Low levels of vitamin D and coronary artery disease:  Is it time for therapy?

Monica Verdoia; Rocco Gioscia; Matteo Nardin; Andrea Rognoni; Giuseppe De Luca

doi:10.33963/KP.a2022.0079

Polish Heart Journal (Kardiologia Polska)
Vol 80, No 4 (2022) Low levels of vitamin D and coronary artery disease: Is it time for therapy?

Vol 80, No 4 (2022)

Review paper

Published online: 2022-03-24

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Low levels of vitamin D and coronary artery disease: Is it time for therapy?

Monica Verdoia¹², Rocco Gioscia¹, Matteo Nardin³, Andrea Rognoni¹², Giuseppe De Luca⁴

DOI: 10.33963/KP.a2022.0079

Pubmed: 35546270

Kardiol Pol 2022;80(4):409-416.

Abstract

The association between vitamin D and the prevalence and severity of coronary artery disease (CAD), major established cardiovascular risk factors, and acute ischemic events has been consistently demonstrated in large-scale observational studies and meta-analyses, with relevant prognostic implications. The rise in prevalence of hypovitaminosis D in recent years, reaching pandemic pro-portions, has pointed to the importance of the identification and optimization of the indications and strategies for the therapeutic use of vitamin D, with particular relevance for cardiovascular health. However, vitamin D supplementation has provided so far inconsistent results in primary prevention, with even fewer data reported in patients with established CAD. The present review aims to provide an updated overview of the available evidence and potential therapeutic applications of vitamin D in patients with CAD.

Keywords: vitamin Datherosclerosisinflammationthrombosispharmacological therapy

Review

Low levels of vitamin D and coronary artery disease: Is it time for therapy?

Monica Verdoia12Rocco Gioscia1Matteo Nardin3Andrea Rognoni1Giuseppe De Luca4

1Division of Cardiology, Ospedale degli Infermi, ASL Biella, Biella, Italy

2Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

3Department of Medicine, Spedali Civili Brescia, Italy

4Clinical and Experimental Cardiology Unit, AOU Sassari, Italy

Correspondence to:

Giuseppe De Luca, MD, PhD,

Director Clinical and Experimental Cardiology Unit,

AOU Sassari, Sassari,

Associate Professor of Cardiology,

University of Sassari, Sassari, Italy,

phone: +39 079 229 162,

e-mail: gdeluca@uniss.it

DOI: 10.33963/KP.a2022.0079

Received: March 20, 2022

Accepted: March 23, 2022

Early publication date: March 24, 2022

ABSTRACT

The association between vitamin D and the prevalence and severity of coronary artery disease (CAD), major established cardiovascular risk factors, and acute ischemic events has been consistently demonstrated in large-scale observational studies and meta-analyses, with relevant prognostic implications. The rise in prevalence of hypovitaminosis D in recent years, reaching pandemic proportions, has pointed to the importance of the identification and optimization of the indications and strategies for the therapeutic use of vitamin D, with particular relevance for cardiovascular health. However, vitamin D supplementation has provided so far inconsistent results in primary prevention, with even fewer data reported in patients with established CAD. The present review aims to provide an updated overview of the available evidence and potential therapeutic applications of vitamin D in patients with CAD.

Key words: vitamin D, atherosclerosis, inflammation, thrombosis, pharmacological therapy

INTRODUCTION

Vitamin D is a secosteroid mainly involved in the homeostasis of calcium and bone tissue but also displaying a broad spectrum of systemic hormonal effects, including both the modulation of the expression of about 3% of the human genome, and “acute”, non-genomic-dependent effects, mediated by the regulation of intracellular calcium [1].

Several large-scale studies have previously demonstrated that vitamin D deficiency is associated with the development of atherosclerosis and its thrombotic complications, which increases the risk of cardiovascular events and mortality [2–5].

Inadequate levels of vitamin D deficiency or insufficiency, defined as <20 ng/ml, have reached dramatic prevalence in the last years, exceeding 50% in certain areas and subsets of population, and especially among elderly and more frail subjects, with chronic comorbidities, renal failure, diabetes, and inflammatory disease [6, 7]. This has attracted attention to the consequences of vitamin D deficiency in the pathogenesis of coronary artery disease (CAD) and potential benefits of vitamin D supplementation.

