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Prognostic impact of Vitamin D deficiency in patients with coronary artery disease undergoing percutaneous coronary intervention

Published:August 20, 2020DOI:https://doi.org/10.1016/j.ejim.2020.08.016

      Highlights

      • Vitamin D deficiency is a pandemic disorder affecting over 1 billion of subjects worldwide.
      • Its implications on cardiovascular and inflammatory disorders are still debated.
      • We evaluated the prognostic impact of the levels of vitamin D among patients with CAD undergoing PCI.
      • We demonstrated that lower 25(OH)D is associated with an impaired survival and a higher rate of recurrent cardiovascular events at over 3-years follow-up.

      Abstract

      Background

      Whether Vitamin D deficiency represents an independent predictor of mortality and major cardiovascular events or rather the mirror of a more advanced clinical condition with increased comorbidities is still debated. We aimed at assessing the impact of vitamin D levels on the long-term outcomes among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention.

      Methods

      Consecutive patients from a single centre were included. Vitamin D levels were measured at admission by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). Severe deficiency was defined for 25(OH)D < 10 ng/ml. The primary study endpoint was overall mortality. Secondary endpoints were cardiovascular mortality, recurrent acute coronary syndrome or major cardiovascular events (a composite of death, recurrent MI and target vessel revascularization) at the longest available follow-up.

      Results

      We included a total of 705 patients, that were divided according to vitamin D tertiles (<12.7; 12.7-21.59; ≥21.6 ng/ml). Lower levels of Vitamin D were associated with renal failure (p=0.03), more severe coronary disease (p=0.001), diabetes mellitus and previous CABG (p<0.001), lower ejection fraction (p=0.02), acute presentation (p=0.04), use of statins (p=0.02), diuretics, nitrates and clopidogrel (p<0.001) and RASI (p=0.008). An inverse association was documented with BMI, glycemia, total cholesterol (p<0.001), creatinine and WBC (p=0.001). At a median follow-up of 996.5 [377-1552] days, 3.8% of the patients died. Vitamin D deficiency was significantly associated with overall mortality (7.6% vs 2.9% vs 0.4%, adjusted HR[95%CI]=3.6[1.43-8.9], p=0.006), MACE (adjusted HR[95%CI]=1.32[1.07-1.63], p=0.01) and the composite of death and MI (adjusted HR[95%CI]=1.3[1.03-1.65], p=0.03). A similarly increased risk was confirmed for all major higher-risk subsets of patients, with no significant interaction according to age, gender, diabetes mellitus or chronic kidney disease.

      Conclusion

      Among patients undergoing percutaneous coronary interventions, lower levels of vitamin D are associated with an over 3-fold increased risk of mortality and major cardiovascular events. Future larger studies are certainly warranted in order to define the prognostic implications of cholecalciferol supplementation among high-risk patients with established coronary artery disease.

      Keywords

      1. Introduction

      Vitamin D (25(OH)D) is a fat-soluble vitamin, representing not only the principal modulator of calcium and bone homeostasis, but also a key-hormone, regulating the transcription of about 2000 to 8000 genes [
      • Gil Á
      • Plaza-Diaz J
      • Mesa MD
      Vitamin D: classic and novel actions.
      ].
      Recent attention has been paved to vitamin D deficiency, reaching pandemic proportions, since affecting over 1 billion people worldwide, irrespective of age, ethnicity and comorbidities [
      • Palacios C
      • Gonzalez L.
      Is vitamin D deficiency a major global public health problem?.
      • Holick MF
      Vitamin D deficiency.
      ], but with severe clinical implications. In fact, hypovitaminosis D has been involved in several inflammatory, neoplastic and infectious disease and with the risk of cardiovascular events, therefore potentially conditioning the long-term prognosis [
      • Rosen CJ
      • Adams JS
      • Bikle DD
      • Black DM
      • Demay MD
      • Manson JE
      • Murad M
      • Kovacs CS
      The nonskeletal effects of vitamin D: an endocrine society scientific statement.
      • Grant WB
      • Lahore H
      • McDonnell SL
      • et al.
      Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
      ].
      Different studies and a recent meta-analysis have demonstrated the clear negative prognostic impact of vitamin D deficiency on all-cause and cardiovascular mortality, showing an increase in cardiovascular risk for every 10 ng/ml reduction in 25(OH)D [
      • Wang C
      Role of vitamin D in cardiometabolic diseases.
      • Chowdhury R
      • Kunutsor S
      • Vitezova A
      • Oliver-Williams C
      • Chowdhury S
      • Kiefte-de-Jong JC
      • Khan H
      • Baena CP
      • Prabhakaran D
      • Hoshen MB
      • Feldman BS
      • Pan A
      • Johnson L
      • Crowe F
      • Hu FB
      • Franco OH
      Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
      ].
      Indeed, Vitamin D has been suggested to modulate the endothelial function, the proliferation of cardiomyocytes, endothelial cells, and to regulate the inflammatory processes involved in the development of atherosclerosis and its thrombotic complications [
      • Kunadian V
      • Ford GA
      • Bawamia B
      • Qiu W
      • Manson JE
      Vitamin D deficiency and coronary artery disease: a review of the evidence.
      • Verdoia M
      • Schaffer A
      • Sartori C
      • Barbieri L
      • Cassetti E
      • Marino P
      • Galasso G
      • De Luca G
      Vitamin D deficiency is independently associated with the extent of coronary artery disease.
      ].
      However, the independent prognostic role of vitamin D is still debated, especially after the results of recent trials, failing to demonstrate any benefit of vitamin D supplementation in primary cardiovascular prevention and, also, in consideration of the strict association of vitamin D deficiency with major established cardiovascular risk factors [
      • Elamin MB
      • Abu Elnour NO
      • Elamin KB
      • et al.
      Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis.
      ,
      • Bjelakovic G
      • Gluud LL
      • Nikolova D
      • Whitfield K
      • Wetterslev J
      • Simonetti RG
      • Bjelakovic M
      • Gluud C
      Vitamin D supplementation for prevention of mortality in adults.
      ,
      • Pilz S
      • Gaksch M
      • O'Hartaigh B
      • Tomaschitz A
      • März W
      The role of vitamin D deficiency in cardiovascular disease: where do we stand in 2013?.
      ].
      Therefore, the aim of the present study was to evaluate the impact of vitamin D levels on the long-term survival and the risk of major cardiovascular events among patients undergoing percutaneous coronary intervention for coronary artery disease (CAD).

