Preformed vitamin A (retinol and retinyl esters) and provitamin A carotenoids, such as beta-carotene, which are converted to retinol, are the two main forms of vitamin A in the human diet [13]. It is believed to be involved in angiogenesis, oxidative balance, and cellular development, thus, influencing the cardiovascular system and metabolic disorders [14].

Retinoids, vascular responses to damage, and atherogenesis are all related. Proteins involved in vitamin A metabolism, including retinol-binding protein 4 (RBP4) and aldehyde dehydrogenase 1A1 have been to be associated with metabolic disease [15]. After four days of vitamin A administration, animal studies showed a significant reduction in atheromatous plaque and a decrease in intimal damage via changing the migration and proliferation of smooth muscle cells, which play a crucial role in atherogenesis [16]. According to Noy et al. [17], Vitamin A metabolite all-trans-retinoic acid (RA) regulates growth, remodeling, and metabolic responses in adult tissues. On a cellular level, all trans retinoic acid inhibits neointima formation in endothelial cells by inducing Plasminogen activator inhibitor-1 (PAI-1) [18]. Another study [19] demonstrates that retinoid receptors enhance intracellular adhesion molecule-1 (ICAM-1) protein expression in endothelial cells which is involved in a number of pathologic conditions including atherosclerosis and stroke. There is evidence to support the theory that increased lutein levels are responsible for the protection provided by vegetables and fruits against CVD. It has antioxidant qualities and stops plasma-damaging complement factors from activating. This was determined by comparing two distinct populations, the Mediterranean and Northern Ireland, and it was discovered that there were no appreciable differences between them in terms of the healthier cardiometabolic characteristics that the first population displayed as a result of the higher plasma concentration of lutein and other antioxidants [20]. A relationship between vitamin A and subclinical atherosclerosis was discovered by assessing circulating retinol-binding protein 4 (RBP4), transthyretin (TTR), and the carotid intima-media thickness test (CIMT). Another study states that RBP4 is associated with insulin resistance, diabetes, and atherosclerosis, with retinol being inversely connected to CIMT. Dietary vitamin A showed a significant protective impact against preclinical atherosclerosis, and RBP4 levelss were connected to a specific involvement in atherogenesis [21].

Both studies, ATBC (Alpha-Tocopherol Beta-Carotene Cancer Prevention) and CARET (Beta-Carotene and Retinol Efficacy Trial) assessed the efficacy of beta-carotene in cancer prevention in smokers and included individuals with occupational asbestos exposure [22, 23]; which show no benefit from beta-carotene in terms of the incidence of CVD.

Retinol increases the production of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines, via activating the nuclear retinoid receptors, according to another study [24]. In two successive, non-genomic pathways, Gelain et al. [24] show how retinol stimulates tyrosine hydroxylase. In patients with heart failure with a low left ventricular ejection fraction, blocking $\beta$-adrenoceptors lowers sympathetic nervous system activity and increases survival (LVEF). Another study looked into whether vitamin A status altered the relationship between using $\beta$-blockers and the risk of all-cause mortality [25]. It was shown that $\beta$-blocker therapy was related with better survival in patients with suspected coronary heart disease (CHD), particularly in those with high serum vitamin A levels. Excessive intake of preformed vitamin A, compared to its precursors, has been linked to teratogenicity in human and animal studies [26]. In women taking over 10,000 IUs of preformed vitamin A per day from supplements, it is estimated that 1 of 57 babies is born with a secondary congenital disability [27]. The patient may develop xerosis of the skin, and mucosa due to systemic use. Alopecia, anorexia, pruritus, mucous membrane dryness, muscle and bone pain, and hyperlipidemia are all symptoms of chronic poisoning [28].

B vitamins are a group of eight water-soluble chemicals with chemically different structures that play a crucial role in cell metabolism as coenzymes in several anabolic and catabolic enzymatic activities [29]. Individual B supplements can be used separately because each one has specific properties, such as being a cofactor for essential metabolic processes or a precursor in the same area [30].

