is a reuptake, still inactive form of VitD, via DBP transporting it to the kidneys; where, under the action of α-1 hydroxylase, also known as CYP27B1, an actively biological form of VitD (1,25-dihydroxyvitamin Dt) is produced. Activation occurs due to a second hydroxylation at 1 position of the carbon chain [7]. It is well known that the hormonally active form of VitD controls calcium metabolism, but in recent decades, it has been shown to be a very important regulator of other organismal systems. It is difficult to argue with the importance of VitD in the face of numerous papers proving the usefulness of VitD in the treatment of musculoskeletal disorders, as well as its effect on immune function or correlation with overall body condition [8,9,10,11,12]. However, not only the coexistence of musculoskeletal and cardiovascular conditions associated with VitD deficiency is indicated, but also the independent effect of VitD on the cardiovascular system [13]. One of these is atrial fibrillation (AF), which is the most commonly diagnosed arrhythmia nowadays. The worldwide incidence of AF has increased significantly over the past three decades and is now approximately 60 million cases [14]. In addition to the high prevalence of the disease, the costs associated with hospitalizing and treating patients require large amounts of funding. It has been calculated that the resources devoted to AF-related treatment and campaigning range between $6 and $26 billion per year in the US [15]. Despite the financial outlay and treatment strategies developed, this arrhythmia is still associated with a high number of complications related to thromboembolic stroke, progressive congestive heart failure, reduced quality of life or even sudden cardiac death [16]. Its treatment includes rhythm control through the use of antiarrhythmic drugs which prevents its recurrence and also anticoagulant therapy reducing the risk of thromboembolic stroke [17]. Another option is to undergo surgical ablation of the AF initiating center as an alternative to the conventional treatment [18]. Currently, there are two types of AF, the first of which is incidental AF (IAF) that is caused by the chronic effects of profibrogenic factors, while the second arises most often from heart surgery and is referred to as postoperative atrial fibrillation (PoAF).
2. Pathogenesis of AF and Role of VitD in Its Induction
The pathogenesis of IAF is not fully understood; however, researchers have identified factors that appear to be critical elements in the development of IAF. Among them are disorders of the renin–angiotensin–aldosterone system (RAAS) (Figure 1), indicators of inflammation and especially C-reactive protein (CPR), fatty acid metabolism and reduced levels of VitD which correlate in some way with the previously mentioned factors [19,20,21,22,23,24,25]. In addition, a decrease in its activity in the blood affects the development of diseases that contribute to IAF. Altogether, it significantly affects the balance of extracellular matrix proteins, namely, collagen of various types which is the structural binder of surrounding tissues. Therefore, the determination of biomarkers of synthesis and degradation, such as carboxy-terminal telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III collagen, can indicate atrial structural changes [25,26].
Figure 1. Scheme showing the link between atrial fibrillation and the renin–angiotensin system. The renin–angiotensin–aldosterone system is a widely recognized regulatory axis involved in many processes in the body. It affects, among others, the regulation of blood pressure, and disorders in the system appear to influence the pathogenesis of atrial fibrillation.
The RAAS is a widely understood regulatory axis involved in many processes in the body. Among other things, it influences the regulation of blood pressure, the body’s water and mineral balance or the secretion of hormones (antidiuretic hormone) [28]. Abnormalities in the functioning of this axis cause serious disorders related to the renal or cardiovascular system [29]. Excessive and prolonged stimulation of the RAAS axis leads to chronic heart failure where angiotensin II plays a key role [30]. It leads to hypertrophy of myocardial cells and hyperproliferation of fibroblasts which result in the accumulation of collagen of various types and the appearance of an interstitial fibrosis [31,32]. In addition, during high RAAS activity, the expression of cardiac receptors for aldosterone is increased which further stimulates angiotensin-converting enzyme in myocardial cells increasing the production of angiotensin II driving the process of structural remodeling of the heart and inducing chronic heart failure [33].
Inflammatory factors are believed to lead to IAF in various pathological conditions, including through adipose tissue in obese individuals, hypertensive disease, coronary artery disease or autoimmune reactions. In addition, a phenomenon such as “AF begets AF” has been observed, in that proinflammatory factors induce IAF through cardiac remodeling and interstitial fibrosis, and existing IAF further drives the synthesis of proinflammatory cytokines [21]. Structural remodeling occurs mainly through TNF which activates signaling pathways for TGF-B and stimulates myofibroblasts. In addition, inflammation increases the activity of myeloperoxidase II and IX, known as critical extracellular matrix metalloproteinases [39,40,41]. Others are platelet-derived growth factor A (PDGF) and also HSP27 and IL-6 [38,42,43].
