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Vitamin D deficiency is a pandemic disorder affecting over 1 billion of subjects worldwide.
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Its implications on cardiovascular and inflammatory disorders are still debated.
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We evaluated the prognostic impact of the levels of vitamin D among patients with CAD undergoing PCI.
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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.
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 [
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 [
], 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 [
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 [
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 [
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 [
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% [
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) [
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 [
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) [
]. 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.
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.
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. 1Kaplan Meier curves showing the probability of survival according to vitamin D tertiles values.
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., 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.
], 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 [
Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
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 [
]. 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 [
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. [
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 [
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. [
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 [
In addition, an impaired transformation of 25(OH)D to calcitriol has been documented in several clinical conditions, particularly in patients with CKD [
]. 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, [
] 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. [
], 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 [
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 [
] 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.
Novara Atherosclerosis Study Group (NAS). Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.
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.
Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.
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.
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