2.2.5 Vitamin B6 or Pyridoxal Phosphate (PLP)

Vitamin B6 comprises a group of six water-soluble chemical compounds which includes pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), and their 5${}^{\prime }$-phosphates [73]. About 160 bodily functions require the cofactor pyridoxal phosphate (PLP), which is the active form. It takes part in the transformation of lipids, nucleic acids, amino acids, and carbohydrates, as well as the breakdown of glycogen. The main metabolic processes that vitamin B6 regulates include the breakdown of tryptophan [74], sphingosine phosphate [75], and the activity of the transcription factor NF-B. By modulating the activity of inflammasomes and particularly its component, the NLRP3 sensory protein, it has the effect of lowering inflammation in the body [76]. The effect of vitamin B6 in CVDs and in decreasing blood pressure is one of the benefits of the vitamin that is frequently highlighted. Humans with high-risk atherosclerosis, strokes, and thrombosis also have low plasma levels of PLP [76, 77, 78]. A study on the effects of B6 on a sizable population of Koreans was undertaken by Jeon and Park. They found that higher vitamin B6 intake reduced the chance of developing CVDs in males, but there was no correlation in women [79]. Page carried out research on the effects of PLP concentration on post-menopausal women [80]. The conclusion was that the risk of myocardial infarction is inversely related to the concentration in plasma.

Recent epidemiologic studies have found a link between low vitamin B6 level and an increased risk of cardiovascular disease, albeit the precise mechanism is still unknown despite several potential explanations. The fact that vitamin B6 is a coenzyme for numerous processes suggests that it may have a cardioprotective impact. PLP is a coenzyme that is required for numerous metabolic processes, and it has also been linked to inflammation [81, 82], immunological function [82] thrombosis [83, 84], all of which are crucial factors across all phases of the atherosclerotic process. Fig. 1 summarises the proposed candidate processes for atherogenesis linked to vitamin B6.

Fig. 1.

Mechanisms of the atherogenic effects linked to vitamin B6.

Vitamin C, also known as ascorbic acid, serves as an important micronutrient and antioxidant for the body. It functions as a reducing agent as it acts as an electron donor while itself being oxidized to a radical, thereby helping in mediating reactive oxygen species-induced damage, as well as regenerating other antioxidants [107]. It has both enzymatic and non-enzymatic functions, however, in the context of cardiovascular health, vitamin C has shown to have positive impacts on reducing oxidative stress and damage, blood pressure, and improving endothelial function among other risk factors of atherosclerosis [108, 109, 110, 111].

Various types of studies have highlighted the benefit of vitamin C on cardiovascular health, attributing its positive impacts to its antioxidant capabilities. One review established that supplementation with vitamin C reduced systolic and diastolic blood pressures [112], and another study suggested that vitamin C has a protective effect on arterial stiffness [113], both associated factors for atherosclerosis. A review of RCTs determined the effect of ascorbic acid supplementation on endothelial function. The authors found that an improvement in endothelial function was seen in doses greater than 500 mg/d and a better effect was noted in those with a higher CVD risk [109]. Antioxidants like vitamin C have been found to contribute to endothelial function by regulating nitric oxide level of the endothelium, and impeding inflammation, lipid peroxidation, platelet oxidation, and LDL oxidation - factors that can worsen the status of ED [114]. In the European Prospective Investigation of Cancer (EPIC) - Norfolk study, plasma ascorbic acid’s relationship with mortality was examined in 19,496 men and women. An inverse relationship existed between ascorbic acid and cardiovascular risk factors. Plasma ascorbic acid concentration was also found to be inversely related to ischemic heart disease (IHD) and mortality due to CVD [115]. A meta-analysis of 16 prospective studies found a notable inverse relationship between dietary consumption and circulating vitamin C levels and the risk of stroke [116].