      2. Methods

      Our population is represented by consecutive patients undergoing coronary angiography and percutaneous coronary interventions (PCI) between January 2013 and June 2018 at the Ospedale “Maggiore della Carità”, Novara, Italy. Informed consent was obtained by all patients before angiography. The study was approved by our local Ethical Committee. All demographic and clinical data were prospectively collected in a dedicated database. Hypertension was defined as systolic pressure > 140 mm Hg and/or diastolic pressure > 90 mm Hg or if the individual was taking any antihypertensive medication. Diabetes mellitus was defined as previous diagnosis, specific treatment administration (oral drug or insulin), fasting glycaemia > 126 mg/dL or HbA1c > 6.5% [
      • De Luca G
      • Secco GG
      • Santagostino M
      • Venegoni L
      • Iorio S
      • Cassetti E
      • Verdoia M
      • Coppo L
      • Di Mario C
      • Bellomo G
      • Marino P
      Novara Atherosclerosis Study Group (NAS). Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.
      ]. Chronic renal failure was considered for history of renal failure or an admission glomerular filtration rate (GFR) < 60 ml/min/1.73m2 as defined by MDRD and severe renal failure for values < 30 ml/min/1.73m2. Myocardial infarction was defined as chest pain lasting more than 10 minutes, associated with elevation of cardiac biomarkers beyond the upper limit of normal (ULN) (respectively 0,04 µg/l for Troponin I and 5,00 µg/l for CK-MB), with or without ECG changes.

      3. Biochemical measurements

      Blood samples were drawn at admission in patients undergoing elective (following a fasting period of 12 h) or urgent coronary angiography. Glucose, creatinine, glycosylated haemoglobin (HbA1c) and lipid profile were determined by standard methods.
      White blood cells count and formula were measured in a blood sample collected in tripotassium EDTA (7.2 mg) tubes. These blood samples were analysed within 2 h from venepuncture by automatic blood counter (A Sysmex XE-2100) [
      • De Luca G
      • Secco GG
      • Santagostino M
      • Venegoni L
      • Iorio S
      • Cassetti E
      • Verdoia M
      • Coppo L
      • Di Mario C
      • Bellomo G
      • Marino P
      Novara Atherosclerosis Study Group (NAS). Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.
      ].
      Measurement of 25-hydroxyvitamin D was performed by chemiluminescence method through LIAISON® Vitamin D assay (Diasorin Inc). Severe 25-hydroxyvitamin D deficiency was considered if < 10 ng/ml according to the US Endocrine Society guidelines [
      • Holick MF
      Vitamin D deficiency.
      • Davidson MH1
      • Corson MA
      • Alberts MJ
      • Anderson JL
      • Gorelick PB
      • Jones PH
      • Lerman A
      • McConnell JP
      • Weintraub HS
      Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines.
      ]

      4. Coronary angiography and PCI

      Coronary angiography was routinely performed by the Judkins technique using 6-French catheters. Quantitative coronary angiography was performed by experienced interventional cardiologists by an automatic edge-detection systems (Siemens Acom Quantcor QCA, Erlangen, Germany) [
      • Davidson MH1
      • Corson MA
      • Alberts MJ
      • Anderson JL
      • Gorelick PB
      • Jones PH
      • Lerman A
      • McConnell JP
      • Weintraub HS
      Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines.
      ]. Coronary angioplasty was performed with standard techniques. Use of stents, type of stents and stent implantation techniques, as much as the use of directional or rotational atherectomy, IVUS, glycoprotein IIb-IIIa inhibitors, was left at the discretion of the operators. The recommended duration of DAPT was 12 months if tolerated.

