Abstract
Background:
Inflammation is an important factor in the development of cardiac injury during and after percutaneous coronary intervention (PCI). Vitamin D receptors play a significant role in the cardiovascular system and have anti-inflammatory effects. Hence, our goal was to evaluate the impact of calcitriol and cholecalciferol as vitamin D receptors agonists on inflammatory biomarkers in patients who are undergoing elective PCI.
Methods:
In this controlled clinical trial, patients undergoing elective PCI were randomly assigned to receive either calcitriol and cholecalciferol or were placed in the control group from July 2021 to November 2022. Calcitriol and cholecalciferol were administered at doses of 1 mcg and 300,000 international units, respectively, before the procedure. High-sensitive C-reactive protein (hs-CRP) was evaluated as the main inflammatory biomarker and other relevant clinical and laboratory data were also included.
Results:
During the study, 180 patients were allocated into three groups, each consisting of 60 patients, with a mean age of 62.26 ± 8.73 years. The prevalence of the underlying conditions was not different among the groups. After 24 hours, hs-CRP levels were lower (P = .012), and a significantly lower increase from baseline was observed (P = .003) in the group that received calcitriol. However, no significant differences were observed in Troponin I and creatine kinase-MB levels (P > .05).
Conclusions:
Administration of calcitriol was associated with significantly lower levels of hs-CRP, the main cardiac inflammatory marker, in patients undergoing elective PCI. Further clinical studies with a larger sample size are needed to assess the clinical impact of this anti-inflammatory effect.
Keywords: anti-inflammatory agents, calcitriol, cholecalciferol, heart injury, inflammation, percutaneous coronary intervention
1. Introduction
The global burden of coronary heart disease is rapidly increasing due to an aging population and the rising prevalence of comorbid conditions such as hypertension, diabetes, and dyslipidemia. Despite significant advances in pharmacotherapy and interventional cardiology, a growing number of patients require percutaneous coronary intervention (PCI) for the treatment of coronary artery occlusion.[1] While PCI is a minimally invasive and effective approach for managing acute coronary syndromes, it is associated with potential complications, including periprocedural myocardial injury (PMI). PMI occurs in approximately 25% to 70% of patients undergoing PCI,[2] and has been linked to increased long-term mortality.[3] Notably, PMI can be clinically silent, making its early detection crucial. Cardiac and inflammatory biomarkers serve as valuable tools for diagnosing PMI,[4] with troponin I being the most sensitive and specific marker. Although creatine kinase-MB (CK-MB) is also used, it has lower sensitivity and specificity, particularly in cases involving skeletal muscle injury.[5] Additionally, high-sensitivity C-reactive protein (hs-CRP) is an important marker of systemic inflammation, which has been implicated in PMI pathophysiology.[6] Elevated inflammatory biomarkers, including hs-CRP, correlate with increased periprocedural inflammation and a higher risk of PMI.[7]
Natural compounds, dietary supplements, and complementary therapies have gained attention for their potential role in promoting human health, preventing chronic diseases, and modulating inflammatory responses. Several natural products, such as propolis, pycnogenol, and conjugated linoleic acids, have been studied for their antioxidant and anti-inflammatory properties, with varying degrees of effectiveness in reducing oxidative stress and systemic inflammation, a natural stress.[8–10] Some studies have explored their role in managing cardiovascular diseases, but more research is needed to confirm their benefits. Among these compounds, vitamin D3 (cholecalciferol) is a key regulator of calcium homeostasis and bone metabolism. It also exerts systemic effects through its active form, calcitriol, (1,25-dihydroxyvitamin D), which interacts with the vitamin D receptor (VDR). The VDR is widely expressed in cardiovascular cells and regulates genes involved in cell proliferation, apoptosis, inflammation, and oxidative stress.[11] Although one found that lower vitamin D levels did not significantly impact the risk of PMI or myocardial damage,[11] growing evidence suggests that calcitriol suppresses pro-inflammatory mediator production in adipocytes, monocytes, and macrophages.[12] Additionally, vitamin D modulates several pathways implicated in cardiovascular diseases.[13] Calcitriol and cholecalciferol are two distinct vitamin D analogs, with calcitriol exhibiting over 100 times greater affinity for VDR and possessing stronger anti-inflammatory properties.[14–16] Despite these findings, the role of vitamin D supplementation in cardiovascular diseases prevention remains inconclusive. Limited studies have investigated the effects of cholecalciferol and calcitriol in reducing myocardial injury following elective PCI, with some reporting beneficial anti-inflammatory effects.[17,18] However, a direct comparison between these two forms of vitamin D in this context is lacking. Additionally, no studies have specifically evaluated their effects in patients with vitamin D deficiency.