However, there is still much uncertainty about the underlying pathophysiological mechanisms. The results of the studies conducted so far to assess the cardioprotective benefits of vitamin D are still unclear and make it impossible to reach a general consensus, develop consistent guidelines, and use vitamin D on a large scale as a pharmacological therapy.

The present review provides an update on the existing evidence and the current indications for the supplementation with vitamin D in patients with CAD, focusing on potential future perspectives.

VITAMIN D DEFICIENCY: A PANDEMIC DISORDER

Severe vitamin D deficiency can cause rickets and osteomalacia, which are rarely observed in developed countries. However, less severe deficiency is more frequent and associated with osteoporosis and the risk of bone fractures [8]. Vitamin D deficiency is currently considered a global health problem [9, 10], especially in low- and middle-income countries, where it affects about 50% of adults and 90% of infants. In the USA, up to 37% of adults and up to 46% of dark-skinned infants suffer from this condition [9]. A recent analysis considering mostly Nordic and western European populations found significant variability between countries [10]. In fact, when restricted to the adult population, Nordic countries appear to have a lower incidence of vitamin D deficiency, most probably due to increased vitamin supplementation or food fortification compared to lower-latitude countries.

VITAMIN D METABOLIC PATHWAY

Cholecalciferol, the form of vitamin D named D3, is synthetized in the skin from 7-dehydrocholesterol upon irradiation with ultraviolet waves (ultraviolet B light [UV-B]) (Figure 1) [11].

Table 1. Derivates of vitamin D with clinical indications

Compound	Clinical indication
Calcidiol 3,25(OH)D3	Renal osteodystrophy
Calcitriol 4,1,25(OH)	Renal osteodystrophy
Calcipotriol 5, 22-ene-26, 27-dehydro-1,25(OH)2D3	Psoriasis
Doxercalciferol 6, 1α(OH)D2	Secondary hyperparathyroidism
Alfacalcidol 7,1α(OH)D3	Osteoporosis
Tacalcitol 8, 1α, 24(OH)2D3	Psoriasis
Oxacalcitriol 10, 22-oxa-1, 25(OH)2D3	Psoriasis
Falecalcitriol 11, 1,25(OH)2-26, 27-F6-D3	Secondary hyperparathyroidism

7-dehydrocholesterol is part of the metabolic pathway that controls the synthesis of cholesterol in human cells. By absorbing ultraviolet radiation, 7-dehydrocholesterol turns into pre-vitamin D3, which, because of its molecular instability, subsequently converts to cholecalciferol that is expelled in the extracellular space, binding to a carrier (vitamin D-binding protein). Although production of vitamin D3 in the skin is its primary source in humans, it can be derived from food, such as fish oil or mushrooms, in the form of ergocalciferol (Figure 2) [12].

Table 2. Vitamin D and atherosclerosis: mechanistic links

Lipid profile	• Reduces total cholesterol • Reduces LDL-C • Reduces triglycerides • Increases HDL-C
Endothelial adhesion and activation	• Reduces vascular cell adhesion molecule 1 • Reduces E-selectin
Vascular tone and endothelial function	• Increases the level of nitric oxide • Reduces the level of reactive oxygen species released
Inflammation and atherosclerosis	• Reduces proinflammatory type 1 cytokines: IL-12, IL-6, IL-8, IFN-gamma, TNF-alpha • Increase anti-inflammatory type 2 cytokines: IL-4, IL-5, and IL-10 • Reduces oxidative stress through reducing cathepsin, IL-6 and adiponectin
Coagulation and platelet aggregation	• Increases trombomodulin expression • Reduces tissue factor expression • Reduces PAI-1 expression • Reduces thrombospondin expression • Increases the level of nitric oxide • Decreases ADP-induced aggregation
Arterial smooth muscle cells	• Decreases production of angiotensin II • Decreases oxidative stress • Inhibits cellular senescence • Reduces tissue factor expression

Abbreviations: ADP, adenosine diphosphate; HDL-C, high density lipoprotein cholesterol; IFN, interferon; IL, interleukin; LDL-C, low density lipoprotein cholesterol; PAI-1, plasminogen activator inhibitor-1; TNF, tumor necrosis factor

Skin synthesis of vitamin D3 rises proportionally with the intensity of the UV radiation. It also reduces proportionally with sunblock usage or the quantity of melanin encountered in the skin, i.e., in higher-latitude-living populations, during months with reduced sun exposure, or in patients with darker skin [11, 13, 14]. However, cholecalciferol is not biologically active; thus, vitamin D is hydroxylated in the liver cells to form 25(OH)D followed by 1α-hydroxylation [11]. The active hormonal form is produced in this last step of 1α-hydroxylation mainly in the kidneys and at other extrarenal sites, resulting in a compound named 1,25(OH)2D3 [15–17].