Vitamin C is generally tolerable at high dosages in healthy individuals. There is a possibility that high levels may lead to the formation of kidney stones, risk of iron overload, or even hemolysis in glucose-6-phosphate dehydrogenase deficient people [117]. There is very limited data on the negative impacts of vitamin C-only supplementation on cardiovascular health. One important study to be noted is the Iowa Women’s Health Study which examined how vitamin C would alter the mortality from CVD in postmenopausal diabetic women. A disturbing association was noted; supplementing high doses of vitamin C was associated with an increased risk of CVD mortality [118]. Other negative association of vitamin C in postmenopausal women has been noted while being co-supplemented with vitamin E, further explained later in the article in the ‘recommendations’ section.

To summarize, vitamin C is one of the most important vitamins required for cardiovascular health. Though few studies are highlighting the risks in postmenopausal women, a regular intake should be recommended to individuals at risk of any form of CVD.

The group of secosteroids, Vitamin D, well known for its vital role in homeostasis of calcium and bone mineralization, falls under one of the most common nutritional deficiencies worldwide, prevalent in more than one billion people [119]. Even though the effects of this vitamin have been widely researched in various medical conditions and diseases, establishing a strong clinical relation between vitamin D and its influence on cardiovascular health has been difficult. Since the finding of vitamin D receptor (VDR), an intracellular receptor, in various cardiovascular tissues such as cardiomyocytes, endothelial cells, smooth muscle cells of the vasculature, and platelets, amongst others [120], the topic of vitamin D’s role in CVD has been of much debate. In addition to the VDR, vitamin D–binding proteins in the blood circulation, whose concentration and binding affinity, if affected, has been stated to lead to a risk of vitamin D deficiency and other CVDs [121].

Evidence from existing literature documents various roles of vitamin D which have been postulated in modulating CVD, such as atherosclerosis, blood pressure, IHD, and cardiac failure [120, 122, 123]. Since VDRs are also found on vascular endothelial cells, studies have revealed possible vitamin D effects linked to endothelial function. In a study by Zhang et al. [124], endothelial function was assessed by measuring and comparing brachial artery flow-mediated dilation (BAFMD), sE-selectin and soluble vascular cell adhesion molecule-1 in 117 non-dialysis chronic kidney disease (CKD) patients. The results concluded that BAFMD was lower in patients with low-to-no vitamin D levels than in individuals with normal vitamin D levels. The remaining findings also showed associations and correlations that indicated low-to-deficient vitamin D levels with ED [124]. With the relation between vitamin D deficiency and ED, and the fact that ED also correlates to an increased risk in CVD mainly by contributing to hypertension and atherosclerosis [122, 125], it can be assumed that there is indirect causation of vitamin D deficiency in CVD. Many studies have also shown an inverse relationship between plasma 25(OH)D levels and hypertension, one even concluding that vitamin D can be used as an ‘adjuvant therapy for patients with grades I–II essential hypertension’ [126, 127]. The protective nature of vitamin D against myocardial infarction (MI) and stroke has been hypothesized and studied, mainly displaying results in favor of the hypothesis. In a review by Muscogiuri [123] in which the effects of vitamin D on CVD, mainly MI and stroke was explored, studies confirmed that vitamin D might protect against these CVDs, in contrast to a few that proposed the opposite. However, it was made sure that hypovitaminosis D promotes atheroma formation and increases the risk of vessel wall calcification, factors both which contribute heavily to major CVDs [128].

Large-scale randomized trials have produced results that do not favor the hypothesis of vitamin D supplementation providing any benefit against CVD. For example, VITAL, a randomized, double-blind, placebo-controlled trial to examine the benefits and risks of vitamin D${}_3$, supplemented a dosage of 2000 IU/day to over 25,800 adults across the U.S. After a median 5.3-year intervention, the study concluded that daily high dosage vitamin D did not affect the incidence of any cardiovascular events, major or minor [128]. Another randomized clinical trial exploring the effect of monthly high dosage supplementation also yielded similar results [129]. A Mendelian randomization study tested the association of genetically reduced plasma 25(OH)D with the increased risk of IHD and MI and found no evidence of such association [130]. In addition, recent randomized controlled trials have had results indicating no benefit of vitamin D on the management of hypertension [131, 132]. With many studies highlighting hypovitaminosis D and its correlation with CVD risk, the exact nature of the relationship between vitamin D and cardiac vasculature remains disputable.