Given the high prevalence of vitamin D insufficiency in the general population[19] and particularly high deficiency rates in Iran,[20] along with the stronger VDR binding affinity of calcitriol and its potential anti-inflammatory effects, this study aimed to evaluate the effects of calcitriol and cholecalciferol on inflammatory biomarkers and the prevention of PMI in patients with coronary artery disease undergoing elective PCI, specifically in those with vitamin D insufficiency or deficiency.
2. Materials and methods
2.1. Study design and setting
This study was a prospective, randomized controlled clinical trial conducted at 2 tertiary medical centers: Al-Zahra Heart Center and Shahid Faghihi Medical Center, both affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. Patients were randomly assigned to parallel groups in a 1:1:1 allocation ratio of.
2.2. Patient selection
The study enrolled patients aged between 18 to 80 years who were scheduled for elective PCI with stent placement between July 2021 and November 2022.
2.2.1. Sample size calculation
The study aimed to enroll 159 subjects to achieve 80% statistical power at a two-sided significance level of 0.05. An effect size of 0.25 was assumed. Accounting for a 15% dropout rate, 60 patients per group was targeted. Sample size calculation were performed using G*Power software (Version 3.1.9.4) based on analysis of variance for comparison of means.
2.2.2. Inclusion criteria
Eligible patients had vitamin D insufficiency or deficiency, defined as a serum level < 30 ng/mL,[21] and provided written informed consent prior to undergoing angioplasty.
2.2.3. Exclusion criteria
Patients were excluded if they had elevated cardiac biomarkers (troponin I or CK-MB) above the normal upper limit at baseline, a recent history of MI within three months, prior coronary artery bypass grafting, or an unsuccessful PCI. Additional exclusion criteria included left ventricular ejection fraction < 30% were excluded reent vitamin D or multivitamin supplementation (within the past month), recent use of anti-inflammatory drugs (except aspirin and statins) within the previous seven days, nephrolithiasis, hypercalcemia, malabsorption syndrome, active infection, malignancy, renal insufficiency (creatinine clearance < 60 mL/min/1.73 m2), severe hepatic dysfunction (Child-Pugh class C), uncontrolled autoimmune disorders, hypersensitivity to calcitriol and cholecalciferol, pregnancy, or breastfeeding.
2.3. Data collection and procedures
All eligible patients were admitted 1 day before PCI. Baseline demographic data, medical history, lifestyle habits, and medication history were recorded. Laboratory assessments included hs-CRP, troponin-I, CK-MB levels, renal and hepatic function tests, 25-OH vitamin D levels, and lipid profile. Ejection fraction was determined via transthoracic echocardiography. PCI-related myocardial injury was defined based on the Fourth Universal Definition of MI as an elevation in cardiac biomarkers post-procedure.[5]
2.3.1. Randomization
A stratified randomization scheme with variable block sizes was generated by an independent statistician. The randomization code was securely maintained by the research pharmacist responsible for treatment allocation. The study remained blinded to patients, investigators, and the clinical team until the completion of the 30-day follow-up and database finalization.
2.3.2. Study protocol
Baseline troponin I levels were measured before PCI and reassessed 22 to 24 hours post-procedure. Clinical follow-up was performed at 30 days. hs-CRP and CK-MB levels were also measured at baseline and 22 to 24 hours post-PCI using the Siemens ADVIA 1800 chemistry analyzer.