      5. Outcome endpoints

      Follow-up data were obtained by records of outpatient visits or telephone contact, in case the patient had not been further evaluated after discharge. The primary study endpoint was overall mortality at the maximum available follow-up. The following secondary endpoints were considered: a composite of major cardiovascular events (MACE: overall mortality, Myocardial Infarction, target vessel revascularization), a composite of death or myocardial infarction and the individual endpoints (Mortality, cardiovascular mortality and recurrent myocardial infarction (MI)). Data collection and study endpoints adjudication was independently performed by different investigators (MV, RG, FN, GDL). Controversies were resolved by internal discussion. Patients with short-term follow-up (less 30 days) were excluded from the analysis.

      6. Statistical analysis

      Statistical analysis was performed using SPSS 15.0 statistical package. Continuous data were expressed as mean ± SD and categorical data as percentage. Analysis of variance and the chi-square test were used for continuous and categorical variables, respectively. Patients were grouped according to vitamin D tertiles values. Kaplan-Meier survival analysis and Cox regression were used to define the role of vitamin D deficiency on the main prognostic indicators across vitamin D tertiles, after correction for baseline differences (all variables statistically significant at univariate analysis), that were entered in the model in block. The p-value for vitamin D was calculated across tertiles, with the highest tertile being taken as a reference. A subgroup analysis was performed to evaluate the prognostic impact of low Vitamin D (lower tertile) in major high-risk subgroups such as according to age, gender, diabetes mellitus or CKD. A p value < 0.05 was considered statistically significant.

      7. Results

      We included a total of 705 patients, that were divided according to vitamin D tertiles (<12.7, n=250; 12.7-21.59, n=235; ≥21.6 ng/ml, n=220).
      Table 1 shows main clinical and demographic features of our population according vitamin D levels. Lower levels of Vitamin D were associated with renal failure (p=0.03), more severe coronary disease (p=0.001), diabetes mellitus and previous CABG (p<0.001), lower ejection fraction (p=0.02), acute presentation (p=0.04), use of statins (p=0.02), diuretics, nitrates and clopidogrel (p<0.001) and RASI (p=0.008). An inverse association was documented with BMI, glycemia, total cholesterol (p<0.001), creatinine and WBC (p=0.001).
      Table 1Clinical and demographical characteristics according to vitamin D tertiles.
      Baseline Clinical CharacteristicsI tertileII tertileIII tertileP value
      (n=250)(n=235)(n=220)
      Age (mean±SD)67.8±11.166.6±10.867.5±10.40.20
      Male Sex (%)72.784.375.80.29
      Dyslipidemia (%)65.856.959.10.04
      Body Mass Index (mean±SD)27.7±4.927.9±5.626.2±3.8<0.001
      Renal failure (%)22.916.117.30.03
      Diabetes mellitus (%)4641.431.7<0.001
      Smokers (%)0.34
      Active smokers32.224.521.6
      Previous smoker22.131.830.1
      Arterial hypertension (%)75.175.572.70.40
      History of MI (%)24.125.219.60.09
      Previous PCI (%)36.238.733.10.31
      Previous CABG (%)16.28.17.9<0.001
      Biochemistry
      Platelets Count (10^5/ml; ±SD)246.1±70.4237.8±68.9246.6±74.90.56
      Haemoglobin (g/dl±SD)13.2±1.813.7±1.513.4±1.70.11
      White blood cells (10^3/ml; ±SD)8.2±2.78±2.37.6±2.30.001
      Creatinine (mg/dl±SD)1.1±0.71±0.60.99±0.40.001
      Glycaemia (mg/dl±SD)125.6±50.3122.7±44114.2±32.6<0.001
      HbA1c (%±SD)6.7±3.46.4±1.96±0.990.15
      Total cholesterol (mg/dL±SD)149.7±40.3140.5±34.3141.7±31.6<0.001
      Triglycerides (mg/dL±SD)137.3±80128. ±76.8110.9±52.4<0.001
      HDL cholesterol (mg/dl; ±SD)42.4±13.641.4±13.242.6±120.33
      C reactive protein (mg/dl±SD)0.9±1.60.8±1.90.6±1.50.09
      Indication to angiography0.04
      Stable angina (%)30.233.232.7
      Acute coronary syndrome (%)58.859.660
      Arrhytmias/Valvulopathy/LV dysfunction (%)117.26.7
      Coronary angiography
      LM -3VD (%)46.735.535.40.001
      Ejection fraction (%±SD)50.8±10.952.3±9.952.7±100.02
      Therapy at admission
      RASI (%)68.174.675.80.008
      Beta blockers (%)78.882.283.30.08
      Calcium antagonists (%)23.62622.40.66
      Nitrates (%)46.341.135.40.001
      Diuretics (%)41.233.429.5<0.001
      Cholecalciferol (%)4.89.515.5<0.001
      Statins (%)88.487.578.50.02
      ASA (%)8991.292.10.11
      P2Y12 inhibitor (%)<0.001
      Clopidogrel (%)44.738.837.9
      Ticagrelor (%)32.235.437.3
      DM= diabetes mellitus; MI= myocardial infarction; PCI= percutaneous coronary intervention; CABG= coronary artery bypass grafting; CVA= cerebrovascular accident; RASI= renin-angiotensin system inhibitors, WBC= white blood cells; HDL= high-density lipoprotein; SD= standard deviation; ASA= acetylsalicylic acid
      At a median follow-up of 996.5 [377-1552] days, 27 (3.8%) patients had died. Vitamin D deficiency was significantly associated with overall mortality (7.6% vs 2.9% vs 0.4%, HR[95%CI]=4.26[1.78-10.2], p=0.001) (Table 2).
      Table 2Endpoints up to maximum available follow-up according to vitamin D levels.
      EventIIIIIIHazard RatioAdjusted Hazard RatioAdjusted P value
      tertiletertiletertile
      (n=250)(n=235)(n=220)
      Overall Mortality19 (7.6)7 (2.9)1 (0.4)4.26[1.78-10.2], p=0.0013.6[1.43-8.9]0.006
      Cardiovascular death6 (2.4)1 (0.4)0 (0)6.9[1.01-46.5], p=0.054.28[0.57-32]0.16
      Myocardial Infarction52 (21.2)42 (17.9)24 (10.9)1.31[1.04-1.66], p=0.021.25[0.97-1.6]0.08
      Death or Myocardial Infarction66 (26.3)47 (19.7)25 (11.2)1.35[1.08-1.70], p=0.011.3[1.03-1.65]0.03
      MACE79 (31.6)63 (26.8)32 (14.5)1.39[1.12-1.67], p=0.0021.32[1.07-1.63]0.01
      Kaplan Meier estimates for the probability of survival according to vitamin D tertiles are shown in Fig. 1. Results were confirmed after correction for baseline differences (adjusted HR[95%CI]=3.6[1.43-8.9], p=0.006).
      Fig. 1
      Fig. 1Kaplan Meier curves showing the probability of survival according to vitamin D tertiles values.
      Fig. 2
      Fig. 2Risk of mortality at subgroup analysis (DM= diabetes mellitus; CKD= chronic kidney disease), (INT = interaction).
      Lower levels of vitamin D significantly increased the risk of MACE (adjusted HR[95%CI]=1.32[1.07-1.63], p=0.01) and the composite of death or MI (adjusted HR[95%CI]=1.3[1.03-1.65], p=0.03). A similar increased risk was observed for the individual outcome endpoints, as displayed in Table 2.
      Results were confirmed in major higher-risk subsets of patients, with no significant interaction according to age (≥ 75 years: HR[95%CI]=5.2[0.84-31.4], p=0.08, < 75 years: HR[95%CI]=4.03[1.46-11.2], p=0.007, p interaction=0.93), gender (females: HR[95%CI]=1.66[0.46-5.97], p=0.44, males: HR[95%CI]=6.03[1.92-18.9], p=0.002, p int=0.15), diabetes mellitus (DM: HR[95%CI]=3.2[1.01-10.2], p=0.05; no DM: HR[95%CI]=4.56[1.17-17.8], p=0.03, p int=0.96) or chronic kidney disease (CKD: HR[95%CI]=3.7[0.67-21], p=0.13; no CKD: HR[95%CI]= 3.6[1.3-9.8], p=0.01, p int=0.82), Fig. 2.