Vitamin E is an essential, lipid-soluble, non-enzymatic antioxidant, which exists in 2 primary forms, tocopherols and tocotrienols, each having four subtypes (a-, b-, g-, and d-) [133]. Its importance mainly lies with the anti-inflammatory and antioxidant properties, as seen in numerous in vitro and animal studies. Its role in lipid peroxidation has mainly brought forward the idea of its potential cardioprotective effects.

Studies have usually shown an inverse association between plasma concentrations of antioxidants and CVD [134, 135]. A possible mode of action of vitamin E that likely contributes to reduced risk of CVD is through the antioxidant protection of LDL [136]. Oxidized LDL attracts circulating monocytes and inhibits macrophage movement in the intima. Oxidatively modified LDL uptake via scavenger receptors of macrophages, therefore, then leads to cholesterol-laden foam cells and fatty-streak formation - causing atherosclerosis. Another way of preventing formations and/or progression of the fatty streak is via inhibiting platelet adherence and aggregation, which vitamin E is believed to carry out [137]. In oxidative stress, a decrease in d-a-tocopherol levels from smooth muscle cells results in the growth and proliferation of these cells, which contributes to atherosclerosis [136].

Patients undergoing hemodialysis treatment for end-stage renal disease have been found to have an increased risk of cardiovascular events [138]. A study by Mune et al. [139] investigated the vitality of vitamin E supplementation on HDL and endothelial function in end-stage renal disease (ESRD) patients undergoing hemodialysis. The study showed promising positive results and concluded that the supplementation significantly improved HDL function of cholesterol efflux capacity and endothelial function [139]. A daily supplement of 400–800 IU is recommended in secondary prevention of cardiovascular events in maintenance hemodialysis patients [140]. A 30-year prospective cohort analysis analyzed the effect of serum $\alpha$-tocopherol on long-term overall and cause-specific mortality. The results defined that increased baseline serum $\alpha$-tocopherol levels were linked with lower risk of overall and all significant causes of mortality [141].

Studies have highlighted that there are no effects and/or adverse effects on the cardiovascular system due to vitamin E supplementation. The Physicians’ Health Study II randomized trial explored the effect of long-term supplementation of vitamin E and C on the risk of CV events in over 14,600 men. After ten years, the study concluded that vitamin E or vitamin C had no significant effects on the primary endpoint of major cardiovascular events, individual cardiovascular events (including MI and total stroke), cardiovascular mortality, and adverse effects such as hematuria, easy bruising, and epistaxis. However, it is to be noted that a significant association was seen between vitamin E and increased risk of hemorrhagic stroke (HR, 1.74; 95% CI, 1.04–2.91; p = 0.036) [142]. In a trial in 28,519 male cigarette smokers, a 50% higher risk of subarachnoid hemorrhage with 50 mg per day of $\alpha$-tocopherol supplementation, while no effect was seen on the risk of intracerebral hemorrhage [143]. In a Mendelian randomization study by Wang et al. [144], higher vitamin E levels were related with increased possibilities of CAD and MI. Furthermore, vitamin E levels were also appreciably linked with CAD risk factors, including LDL-cholesterol, total cholesterol, and triglycerides [144]. The HOPE-TOO study, which was an extension of the al Heart Outcomes Prevention Evaluation [HOPE] trial, monitored the long-term supplementation effects of vitamin E and found a somewhat concerning vitamin E effect, as it stated that though there was no significant effect on major CVD events and total mortality, increased HF rates were noted in patients supplemented with vitamin E [145].

It is possible that vitamin E only offers benefits to cardiovascular health in certain patient groups such as those under high oxidative stress, however, more insight regarding the relation of its antioxidant nature with reducing CVD risk is required.