A blinded Data Safety Monitoring Team, comprising a cardiologist and a clinical pharmacist, ensured unbiased monitoring of adverse events.
Patients were randomly assigned to three arms of the study to receive either calcitriol, cholecalciferol, or be in the control group. Patients in intervention groups received calcitriol 1 mcg (Zavitrol®, Zahravi pharmaceutical company, Iran) orally, 6 hours before PCI according to the time to peak plasma concentration of calcitriol or cholecalciferol 300,000 IU (D-Vigel®, Dana Pharmaceutical Company, Tehran, Iran) orally, 12 hours before PCI according to the time to peak plasma level of oral cholecalciferol. Standard pharmacotherapy was consistent across all groups. Patients were directly observed for medication adherence.
All patients received aspirin 325 mg, clopidogrel 300 to 600 mg, and weight-adjusted intravenous heparin. The contrast agents used were iodixanol (Visipaque®, GE Healthcare, Marlborough, MA) or iopamidol (ScanLux®, Sanochemia, Austria). PCI was performed by the same experienced interventional cardiologist for all patients.
2.4. Outcomes
The primary outcome was PCI-related myocardial injury, as determined by the Universal Definition, based on Troponin I measurements taken 22 to 24 hours after the PCI procedure. To elaborate, PCI-related myocardial injury was defined as an increase of over 20% from the most recent pre-procedural Troponin I level. Secondary outcomes included the incidence of Major Adverse Cardiovascular Events (MACE), a composite endpoint comprising all-cause mortality, nonfatal MI, target vessel revascularization, and ischemic stroke. Additionally, changes in hs-CRP and CK-MB levels post-procedure were evaluated.
At the 12-week follow-up, patients were assessed for MACE and adverse drug reaction using the Naranjo scale.[22]
The study was approved by the Ethics Committee of Shiraz University of Medical Sciences (Approval code: IR.SUMS.REC.1398.513) and registered in the Iranian Registry of Clinical Trials under registration number IRCT20150518022306N3 on August 20, 2020. All participants provided written informed consent. The study was conducted following the Declaration of Helsinki.
2.5. Statistical analysis
Data analysis followed an intention-to-treat analysis for randomized subjects undergoing PCI. The entire randomized study cohort was used for safety assessment. All statistical analyses were carried out using the Statistical Package for the Social Sciences version 20 (IBM Company, New York, NY). Categorical variables were expressed as frequency (%) and normally distributed continuous variables as mean + standard deviation. Chi2 or Fisher exact tests (if 20% of the variables have a frequency of <5) were performed to analyze the differences in the distribution of the categorical variable between the groups. Data descriptions for continuous variables were performed using mean ± standard deviation. These variables were compared using a One-way analysis of variance test or Kruskal Wallis test between the three study arms. post hoc multiple comparison analysis was performed using Tukey or Games-Hawell based on equality of the variances status. P-value less than .05 was considered statistically significant in all analyses.
3. Results
Between July 2021 and November 2022, 329 patients were initially eligible for the trial. Of these, 214 (approximately 65%) had vitamin D levels below 30 ng/mL and were included in the study (Fig. 1).
Figure 1.
Study CONSORT flow diagram.
3.1. Baseline characteristics
Table 1 summarizes the baseline characteristics of the study population. The mean age was 62.26 ± 8.73 years, and 91 patients (55.5 %) were female. Hypertension and diabetes were present in 78 (47.6%) and 60 (36.6%) patients, respectively. Baseline demographic and clinical characteristics were comparable across study groups, except for significantly higher triglyceride levels in the control group (P = .03). Medication history did not differ significantly among the 3 groups.
Table 1.