      8. Discussion

      The present study represents one of the largest cohorts of patients where we evaluated the prognostic impact of the levels of vitamin D among patients with CAD undergoing PCI.
      We demonstrated that lower levels of 25(OH)D are associated with an impaired survival and a higher rate of recurrent cardiovascular events at over 3-years follow-up, although resulting as an independent predictor only for overall mortality.
      Vitamin D deficiency is a rising, widespread endemic problem, especially in Western counties, progressing hand in hand with the ageing of the population and the increase of comorbidities, preventing the capability of 25-OH D3 synthesis and outdoors living [
      • Holick M.F.
      • Matsuoka L.Y.
      • Wortsman J.
      Age, vitamin D, and solar ultraviolet.

      Holick, M. F., MacLaughlin, J. A., Doppelt, S. H.Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science, 211, 590-593.

      ]. In fact, lower levels of vitamin D have been reported in the elderly, in female gender and in patients with renal failure [
      • Rostand SG
      • Drueke TB
      Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure.
      ], that are well-established subgroups of patients at high cardiovascular risk. In fact, hypovitaminosis D has been linked to the pathophysiology of hypertension, diabetes and to adverse outcomes [
      • Forman JP
      • Bischoff-Ferrari HA
      • Willett WC
      • Stampfer MJ
      • Curhan GC
      Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies.
      ,
      • Pittas AG
      • Lau J
      • Hu FB
      • Dawson-Hughes B
      The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
      ,
      • Pilz S
      • Marz W
      • Wellnitz B
      • Seelhorst U
      • Fahrleitner-Pammer A
      • Dimai HP
      • Boehm BO
      • Dobnig H
      Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
      ], increasing all-cause and cardiovascular mortality. [
      • Gaksch M
      • Jorde R
      • Grimnes G
      • et al.
      Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.
      ].
      In the largest meta-analysis by Chowdhury et al., each decrease in 25(OH)D of 25 nmol/l was associated with a 16% (95% CI=8-23%) increase in all-cause mortality [
      • Chowdhury R
      • Kunutsor S
      • Vitezova A
      • Oliver-Williams C
      • Chowdhury S
      • Kiefte-de-Jong JC
      • Khan H
      • Baena CP
      • Prabhakaran D
      • Hoshen MB
      • Feldman BS
      • Pan A
      • Johnson L
      • Crowe F
      • Hu FB
      • Franco OH
      Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
      ].
      In the NHANES III study, subjects with vitamin D levels < 20 ng/mL showed an increased occurrence of angina, myocardial infarction and heart failure [
      • Kendrick J
      • Targher G
      • Smits G
      • Chonchol M
      25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the third national health and nutrition examination survey.
      ]
      However, despite the established effect of vitamin D on cardiovascular homeostasis [
      • Buitrago CG
      • Arango NS
      • Boland RL
      1α,25(OH)2D3-dependent modulation of Akt in proliferating and differentiating C2C12 skeletal muscle cells.
      ,
      • van Etten E
      • Mathieu C
      Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.
      ,
      • Silvagno F
      • De Vivo E
      • Attanasio A
      • Gallo V
      • Mazzucco G
      • Pescarmona G
      Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes.
      ], Vitamin D supplementation has not provided, so far, a significant prognostic and cardiovascular benefit among healthy subjects [
      • Mao PJ
      • Zhang C
      • Tang L
      • et al.
      Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials.
      ,
      • Zhang Y
      • Fang F
      • Tang J
      • et al.
      Association between vitamin D supplementation and mortality: systematic review and meta-analysis.
      ,
      • Manson JE
      • Cook NR
      • Lee IM
      • et al.
      on behalf of the VITAL Research Group. Vitamin D supplements and prevention of cancer and cardiovascular disease.
      ]. Nevertheless, different results could be hypothesized in higher risk subsets of patients, as among those with established cardiovascular disease. In fact, in the Randomised Evaluation of Calcium Or vitamin D (RECORD) randomized controlled trial (RCT), treatment with cholecalciferol prevented cardiac failure among 5292 older people but did not appear to protect against MI or stroke [
      • Ford JA
      • MacLennan GS
      • Avenell A
      • et al.
      Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.
      ].
      In addition, Verdoia et al. showed that lower levels of vitamin D were associated with the prevalence and extent of angiographically defined coronary artery disease, especially in higher risk subsets of patients, such as in diabetics and females, and also with an enhanced platelet reactivity among patients on dual antiplatelet therapy after PCI. [
      • Verdoia M
      • Schaffer A
      • Sartori C
      • Barbieri L
      • Cassetti E
      • Marino P
      • Galasso G
      • De Luca G