Obesity, as well as IAF, is a highly topical and growing problem. Figures provided by the WHO for 2022 indicate that the number of obese people has exceeded more than 1 billion people worldwide. Unfortunately, this condition brings with it a number of unpleasant consequences, including an increasing trend in the incidence of various diseases which seems most alarming [52]. Among them, cardiovascular diseases such as heart failure, IAF, hypertension and coronary heart disease account for a large percentage [53]. The development of IAF on a fatty background is related to the deposition of nonesterified fatty acids (NEFAs) in epicardial adipose tissue (EAT) leading, as in previous cases, to structural remodeling of the heart manifested by enlargement and morphological changes of the left atrium [54]. The remodeling includes NEFA-induced myocardial fibrosis. In addition, the already growing EAT activates immune responses, mainly through T cells [55] and produces fibrotic factors, such as reactive oxygen species, proinflammatory cytokines, metalloproteinases and TGF-beta1 [56,57,58].
There are several hypotheses and evidence for the pathomechanism of PoAF, but the exact cause has not yet been defined. It is believed that it is not a single mechanism but a series of processes collectively triggering PoAF. The condition itself carries serious consequences in the form of stroke, thromboembolic diseases or sudden cardiac death [72]. Moreover, it affects between 15 and 60% of the population after cardiac surgery generating increased medical costs and hospital stay [73,74]. Induction of PoAF is associated with a short postoperative period, reaching up to 6 days [75], with the most common cases of PoAF reported between 24 and 72 h [76], which is also consistent with peak levels of leukocytes or inflammatory markers [77]. Considering the pathophysiology of IAF from VitD deficiency, it appears that POAF induction has a very similar basis. The majority of patients showed increased activity of critical proinflammatory factors, i.e., IL-1, IL-6, TNF-alpha and CRP [78], but it is worth mentioning that the activity of these cytokines was not elevated in all PoAF cases [77,79].
3. Relationship of VitD Deficiency and Supplementation to the Risk of PoAF and IAF
3.1. PoAF
The vast majority of the papers addressed the effect of VitD deficiency and/or supplementation on the occurrence of PoAF in the context of coronary artery bypass grafting (CABG) [91,92,93,94]. During the hospitalization period following this procedure, patients often develop AF with varying frequency. Most commonly, a range of 20–30% of patients is indicated, but much lower frequencies in the 12–16% range have also been reported [20]. This is directly related to the level of VitD deficiency. As researchers point out, as a result of the preoperative stress the patient is experiencing, there can be a sudden drop in plasma VitD levels [80,95]. VitD deficiency, which is one of the elements of the pathomechanism of PoAF, can be profound or moderate. Therefore, studies most often use classifications of VitD levels: deficiency to [25(OH)D2] < 20 ng/mL; insufficiency to 20 ng/mL < [25(OH)D2] <30 ng/mL; normal to [25(OH)D2] > 30 ng/mL. AF has been reported in both deficient, insufficiency and normal states, but most often the average VitD level at which AF was reported was below 20 ng/mL [1,3,9,10].
The overwhelming number of studies point to an association between VitD and PoAF. However, without overlooking studies that prove the opposite, there is evidence of an inverse correlation between VitD and PoAF [98,99]. According to some, higher levels of VitD should increase the likelihood of PoAF [94,100]. One should also consider whether VitD is an independent predictor of PoAF. However, it should be noted that in a study that debunks this value of VitD concentration, the PoAF+ group nevertheless has a high level of VitD (19.5 ng/mL) [91].
Using the conclusions of meta-analyses devoted to this topic, the above uncertainties can be partially answered. Of the seven meta-analyses that focused on the level of VitD and its relationship to PoAF frequency, six indicated a significant effect of the VitD concentration [43,101,102,103,104,105,106].
3.2. IAF
Available attempts to determine the frequency of IAF involve different study groups, frequently over many years, often grouping patients with comorbidities [24,107,108,109,110]. Therefore, the frequency of IAF more than once ranges in probability from 1.4% to 27.59% [111,112,113]. The increased risk of AF consists, for example, of cardiovascular diseases such as hypertension or valvular disease [19,24,107]. Moreover, in at-risk groups, lower VitD values contributed to an increased incidence of IAF [107]. In addition, as VitD deficiency worsened, which is also associated with elevated PTH levels, the incidence of AF also increased [114]. To determine the level of deficiency, observational studies use a similar classification to PoAF. Again, [25(OH)D2] values <20 ng/mL are predictive of AF incidence [19,115,116]. Deficient values in one study were associated with 17.2% of AF in the group, while normal values were 10.9% [117].