MECHANISMS OF ACTION AND ITS IMPLICATIONS IN THE PATHOPHYSIOLOGY OF ATHEROSCLEROSIS

The hormonal form of vitamin D, which is a lipid-soluble molecule, is transported in the blood bound to a serum protein named vitamin D-binding protein (DBP) [18]. At molecular level, vitamin D in the form of 1,25(OH)2D3 exerts its actions by binding to a membrane-bound and cytoplasmic receptor, the vitamin D receptor (VDR), which can be found in almost all human tissue, including the cardiovascular system [11, 19]. Binding of vitamin D to its VDR is critical for its action because 1.25 dihydroxy vitamin D, the active form, penetrates the cell membrane and binds to VDR [20]. This vitamin D-VDR complex acts with the retinoic acid receptor and forms important heterodimers that activate elements of vitamin D response elements by initiation of the cascade of molecular interactions regulating the suppression and transcription of specific genes [21]. In total, VDR has a direct action on the expression of more than 1000 genes [22], approximately 3% of the genome [12]. Ways in which vitamin D acts non-genomically have also been identified, such as through intracellular signaling molecules, generation of second messengers, and activation of specific protein kinases [23]. The change in the chemical structure of cholecalciferol leads to the emergence of new molecules, which, surprisingly, can bind to VDR.

Vitamin D deficiency has been consistently associated with the prevalence and severity of CAD and acute ischemic events.

In fact, vitamin D has been shown to promote endothelial function and to counteract inflammation and oxidative stress, thus preventing the development of atherosclerosis and its thrombotic complications [24–27].

In the ARIC study, vitamin D levels were measured in 11 945 participants, and an association with the incidence of coronary heart disease among white-skinned participants was reported [28].

In the LURIC Study, in a large cohort of subjects (n = 1801) referred for coronary angiography, 92% of individuals had suboptimal levels of vitamin D, which was associated with an increased all-cause mortality and cardiovascular mortality [29]. The Framingham Offspring Study found that individuals with 25(OH)D <37.5 nmol/l had a hazard ratio of 1.62 for the development of cardiovascular disease (CVD) compared to those with a level of ≥37.5 nmol/l [30].

In a large cohort study enclosing over 1400 patients undergoing coronary angiography, Verdoia et al. showed that lower circulating 25(OH)D was independently related with the prevalence and extent of CAD, especially for patients with values <10 ng/ml [3].

Furthermore, calcitriol levels have been inversely associated with coronary artery calcifications, thus serving as an early marker of coronary atherosclerosis [2].

In fact, vitamin D can directly improve the endothelial health and function, promoting the production of nitric oxide and reducing the exposure of proteins responsible for the adhesion of leukocytes and platelets. This prevents the inflammatory response and thrombotic phenomena. In addition, the inhibition of the extravasation and activation of macrophages and the antioxidant properties can prevent lipid oxidation and the production of foam cells, which contribute to plaque progression and instability [1, 24]. Indeed, levels of 25(OH)D in healthy volunteers are independently associated with various measures of endothelial function, arterial stiffness, and coronary flow reserve. In a subgroup of participants with vitamin D deficiency, normalization of 25(OH)D levels at 6 months was associated with a significant increase in reactive hyperemia indices, and in other studies, treatment with vitamin D improved arterial stiffness [2].

Moreover, vitamin D has been shown to lower tissue factor, downregulate the pro-thrombotic plasminogen activator inhibitor-1 and thrombospondin-1 mRNA expression, and upregulate thrombomodulin, thus accounting for its antithrombotic properties [31].

Additionally, the vitamin D receptor has been also identified in platelets, which suggests a direct regulatory effect. In effect, platelet activation is a calcium-dependent process, and calcitriol has been shown to display also a “rapid” non genomic action, mediated by the modulation of intracellular calcium. In fact, hypovitaminosis D has been previously linked to an enhanced platelet reactivity and a reduced effectiveness of antiplatelet drugs [25].