Demographics and related clinical data of the included patients.
| Variable | Calcitriol (n = 57) |
Cholecalciferol (n = 51) |
Control (n = 56) |
P-value* |
|---|---|---|---|---|
| Age (years) | 61.04 ± 9.36 | 61.10 ± 7.26 | 64.3 ± 8.74 | .08 |
| Sex, female, n (%) | 28 (49.1) | 30 (58.8) | 33 (58.9) | .49 |
| Weight (kg) | 76.40 ± 11.98 | 70.51 ± 12.79 | 73.84 ± 11.48 | .06 |
| Height (cm) | 167.58 ± 9.97 | 164.46 ± 9.13 | 165.52 ± 8.73 | .24 |
| BMI (kg/m2) | 27.07 ± 2.25 | 25.92 ± 3.24 | 26.85 ± 2.84 | .12 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 74.18 ± 22.93 | 70.43 ± 19.66 | 72.14 ± 20.25 | .688 |
| Fasting blood sugar (mg/dL) | 114.56 ± 21.95 | 120.33 ± 23.66 | 118.19 ± 22.55 | .44 |
| Hemoglobin (g/dL) | 14.20 ± 1.89 | 13.65 ± 2.08 | 13.38 ± 2.01 | .08 |
| TG (mg/dL) | 161.08 ± 29.57 | 166.84 ± 29.39 | 175.89 ± 31.43 | .03 |
| Cholesterol (mg/dL) | 180.29 ± 32.18 | 170.12 ± 28.04 | 173.28 ± 36.03 | .28 |
| LDL (mg/dL) | 123.14 ± 30.81 | 111.92 ± 25.80 | 115.98 ± 34.86 | .20 |
| HDL (mg/dL) | 40.31 ± 6.88 | 39.64 ± 6.20 | 41.26 ± 9.61 | .59 |
| Vit D (ng/mL) | 18.54 ± 5.56 | 17.80 ± 6.45 | 17.60 ± 6.27 | .69 |
| Calcium level (mg/dL) | 9.13 ± 1.24 | 9.20 ± 0.49 | 9.34 ± 0.48 | .44 |
| Ejection fraction (%) | 49.64 ± 6.46 | 50.12 ± 6.43 | 49.01 ± 5.83 | .68 |
| Smoking, n (%) | 20 (35.1) | 17 (33.3) | 16 (28.6) | .74 |
| Alcohol, n (%) | 2 (3.5) | 0 (0) | 4 (7.1) | .20 |
| Hypertension, n (%) | 30 (52.6) | 22 (43.2) | 26 (46.4) | .65 |
| Diabetes mellitus, n (%) | 23 (40.4) | 17 (33.3) | 20 (35.7) | .76 |
| Dyslipidemia, n (%) | 26 (45.6) | 26 (50.9) | 28 (50.0) | .83 |
| Positive familiar history of CVD, n (%) | 22 (38.6) | 18 (35.3) | 19 (33.9) | .87 |
| Beta-blockers, n (%) | 29 (50.9) | 21 (41.1) | 26 (46.4) | .63 |
| ACEIs/ARBs, n (%) | 34 (59.6) | 27 (52.9) | 30 (53.6) | .77 |
| Calcium channel blockers, n (%) | 7 (12.3) | 4 (7.8) | 6 (10.7) | .77 |
| Anti-diabetic drug history, n (%) | 23 (40.4) | 17 (33.3) | 20 (35.7) | .76 |
| Statins, n (%) | 39 (68.4) | 29 (56.8) | 36 (64.3) | .48 |
| Nitrates, n (%) | 26 (45.6) | 25 (49.0) | 29 (51.8) | .81 |
| Antiplatelet, n (%) | 43 (75.4) | 35 (68.6) | 37 (66.1) | .54 |
Data presented as mean ± standard deviation, frequency, and percentage.
Chi2 or Fisher exact tests (if 20% of the variables have a frequency of <5) were performed to analyze quantitative variables. One-way analysis of variances (ANOVA) was used to compare quantitative variables.
ACEI = angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker, BMI = body mass index, HDL = high density lipoprotein, LDL = low density lipoprotein, TG = triglyceride, vit D = vitamin D.
*Statistically significant, P-value < .05.