Vitamin K, which occurs in two forms, vitamin K-1 (phylloquinone) and vitamin K-2 (menaquinones (MKs) [146], is well known for its essential role in hemostasis, where it serves as a cofactor for coagulative and anticoagulative factors’ synthesis. It plays a vital role in the management of CVD besides the coagulative pathway. It is responsible for the first part of a two-step activation of Matrix Gla Protein (MGP) (as shown in Fig. 2), a vitamin K-dependent protein (VKDP) that is required for impeding vascular calcification (VC); a characteristic marker of atherosclerosis, especially in coronary arteries [146]. In fact, in patients diagnosed with CKD, for whom the most common cause of death is CVD, mainly due to the fatal progression of VC, vitamin K supplementation has been explored to decrease CVD-specific mortality [147, 148]. MGP is released by chondrocytes and vascular smooth muscle cells (VSMCs). A laboratory study on mouse models found that of MGP in arteries rescues only the arterial mineralization aspect of the MGP deficient mice, whereas its expression in osteoblasts inhibits bone mineralization [149]. This means that increased systemic levels of active MGP will not affect vascular calcification, indicating the importance of its synthesis via VSMCs and hence adequate vitamin K levels. To identify the vitamin deficiency status, the levels of desphospho-uncarboxylated MGP (dp-ucMGP) or other VKDPs serve as serum markers [150].

Fig. 2.

Two-step activation of the Matrix Gla Protein. dpuc, dephosphorylated uncarboxylated; dpc, dephosphorylated carboxylated; pc, phosphorylated carboxylated.

Several studies have backed up the positive role of vitamin K in reducing the risk of CVD. A population-based study, the Rotterdam Study, examined the effects of the intake of both forms of vitamin K primarily on aortic calcification and coronary heart disease (CHD) in 4807 participants. The results showed that though phylloquinone intake had no association with any CVD events, menaquinone intake was significantly associated with the decreased risk of incident-CHD (RR = 0.59), CHD mortality (RR = 0.43), and all-cause mortality (RR = 0.74). Additionally, with severe arterial calcification, a strong negative correlation with menaquinone intake was seen. This study concluded that menaquinone-rich diets might help prevent CHD, likely by mediating arterial calcification inhibition [151]. Zwakenberg et al. [152] reported that vitamin K intake had no association with CVD but noted the possibility of higher intake of long-chain menaquinones associated with a reduced risk of CHD mortality. Another prospective cohort analysis aimed to evaluate the association of the two forms of vitamin K with cardiovascular mortality concluded that both forms likely have a protective role in cardiovascular health [153]. Supplementation of phylloquinone was also shown to slow the progression of VC of the coronary artery in older adults who had varying forms of pre-existing calcification [154]. A high dose of vitamin K-2 intake was found to protect against CHD, associating this protective effect to the higher subtypes, mainly MK-7, MK-8, and MK-9 [155].

As all vitamins have mixed effects shown by various studies, vitamin K is no different. One study examining the association between forms of vitamin K’s effect on reduced stroke risk did not find any association between phylloquinone and menaquinones’ intake with stroke [156]. Another trial monitored whether supplementation of the vitamin K-2 would affect vascular stiffness in patients with CKD by primarily measuring the carotid-femoral pulse wave velocity and secondarily the blood pressure, abdominal aortic calcification, physical function, and serum markers of vascular health. The results indicated that K2 supplementation had no impact on vascular stiffness or calcification [150]. A randomized controlled trial assessing MK-7 supplementation on VC in type 2 diabetic patients showed increased active VC on 18F-NaF Positron emission tomography (PET) scan [157]. However, the fact that there was a lack of patients with vitamin K deficiency in the patients’ group could have influenced the results.

The effect of vitamin K supplementation does show a potential role in lowering the risk of CVD by reducing vascular stiffness and calcification. With few large-scale randomized controlled trials to date, more research and in-depth analysis is required to explore the detailed impact of vitamin K’s effects on reducing CVD risk.