VITAMIN D AND CARDIOVASCULAR RISK FACTORS

Vitamin D has displayed a positive interaction with major cardiovascular risk factors and was related to the levels of blood pressure and a “healthier” metabolic profile [5, 32, 33].

A Mendelian randomization study suggested a link between vitamin D deficiency and hypertension risk [34], which was further confirmed by experimental evidence in animal studies [35]. In effect, vitamin D promotes the production of nitric oxide, a potent vasodilator, and downregulates the activity of the renin-angiotensin system, thus lowering the blood pressure and positively interacting with anti-hypertensive drugs [36].

Moreover, vitamin D has been shown to lower the glycemia levels in patients with diabetes and to protect against diabetes through the regulation of insulin synthesis and secretion or through direct action on pancreatic beta-cells function [37].

The levels of 25(OH)D have also been shown to condition the lipid asset, which is associated with lower levels of circulating cholesterol and a less atherogenic lipid profile and prevents the formation of foam cells with potentiating the effectiveness of statins [38–40],

Furthermore, vitamin D deficiency could be even more frequent among subjects at increased cardiovascular risk, due to comorbidities, aging or renal failure, or unhealthy lifestyle. In fact, low 25(OH)D concentrations can be enhanced by obesity, air pollution, or limited outdoors activity, which are associated with worse cardiovascular outcomes [41].

VITAMIN D SUPPLEMENTATION IN CAD: CURRENT EVIDENCE

Although several studies have linked lower levels of vitamin D with more severe cardiovascular disease and increased mortality [42–44], controversies still exist about using vitamin D supplementation in cardiovascular prevention [45, 46].

The ViDA (Vitamin D Assessment) study in New Zealand, which randomized over 5 000 subjects, showed an increase in serum 25(OH)D concentrations with the supplementation, although it was ineffective in reducing the primary outcome of incident CVD and death [47].

In the recent VITAL trial [48], which randomized over 25 000 healthy subjects to two groups with either n–3 fatty acid or vitamin D3 supplementation, no prognostic difference was observed at a 5-year follow-up.

However, heterogeneity in these strategies, with inadequate dosing and duration of the treatment and the failure to achieve optimal levels of vitamin D, as summarized in Table 3, could have determined the negative findings of most of the trials.