Out of the total 226 stents used, the majority were drug-eluting stents, while a smaller proportion of patients received bare-metal stents (200 vs 26). Among the vessels undergoing PCI, the left anterior descending artery was the most frequently treated, followed by the right coronary artery and the left circumflex artery (LCX), with 49, 29, and 27 cases, respectively. Details of the treated vessels and the types of stents used across the 3 study groups are presented in Table 2.
Table 2.
Target vessels, type, and number of stents among study groups.
| Variable | Calcitriol (n = 57) |
Cholecalciferol (n = 51) |
Control (n = 56) |
P-value* |
|---|---|---|---|---|
| LAD, n (%) | 18 (31.6) | 16 (31.4) | 15 (26.8) | .841 |
| LCX, n (%) | 8 (14.1) | 9 (17.6) | 10 (17.9) | .824 |
| OM, n (%) | 5 (8.8) | 2 (3.9) | 3 (5.4) | .438 |
| RCA, n (%) | 9 (15.8) | 8 (15.7) | 12 (21.4) | .664 |
| PDA, n (%) | 0 (0) | 1 (2.0) | 0 (0) | .233 |
| LAD + LCX, n (%) | 3 (5.3) | 1 (2.0) | 2 (3.6) | .787 |
| LAD + OM, n (%) | 2 (3.5) | 1 (2.0) | 1 (1.8) | .849 |
| LAD + RCA, n (%) | 3 (5.3) | 3 (5.8) | 4 (7.1) | .888 |
| LCX + OM, n (%) | 1 (1.7) | 1 (2.0) | 1 (1.8) | .954 |
| RCA + OM, n (%) | 1 (1.7) | 0 (0) | 0 (0) | .432 |
| RCA + LCX, n (%) | 2 (3.5) | 1 (2.0) | 2 (3.6) | .957 |
| LAD + PDA, n (%) | 1 (1.7) | 1 (2.0) | 0 (0) | .522 |
| RCA + LAD + LCX, n (%) | 3 (5.3) | 4 (7.8) | 4 (7.1) | .875 |
| LAD + RCA + PDA, n (%) | 1 (1.7) | 0 (0) | 1 (1.8) | .705 |
| Other positions, n (%) | 0 (0) | 3 (5.8) | 1 (1.8) | .206 |
| Bare-metal stent, n (%) | 10 (12.8) | 8 (11.2) | 8 (10.4) | .988 |
| Drug-eluting stent, n (%) | 68 (78.2) | 63 (88.8) | 69 (89.6) | .979 |
| Total number of stents, n | 78 | 71 | 77 | .992 |
Chi2 or Fisher exact tests (if 20% of the variables have a frequency of <5) were performed.
LAD = left anterior descending artery, LCX = left circumflex artery, OM = obtuse marginal, PDA = posterior descending artery, RCA = right coronary artery.
*Statistically significant, P-value < .05.
Baseline levels of hs-CRP, troponin I, and CK-MB were not statistically different among the calcitriol, vitamin D, and control groups (P = .517, P = .881, and P = .218, respectively). However, at 24 hours post-procedure, a significant difference was observed in hs-CRP levels among the three groups (P = .002), with patients receiving calcitriol exhibiting lower levels.
In contrast, no significant differences in troponin I or CK-MB levels were found between the groups at the 24 hours post-PCI (Table 3). Post hoc analysis revealed that, compared to the control group, patients who received calcitriol had significantly lower hs-CRP levels at 24 h post intervention (P = .012), whereas no significant reduction was observed in those who received cholecalciferol (P = .414). Further comparison of mean differences in hs-CRP levels among the 3 groups, indicated a significant reduction in the calcitriol group compared to the control (P = .004), but not in the cholecalciferol group (P = .482).
Table 3.