      Vitamin D deficiency is independently associated with the extent of coronary artery disease.
      • Verdoia M
      • Pergolini P
      • Rolla R
      • et al.
      Impact of high-dose statins on vitamin D levels and platelet function in patients with coronary artery disease.
      ,
      • Nardin M
      • Verdoia M
      • Schaffer A
      • et al.
      Vitamin D status, diabetes mellitus and coronary artery disease in patients undergoing coronary angiography.
      ,
      • Verdoia M
      • Schaffer A
      • Barbieri L
      • et al.
      Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease.
      ]
      Moreover, Lerchbaum et al. documented that 25(OH)D was significantly associated with fatal events in a large cohort of men referred for coronary angiography, and especially if combined with testosterone deficiency [
      • Lerchbaum E
      • Pilz S
      • Boehm BO
      • Grammer TB
      • Obermayer-Pietsch B
      • März W
      Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.
      ].
      However, few data have been reported so far on the prognostic role of vitamin D on recurrent cardiovascular events and in patients with established CAD.
      We showed in a large single centre cohort of consecutive patients undergoing PCI, that lower levels of vitamin D emerged as an independent predictor of mortality and major cardiovascular events, with similar results being observed in higher risk subsets of patients, such as in the elderly, diabetics and in CKD.
      Analogous conclusion had been reached by Yu et al. [
      • Yu C
      • Xue H
      • Wang L
      • et al.
      Serum bioavailable and free 25-hydroxyvitamin D levels, but not its total level, are associated with the risk of mortality in patients with coronary artery disease.
      ] among over 1300 patients undergoing coronary angiography. However, in their study, free 25(OH)D levels rather than total 25(OH)D level were independently associated with an increased risk of all-cause mortality and cardiovascular mortality. In fact, several clinical and genetic factors, conditioning the circulating levels of vitamin D, as the variations in transporting proteins (VDBP, vitamin D binding protein) have been claimed for modulating the cardiovascular effects of vitamin D and therefore, potentially, its prognostic impact [
      • Michos Erin D
      • Misialek Jeffrey R
      • Elizabeth Selvin
      • Folsom Aaron R
      • Pankow James S
      • Post Wendy S
      • Lutsey Pamela L
      25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms and incident coronary heart disease among whites and blacks: the ARIC study.
      ,
      • Daffara V
      • Verdoia M
      • Rolla R
      • et al.
      Impact of polymorphism rs7041 and rs4588 of Vitamin D binding protein on the extent of coronary artery disease.
      ,
      • Powe CE
      • Evans MK
      • Wenger J
      • Zonderman AB
      • Berg AH
      • Nalls M
      • Tamez H
      • Zhang D
      • Bhan I
      • Karumanchi SA
      • Powe NR
      • Thadhani R
      Vitamin D-binding protein and vitamin D status of black Americans and white Americans.
      ]
      In addition, an impaired transformation of 25(OH)D to calcitriol has been documented in several clinical conditions, particularly in patients with CKD [
      • Pasquali M
      • Tartaglione L
      • Rotondi S
      • Muci ML
      • Mandanici G
      • Farcomeni A
      • Marangella M
      • Mazzaferro S
      Calcitriol/calcifediol ratio: an indicator of vitamin D hydroxylation efficiency?.
      ]. In fact, Zitterman et al [
      • Zittermann A
      • Heer M
      • Caillot-Augusso A
      • Rettberg P
      • Scheld K
      • Drummer C
      • et al.
      Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test.
      ]. documented among over 500 patients with heart failure that lower calcitriol was associated with a higher rate of coronary artery disease and increased mid-term mortality, suggesting a greater predictive the direct assessment of 1,25(OH)D could offer a more predictive value. However, in our study the prognostic impact of vitamin D was maintained independently from the renal function.
      Moreover, data from the combined National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study, [
      • Deng X
      • Song Y
      • Manson JE
      • et al.
      Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III.
      ] showed that the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake.
      Thus, it might be argued that different dosing or formulations of vitamin D, including either cholecalciferol or calcitriol, could result differently effective as a supplementation according to the subset of patients. However, few studies have been conducted so far accounting for the genetic and clinical factors conditioning the bioavailability and effectiveness of vitamin D and especially dedicated to higher-risk populations as in coronary disease.
      Therefore, future trials are certainly needed in order to better elucidate the prognostic impact of vitamin D deficiency in CAD and to define those factors and subsets of patients that could condition the achievement of the largest benefit from vitamin D supplementation.