Table 3. Vitamin D supplementation in primary and secondary prevention

Study name	Patients (n)	Inclusion criteria	Vitamin D dosing	Follow-up duration	Study outcome and results
Study name	Patients (n)	Inclusion criteria	Vitamin D dosing	Follow-up duration	Study outcome and results
Secondary prevention
Sokol et al. [49]	90	CAD (angiographic) and vitamin D <30 ng/ml	ergocalciferol (50 000 IU/week)	12 weeks	No difference in blood pressure and all markers of endothelial function
Bahrami et al. [50]	80	CAD (angiographic) and vitamin D <30 ng/ml	Vitamin D 50 000 IU/week	8 weeks	Decreased systolic and diastolic blood pressure, waist circumference and fat percentage
Aslanabadi et al. [51]	99	Patients undergoing elective PCI	300 000 IU dose of cholecalciferol given before PCI	In-hospital	Periprocedural myocardial injury: no difference
Wu et al. [29]	90	CAD (angiographic)	Calcitriol (0.5 µg/day)	6 months	CAD (SYNTAX score) and C-reactive protein significantly decreased
Shaseb et al. [52]	95	T2DM with ischemic heart disease	Single dose of cholecalciferol (300 000 IU, i.m.)	8 weeks	Glycemic status: HbA1c was reduced by 0.48%
Witham et al. [53]	75	Patients with a prior history of MI	Two high-doses of orally administered cholecalciferol (100 000 IU)	6 months	Vascular function (reactive hyperemia index, systolic BP, diastolic BP) and cholesterol levels: no difference. C-reactive protein: reduced significantly
Farrokhian et al. [54]	60	T2DM patients with coronary artery disease.	50 000 IU cholecalciferol every second week	6 months	Significant attenuation in vascular inflammation and improved glycemic status
Schleithoff et al. [55]	123	Participants with heart failure	Vitamin D3, 2000 IU/d	Average 1.3 years	Reduced the inflammatory milieu
Primary prevention
Aloia et al. [56]	27	Postmenopausal women	Vitamin D3, 400 IU/d	2 years	No difference in MACE
Ott et al. [57]	86	Postmenopausal women	Vitamin D3, 1000 mg/d	2 years	No difference in MACE
Komulainen et al. [58]	227	Women in early postmenopause who were non-osteoporotic	Vitamin D3, 300 and 100 IU/d	5 years	No difference in MACE
STOP IT/Gallagher et al. [59]	489	Women aged 65-77 years with femoral neck density in normal range (SD, ≤2) for their age	Calcitriol, 0.25 μg twice daily	3 years	No difference in MACE
Trivedi et al. [60]	2686	Participants aged 65–85 years	Vitamin D3, 100 000 IU/4 months	5 years	No difference in MACE
RECORD/Grant et al. [26]	5292	Participants aged ≥70 years who had had a low trauma, osteoporotic fracture in the previous 10 years	Vitamin D3, 800 IU daily	Median (IQR), 3.8 (3.1–4.3) years	No difference in MACE
Brazier et al. [61]	172	Ambulatory women aged >65 years	Vitamin D3, 400 IU twice daily	1 years	No difference in MACE
WHI/Jackson et al. [62]	36282	Women aged 50–79 years with no evidence of a medical condition	Vitamin D3, 400 IU/d	12 years	No difference in MACE, improvement in hip bone density
Berggren et al. [63]	199	Participants aged ≥70 years who had femoral neck fractures	Vitamin D3, 800 IU/d	1 year	No difference in MACE
Zhu et al. [64]	120	Women aged 70–80 years	Vitamin D3, 1000 IU/d	5 years	No difference in MACE
Prince et al. [65]	302	Women aged 70–90 years	Vitamin D3, 1000 IU/d	1 year	No difference in MACE, reduction in falls
Vital D/Sanders et al. [66]	2256	Women aged ≥70 years at high risk of fracture	Vitamin D3, 500 000 IU/year	Median (IQR), 2.96 (2.92–3.00)	Increased falls, no difference in MACE
Lehouck et al. [67]	182	Current of former smokers with COPD	Vitamin D, 100 000 IU/month	1 year	Reduced COPD exacerbations in vitamin D deficient patients
VITDISH/Witham et al. [68]	159	Participants aged ≥70 years with isolated systolic hypertension	Vitamin D, 100 000 IU/month	1 year	MACE, blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance: no difference
OPERA/Wang et al. [69]	60	Stages 3–5 chronic kidney disease and left ventricle hypertrophy	Paricalcitol, 1 μg/d	1 year	No impact of left ventricular mass, improved secondary hyperparathyroidism
Baron et al. [70]	2259	Participants aged 45–75 years who had ≥1 colorectal adenoma	Vitamin D3, 1000 IU\d	3 years	Adverse events: no difference
EVITA/Zitterman et al. [71]	400	Participants aged 18–79 years who were classified as having New York Heart Association functional class ≥II	Vitamin D3, 4000 IU/d	3 years	No difference in mortality
VIDA/Scragg et al. [47]	5110	Vitamin D insuficient patients	Cholecalciferol (100 000 IU/month)	Median follow-up = 3.3 years	No beneficial effects of cholecalciferol supplementation on CVD risk or mortality
J-DAVID/Shoji et al. [72]	954	Patients on hemodialysis	Alfacalcidol, 0.5 μg/d	Median (IQR), Vitamin D: 4.0 (2.6–4.0)a; Placebo: 4.0 (3.5–4.0)	no difference in selected cardiovascular events
VITAL/Manson et al. [25]	754	All women	Calcium (1000 mg/day) + cholecalciferol (400 IU/day)	Average of seven years	No significant changes in CAC score
Gulseth et al. [73]	62	Subjects with T2DM	Single dose of 400,000 IU oral vitamin D3	4 weeks	No change in insulin sensitivity or insulin secretion
Jorde et al. [74]	438	Overweight or obese subjects	Vitamin D (3) 40 000 IU per week (DD group), vitamin D 20 000 IU per week (DP group)	12 months	Glucose tolerance, blood pressure or serum lipids: no change
BEST-D trial /Clarke et al. [75]	305	Elderly	cholecalciferol (4000 IU or 2000 IU)	12 months	No significant changes in CVD risk factors
Seibert et al. [76]	106	Healthy subjects	cholecalciferol (2000 IU/day)	12 weeks	No difference in mortality, major cardiovascular events and invasive cancer
Forouhi et al. [77]	340	Patients with high risk of diabetes type 2	Ergocalciferol (100,000 IU/month) or cholecalciferol (100 000 IU/month)	4 months	Improvements in pulse wave velocity, no difference in other cardiometabolic parameters