Pre- and post-intervention mean hs-CRP, Troponin I and CK-MB levels.
| Calcitriol (n = 57) |
Cholecalciferol (n = 51) | Control (n = 56) |
P-value* | |
|---|---|---|---|---|
| hs-CRP (mg/L) | ||||
| Baseline | 3.29 ± 1.07 | 3.20 ± 0.84 | 3.50 ± 1.06 | .517 |
| At 24 hours | 4.32 ± 4.04 | 5.66 ± 3.98 | 6.85 ± 5.07 | .002 |
| Mean difference of baseline to 24 hours | ‐1.03 ± 3.20 | ‐2.46 ± 3.29 | ‐3.35 ± 4.204 | <.001 |
| Troponin I (ng/mL) | ||||
| Baseline | 0.14 ± 0.11 | 0.13 ± 0.08 | 0.15 ± 0.13 | .881 |
| At 24 hours | 0.32 ± 0.63 | 0.56 ± 1.2 | 0.92 ± 1.99 | .295 |
| Mean difference of baseline to 24 hours | ‐0.18 ± 0.56 | ‐0.42 ± 1.13 | ‐0.77 ± 1.92 | .215 |
| CK-MB (IU/L) | ||||
| Baseline | 20.30 ± 3.19 | 19.05 ± 3.12 | 18.76 ± 4.25 | .218 |
| At 24 hours | 23.60 ± 4.28 | 22.37 ± 4.64 | 23.76 ± 5.32 | .630 |
| Mean difference of baseline to 24 hours | ‐3.30 ± 3.16 | ‐3.32 ± 3.02 | ‐5.00 ± 3.80 | .218 |
Kruskal-Wallis test was used.
CK-MB = creatine kinase MB, hs-CRP = high sensitive C-reactive protein.
*Statistically significant, P-value < .05.
Regarding MACE at the 30-day and 3-month follow ups, no significant difference was found between the vitamin D, calcitriol, and the control groups in terms of PCI-related myocardial injury (P = .432). Only one patient in the vitamin D group experienced mortality, and no other MACE occurrences were reported in any of the groups.
4. Discussion
This clinical trial represents the first investigation into the effects of acute pre-procedural administration of both active (calcitriol) and inactive (cholecalciferol) forms of vitamin D compared to control on markers of myocardial injury in patients undergoing PCI. The key findings indicate that the administration of 1 mcg calcitriol prior to PCI did not reduce the risk of PCI-related myocardial injury, PCI-related MI, or MACE at 30-day and 3-month follow-ups compared to the control. However, calcitriol administration was associated with a significant reduction in hs-CRP levels post-PCI compared to control.
The pathogenesis of PCI-related myocardial injury involves several critical mechanisms, including cardiovascular-related inflammation, oxidative stress, platelet aggregation, thrombosis formation, coronary artery vasospasm, and thrombotic plaque embolization.[23–25] Oxidative stress, driven by excessive production of reactive oxygen species in cardiac myocytes, along with intracellular calcium accumulation and acidosis, plays a pivotal role in cellular damage and myocyte death.[26,27] An imbalance between reactive oxygen species production and antioxidant defenses can further exacerbate myocardial injury.[5,27]
The American College of Cardiology/American Heart Association recommend evaluating cardiac biomarkers.[28] Additionally, considering the significant role of inflammation, the European Society of Cardiology suggests measuring hs-CRP levels to assess cardiovascular disease risk in these patients.[29,30]
VDRs are widely expressed in immune cells, including T cells and macrophages, where they modulateimmune responses by suppressing pro-inflammatory cytokines and enhancing anti-inflammatory cytokines.[31,32] Through VDR activation, vitamin D plays a role in regulating inflammation, potentially mitigating excessive immune responses that contribute to myocardial injury. Specifically, VDR signaling has been shown to attenuate T-helper 2-biased inflammation in the heart, a mechanism implicated in conditions such as myocarditis, where reduced VDR expression correlates with increased T helper 2 cytokine production and exacerbated cardiac inflammation.[32] Vitamin D modulates gene transcription to suppress pro-inflammatory cytokines such as tumor necrosis factor-alpha while promoting anti-inflammatory cytokines like interleukin-10, thereby helping to minimize tissue damage during inflammatory responses.[31]
Previous studies have evaluated the effects of high-dose vitamin D administration in various inflammatory conditions. In patients with peripheral artery disease, a single high-dose vitamin D supplementation (100,000 IU) increased serum 25-hydroxyvitamin D levels without significantly affecting endothelial function or inflammation markers.[33] In contrast, in healthy individuals, high-dose vitamin D administration has been shown to reduce certain inflammatory cytokines.[34,35]