      9. Limitations

      A first limitation of our study can be represented by the heterogeneity of the included population, comprising patients referred for chronic CAD or acute cardiovascular events and with different comorbidities. However, in our study, as in the previous meta-analysis by Chowdhury et al. [
      • Chowdhury R
      • Kunutsor S
      • Vitezova A
      • Oliver-Williams C
      • Chowdhury S
      • Kiefte-de-Jong JC
      • Khan H
      • Baena CP
      • Prabhakaran D
      • Hoshen MB
      • Feldman BS
      • Pan A
      • Johnson L
      • Crowe F
      • Hu FB
      • Franco OH
      Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
      ], the independent role of vitamin D levels on mortality was confirmed in major higher risk subsets of patients.
      Moreover, despite previous studies have suggested that vitamin D could represent a negative acute phase reactant in acute illnesses [
      • Kostoglou-Athanassiou I
      • Pantazi E
      • Kontogiannis S
      • Kousouris D
      • Mavropoulos I
      • Athanassiou P
      Vitamin D in acutely ill patients.
      • Krishnan A
      • Venkatesh B
      Vitamin D measurement in the intensive care unit: methodology, clinical relevance and interpretation of a random value.
      ], in consequence of consumption and variations in its binding proteins, we do not expect an impact of such issue of our results. In fact, in case of patients with ACS, we preferred to draw non-fasting blood samples for vitamin D on admission, so immediately at the onset of the event, thus probably before significant variations had occurred.
      In addition, the low rate of events, especially among patients with higher vitamin D levels, could have reduced the statistical power of our analysis, preventing to observe a significant difference for certain more specific endpoints such as cardiovascular mortality or TVR.
      Moreover, inadequate levels of vitamin D (< 20 ng/ml) were present in the majority of the study population, potentially preventing to observe larger differences, if including patients with normal levels of cholecalciferol. However, we included a real-life population, where vitamin D supplementation was only modestly applied.
      In addition, we did not evaluate the levels of serum calcium, a parameter that has been reported to be an independent predictor for in-hospital and long-term mortality following acute coronary syndromes [
      • Grandi NC
      • Brenner H
      • Hahmann H
      • et al.
      Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease.
      • Gu X
      • Ding X
      • Sun H
      • et al.
      Usefulness of serum calcium in the risk stratification of midterm mortality among patients with acute coronary syndrome.
      ].
      Finally, we did not consider the impact of vitamin D on the quality of life, functional status and neither on the metabolic parameters, that have been previously related with vitamin D levels and with long-term outcomes [
      • Mendes J
      • Santos A
      • Borges N
      • et al.
      Vitamin D status and functional parameters: a cross-sectional study in an older population.
      • Bellan M
      • Guzzaloni G
      • Rinaldi M
      • et al.
      Altered glucose metabolism rather than naive type 2 diabetes mellitus (T2DM) is related to vitamin D status in severe obesity.
      ] In fact, in our study patients with lower vitamin D displayed higher glycemia and cholesterol levels, even despite a larger use of statins.

      10. Conclusions

      Among patients undergoing percutaneous coronary interventions, lower levels of vitamin D are associated with an over 3-fold increased risk of mortality and major cardiovascular events. Future larger studies are certainly warranted in order to define the prognostic implications of cholecalciferol supplementation in this higher-risk subset of patients and its potential implications in the prevention of cardiovascular disease and of a broad spectrum of inflammatory disease, including Sars-Cov2 infection.