Abbreviations: CVD, cardiovascular disease; IQR, interquartile range; IU, international units; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention; S, supplementary; T2DM, type 2 diabetes mellitus

Endothelial adhesion and activation # reduces vascular cell adhesion molecule 1 (VCAM-1) # reduces E-selectin Vascular tone and endothelial function • increases the level of nitric oxide • reduces the level of reactive oxygen species released Inflammation and atherosclerosis # reduces proinflammatory type 1 cytokines: IL-12, IL-6, IL-8, IFN-gamma, TNF-alpha # increase anti-inflammatory type 2 cytokines: IL-4, IL-5, and IL-10 # reduces oxidative stress through reducing cathepsin, IL-6 and adiponectin Arterial smooth muscle cells • decreases production of angiotensin II • decreases oxidative stress • inhibits cellular senescence • reduces tissue factor expression

Moreover, increased benefits could be expected when focusing on higher-risk populations, such as patients with established cardiovascular disease. In the randomized controlled trial: the Randomised Evaluation of Calcium Or vitamin D (RECORD), treatment with cholecalciferol prevented cardiac failure among 5292 older people but did not appear to protect against myocardial infarction or stroke [78].

In addition, Le et al. [79] explored the effects of vitamin D on cardiac function in mice with post-myocardial infarction, showing a significant reduction in the fibrotic scar area and wall thinning in the animals receiving calcitriol supplementation, mediated by a reduction of fibrosis and enhanced myocytes differentiation. Thus, these data could further reinforce the incoming evidence of the potential benefits of using vitamin D in patients with left ventricular dysfunction and heart failure [80].

In a study in which calcitriol was administered over 6 months (0.5 mg/day) in patients with stable CAD, improvements were noted in the SYNTAX score and cardiometabolic variables [81].

Moreover, Bonakdaran et al. [82] reported that calcitriol supplementation could improve metabolic parameters and the control of cardiovascular risk factors among 119 patients with diabetes, suggesting that inadequate activation of vitamin D to its active metabolite, calcitriol, could represent a cause of the failure of major trials.

In fact, Saghir Afifeh et al. [83] previously reported a prevalence of calcitriol deficiency of about 10% in the patients with CAD, even despite adequate levels of vitamin D.

FUTURE PERSPECTIVES

Thus, future trials specific for subsets of higher-risk patients are certainly warranted to define whether a more tailored approach with vitamin D supplementation could be beneficial. Nevertheless, considering the positive effects on reducing overall mortality, cancer and functional status, consistently demonstrated in different trials and meta-analyses, and the safety, tolerability and low cost of vitamin D supplementation, such a strategy should certainly be considered, in particular in subjects at higher risk of deficiency [46, 84].

Such strategy should certainly be further reinforced in the context of the ongoing COVID-19 pandemic. In fact, the role of vitamin D in the modulation of the immune system and inflammation, and the prevention of thrombotic events, has been suggested. Vitamin D was reported to lower the rate of complications and improve the outcomes for infected patients [85]. Moreover, in addition to empowering the immune defense, vitamin D could prevent of contagion, by lowering the expression of the ACE-2 enzyme [86], thus leading the scientific societies to recommend the maintenance of adequate levels of vitamin D, and especially among subjects with increased risk for complications, as in patients with CAD [87, 88].

Moreover, the exact definition of the optimal vitamin D levels to reduce the cardiovascular risk and the appropriate dosing of pharmacological therapy, still need to be settled by experts’ agreement. Possibly, the achievement of levels higher than expected is required to observe the cardioprotective effects of vitamin D, especially in those severely deficient subjects [89].

Finally, a tailored approach to vitamin D supplementation, accounting for the differential mechanisms of deficiency and comorbidities conditioning its effectiveness [90], certainly represents a promising option, which should be further assessed in future randomized trials.

Supplementary material

Supplementary material is available at https://journals.viamedica.pl/kardiologia_polska.

Article information

Conflict of interest: None declared.

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