4. Why Is It So Difficult to Determine the Effect of VitD on AF Incidence?—Limitations
Despite high hopes for the potential properties of VitD in reducing the likelihood of AF episodes, there is still no clear answer to the question of the VitD utility in this regard [101,103,105,120,121,122]. This has to do with the limitations posed to researchers by the substance itself, whose metabolism is extensive and affects numerous tissues through interactions with nuclear and membrane cell receptors [123,124,125,126]. In addition, VitD interacts with hormones that globally affect the entire body [127,128]. There are also technical and presumptive limitations related to the study group, the study methodology, the detection of AF and the determination of its nature, as well as how VitD is supplemented.
VitD is a substance that is subject to seasonal variations [96,129]. Therefore, depending on the season, it can expect different levels of VitD, and thus, there may be difficulties in adjusting the appropriate dose of supplementation [93,103,108,130]. In some cases, additional supplementation that was not included in the medical records could not be ruled out [107,131]. Depending on the biosynthesis and administration in food or supplements, VitD affects the degree of calcium resorption from the diet and also stimulates the release of calcium and phosphate from bone, so it is a very important element in maintaining calcium–phosphate homeostasis and musculoskeletal health [124]. Although researchers are not sure which form, VitD2 or VitD3, supplemented most strongly influences the elevation of serum VitD concentrations, they collectively assert that many factors model the absorption of VitD from the gastrointestinal tract [132,133]. For VitD contained in food to be utilized, it must be released from the food. First and foremost, the presence, amount and type of fats are important for VitD, due to its hydrophobic properties [134]. The influence of fiber, age, degree of obesity and vitamin status is also indicated [135,136]. The degree of hydration of vitamin D used for supplementation is also important. It has been indicated that hydroxylated vitamin D3, i.e., (25(OH)D3), has a higher potential to raise plasma VitD concentrations than nonhydrated forms [132]. Thus, it is important to be mindful of the actual amount of VitD intake, especially since there are reports of cardiotoxic and proarrhythmic effects of too high VitD concentrations [113]. In turn, calcium deficiency and VitD are known to cause secondary hyperparathyroidism, which results in loss of bone mass and, most importantly, is associated with a higher frequency of AF [129]. Thus, the measurement of PTH levels is not only one of the parameters that clarifies the knowledge of VitD status but also the risk of AF [111].
It is also necessary to discuss the limitations associated with the study group. There are papers that appear in which the limitation is still the small size of the study group as well as the very large size of the study group which is difficult to systematize [96,113,140]. Therefore, it is currently more difficult and important to complete a representative group that will apply to a random patient [25,107,110]. The difference in skin pigmentation is significant enough to influence the results of the study, thus obscuring important conclusions [111,141]. Therefore, studies on Caucasian populations, a complexion-diverse study group from Turkey, or results obtained from measurements among veterans are difficult to transfer to a random patient [25,107,110,111]. Finally, analyzing patients with comorbidities, such as hypertension, diabetes mellitus and obesity, who in addition use medications, is an important factor limiting the usefulness of the results, since these entities are factors that increase the occurrence of AF regardless of the level of VitD [25,97,113,142].
The onset of AF is associated with nonspecific symptoms, such as shortness of breath, sweats, fainting, dizziness and rapid fatigue [143]. AF can also occur incidentally or be provoked by a cardiac procedure performed [94,142]. This causes many moments of AF to go unnoticed and often leaves no serious consequences, but undiagnosed AF is an important limitation in studying the impact of VitD deficiency. Therefore, ECG is used to detect AF [143]. However, some authors have focused only on the period of hospitalization or used medical records, which are not always perfect [87,110]. In particular, those AFs that are paroxysmal and asymptomatic pose difficulties; however, they are those that make up a significant portion of the total, so knowing their frequency would be very valuable [94,108,144]. One solution is to use Holter monitoring during hospitalization and follow-up examinations after leaving the hospital, which would allow continuous observation of the heart rhythm [91,93]. This would be particularly appropriate in studies focusing on the postoperative AF [82].
This entry is adapted from the peer-reviewed paper 10.3390/nu15122725
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