      Declaration of Competing Interest

      The authors declare no conflict of interest. The study was financially supported by the Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.

      References

        • Gil Á
        • Plaza-Diaz J
        • Mesa MD
        Vitamin D: classic and novel actions.
        Ann Nutr Metab. 2018; 72: 87-95
        • Palacios C
        • Gonzalez L.
        Is vitamin D deficiency a major global public health problem?.
        J Steroid Biochem Mol Biol. 2014; 144 Pt A: 138-145https://doi.org/10.1016/j.jsbmb.2013.11.003
        • Holick MF
        Vitamin D deficiency.
        N Engl J Med. 2007; 357: 266-281
        • Rosen CJ
        • Adams JS
        • Bikle DD
        • Black DM
        • Demay MD
        • Manson JE
        • Murad M
        • Kovacs CS
        The nonskeletal effects of vitamin D: an endocrine society scientific statement.
        Endocr Rev. 2011; 33: 456-492
        • Grant WB
        • Lahore H
        • McDonnell SL
        • et al.
        Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
        Nutrients. 2020; 12 (Published 2020 Apr 2): E988
        • Wang C
        Role of vitamin D in cardiometabolic diseases.
        J Diabetes Res. 2013; 2013243934
        • Chowdhury R
        • Kunutsor S
        • Vitezova A
        • Oliver-Williams C
        • Chowdhury S
        • Kiefte-de-Jong JC
        • Khan H
        • Baena CP
        • Prabhakaran D
        • Hoshen MB
        • Feldman BS
        • Pan A
        • Johnson L
        • Crowe F
        • Hu FB
        • Franco OH
        Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
        BMJ. 2014; 348: g1903
        • Kunadian V
        • Ford GA
        • Bawamia B
        • Qiu W
        • Manson JE
        Vitamin D deficiency and coronary artery disease: a review of the evidence.
        Am Heart J. 2014; 167: 283-291
        • Verdoia M
        • Schaffer A
        • Sartori C
        • Barbieri L
        • Cassetti E
        • Marino P
        • Galasso G
        • De Luca G
        Vitamin D deficiency is independently associated with the extent of coronary artery disease.
        Eur J Clin Invest. 2014; 44: 634-642
        • Elamin MB
        • Abu Elnour NO
        • Elamin KB
        • et al.
        Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2011; 96: 1931-1942
        • Bjelakovic G
        • Gluud LL
        • Nikolova D
        • Whitfield K
        • Wetterslev J
        • Simonetti RG
        • Bjelakovic M
        • Gluud C
        Vitamin D supplementation for prevention of mortality in adults.
        Cochrane Database Syst Rev. 2014; 1CD007470
        • Pilz S
        • Gaksch M
        • O'Hartaigh B
        • Tomaschitz A
        • März W
        The role of vitamin D deficiency in cardiovascular disease: where do we stand in 2013?.
        Arch Toxicol. 2013; 87: 2083-2103
        • De Luca G
        • Secco GG
        • Santagostino M
        • Venegoni L
        • Iorio S
        • Cassetti E
        • Verdoia M
        • Coppo L
        • Di Mario C
        • Bellomo G
        • Marino P
        Novara Atherosclerosis Study Group (NAS). Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.
        Nutr Metab Cardiovasc Dis. 2012; 22: 426-433
        • Davidson MH1
        • Corson MA
        • Alberts MJ
        • Anderson JL
        • Gorelick PB
        • Jones PH
        • Lerman A
        • McConnell JP
        • Weintraub HS
        Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines.
        Am J Cardiol. 2008 16; 101: 51F-57F
        • Holick M.F.
        • Matsuoka L.Y.
        • Wortsman J.
        Age, vitamin D, and solar ultraviolet.
        Lancet. 1989; 2 (1989): 1104-1105
      1. Holick, M. F., MacLaughlin, J. A., Doppelt, S. H.Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science, 211, 590-593.

        • Rostand SG
        • Drueke TB
        Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure.
        Kidney Int. 1999; 56 (39): 383
        • Forman JP
        • Bischoff-Ferrari HA
        • Willett WC
        • Stampfer MJ
        • Curhan GC
        Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies.
        Hypertension. 2005; 46: 676-682
        • Pittas AG
        • Lau J
        • Hu FB
        • Dawson-Hughes B
        The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2007; 92: 2017-2029
        • Pilz S
        • Marz W
        • Wellnitz B
        • Seelhorst U
        • Fahrleitner-Pammer A
        • Dimai HP
        • Boehm BO
        • Dobnig H
        Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
        J Clin Endocrinol Metab. 2008; 93: 3927-3935
        • Gaksch M
        • Jorde R
        • Grimnes G
        • et al.
        Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.
        PLoS One. 2017; 12e0170791
        • Kendrick J
        • Targher G
        • Smits G
        • Chonchol M
        25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the third national health and nutrition examination survey.
        Atherosclerosis. 2009; 205: 255-260
        • Buitrago CG
        • Arango NS
        • Boland RL
        1α,25(OH)2D3-dependent modulation of Akt in proliferating and differentiating C2C12 skeletal muscle cells.
        J Cell Biochem. 2012; 113: 1170-1181
        • van Etten E
        • Mathieu C
        Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.
        J Steroid Biochem Mol Biol. 2005; 97: 93-101
        • Silvagno F
        • De Vivo E
        • Attanasio A
        • Gallo V
        • Mazzucco G
        • Pescarmona G
        Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes.
        PLoS One. 2010; 5: e8670
        • Mao PJ
        • Zhang C
        • Tang L
        • et al.
        Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials.
        Int J Cardiol. 2013; 169: 106-111
        • Zhang Y
        • Fang F
        • Tang J
        • et al.
        Association between vitamin D supplementation and mortality: systematic review and meta-analysis.
        BMJ. 2019; 366: l4673
        • Manson JE
        • Cook NR
        • Lee IM
        • et al.
        on behalf of the VITAL Research Group. Vitamin D supplements and prevention of cancer and cardiovascular disease.
        N Engl J Med. 2019; 380: 33-44
        • Ford JA
        • MacLennan GS
        • Avenell A
        • et al.
        Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.
        Am J Clin Nutr. 2014; 100: 746-755
        • Verdoia M
        • Pergolini P
        • Rolla R
        • et al.
        Impact of high-dose statins on vitamin D levels and platelet function in patients with coronary artery disease.
        Thromb Res. 2017; 150: 90-95
        • Nardin M
        • Verdoia M
        • Schaffer A
        • et al.
        Vitamin D status, diabetes mellitus and coronary artery disease in patients undergoing coronary angiography.
        Atherosclerosis. 2016; 250: 114-121
        • Verdoia M
        • Schaffer A
        • Barbieri L
        • et al.
        Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease.
        Nutr Metab Cardiovasc Dis. 2015; 25: 464-470
        • Lerchbaum E
        • Pilz S
        • Boehm BO
        • Grammer TB
        • Obermayer-Pietsch B
        • März W
        Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.
        Clin Endocrinol (Oxf). 2012; 77: 475-483
        • Yu C
        • Xue H
        • Wang L
        • et al.
        Serum bioavailable and free 25-hydroxyvitamin D levels, but not its total level, are associated with the risk of mortality in patients with coronary artery disease.
        Circ Res. 2018; 123: 996-1007
        • Michos Erin D
        • Misialek Jeffrey R
        • Elizabeth Selvin
        • Folsom Aaron R
        • Pankow James S
        • Post Wendy S
        • Lutsey Pamela L
        25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms and incident coronary heart disease among whites and blacks: the ARIC study.
        Atherosclerosis. 2015; 241: 12-17
        • Daffara V
        • Verdoia M
        • Rolla R
        • et al.
        Impact of polymorphism rs7041 and rs4588 of Vitamin D binding protein on the extent of coronary artery disease.
        Nutr Metab Cardiovasc Dis. 2017; 27: 775-783
        • Powe CE
        • Evans MK
        • Wenger J
        • Zonderman AB
        • Berg AH
        • Nalls M
        • Tamez H
        • Zhang D
        • Bhan I
        • Karumanchi SA
        • Powe NR
        • Thadhani R
        Vitamin D-binding protein and vitamin D status of black Americans and white Americans.
        N Engl J Med. 2013 21; 369 (1991-20)
        • Pasquali M
        • Tartaglione L
        • Rotondi S
        • Muci ML
        • Mandanici G
        • Farcomeni A
        • Marangella M
        • Mazzaferro S
        Calcitriol/calcifediol ratio: an indicator of vitamin D hydroxylation efficiency?.
        BBA Clin. 2015; 3: 251-256
        • Zittermann A
        • Heer M
        • Caillot-Augusso A
        • Rettberg P
        • Scheld K
        • Drummer C
        • et al.
        Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test.
        Eur J Clin Invest. 2000; 30: 1036-1043
        • Deng X
        • Song Y
        • Manson JE
        • et al.
        Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III.
        BMC Med. 2013; 11: 187
        • Kostoglou-Athanassiou I
        • Pantazi E
        • Kontogiannis S
        • Kousouris D
        • Mavropoulos I
        • Athanassiou P
        Vitamin D in acutely ill patients.
        J Int Med Res. 2018; 46: 4246-4257https://doi.org/10.1177/0300060518792783
        • Krishnan A
        • Venkatesh B
        Vitamin D measurement in the intensive care unit: methodology, clinical relevance and interpretation of a random value.
        Inflamm Allergy Drug Targets. 2013; 12: 230-238
        • Grandi NC
        • Brenner H
        • Hahmann H
        • et al.
        Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease.
        Heart. 2012; 98: 926-933
        • Gu X
        • Ding X
        • Sun H
        • et al.
        Usefulness of serum calcium in the risk stratification of midterm mortality among patients with acute coronary syndrome.
        Biomed Res Int. 2019; 20199542054
        • Mendes J
        • Santos A
        • Borges N
        • et al.
        Vitamin D status and functional parameters: a cross-sectional study in an older population.
        PLoS One. 2018; 13e0201840
        • Bellan M
        • Guzzaloni G
        • Rinaldi M
        • et al.
        Altered glucose metabolism rather than naive type 2 diabetes mellitus (T2DM) is related to vitamin D status in severe obesity.
        Cardiovasc Diabetol. 2014; 13: 57