In this study, hs-CRP was assessed as the primary inflammatory marker. While baseline levels did not differ significantly among the three study arms, post-procedural hs-CRP levels were significantly lower in patients who received 1 mcg of calcitriol before PCI. Recent research on systemic inflammation biomarkers has demonstrated their association with adverse cardiovascular outcomes, including mortality, infarction, and restenosis.[36,37] Elevated hs-CRP levels before and after PCI have been linked to an increased risk of major adverse cardiac events.[38–41]
Elevation in cardiac biomarkers, specifically CK-MB and troponin I, have been associated with both short-term and long-term adverse events following PCI.[42] Troponin I is more sensitive than CK-MB in detecting myocardial injury.[43] In our study, no significant difference were observed in CK-MB or troponin I levels among the three study arms, consistent with previous studies that found no significant impact of vitamin D or calcitriol administration on these biomarkers.[17,18] Aslanabadi et al reported that cholecalciferol administration was associated with lower increases in CK-MB and hs-CRP levels,. whereas Dastan et. al., found that calcitriol significantly reduced hs-CRP levels but did not affect CK-MB or troponin levels. Comparing these findings with our results, it appears that calcitriol has a more pronounced anti-inflammatory effect than cholecalciferol, particularly in individuals with insufficient vitamin D levels. Our findings align with previous research indicating that calcitriol administration leads to a reduction in serum hs-CRP levels. Dastan F et al demonstrated that intravenous calcitriol significantly reduces hs-CRP in PCI patients.[18] Similarly, Aslanabadi et al reported that vitamin D administration was associated with lower Troponin and hs-CRP levels.[17] However, their study included all patients undergoing elective PCI without considering baseline vitamin D status, and clinical outcomes were assessed over one month. In contrast, our study specifically focused on vitamin D-deficient patients, and directly compared the calcitriol and cholecalciferol in a head-to-head manner, providing clearer evidence of the calcitriol’s superior anti-inflammatory effects in reducing pre-procedural cardiac injury.
Regarding adverse cardiac events at the 3-month follow-up, only one death occurred in the vitamin D group, and no significant difference in MACE incidence were observed among the 3 study arms. This follow-up duration aligns with previous studies assessing MACE timelines.[18]
It is also important to consider the potential influence of concomitant medications on biomarker levels and clinical outcomes. For example, statins have been shown to affect hs-CRP levels.[44,45] However, in our study, statin use was evenly distributed among the 3 groups, and there were no significant differences in the use of other medications, such as aspirin and beta-blockers, that could affect patient outcomes.
Despite these findings, certain limitations should be acknowledged. We did not measure additional inflammatory markers, such as interleukin-6 and tumor necrosis factor-α. Furthermore, our study assessed fixed doses of calcitriol and cholecalciferol in a population that included both vitamin D-deficient and insufficient individuals. A larger sample size may help clarify the anti-inflammatory effects of these agents in preventing of PCI-related myocardial injury. Further we suggest to use placebo in the future study. Future studies should explore different dosing strategies and assess a broader range of inflammatory biomarkers to address these limitations.
5. Conclusion
In conclusion, our study demonstrated that calcitriol significantly reduces hs-CRP levels, an inflammatory marker associated with myocardial injury, in patients undergoing elective PCI. These findings suggest that calcitriol may have a protective role in reducing post-PCI inflammation. However, further clinical trials are needed to fully evaluate its impact on cardiovascular outcomes.
Acknowledgments
This study was performed by Sara Asadi as her clinical pharmacy residency project to fulfill the requirements for certification as a clinical pharmacist. The present article was adopted from proposal number 16903, approved by the Vice-chancellor for Research Affairs of Shiraz University of Medical Sciences. We here thank Zahra Bagheri and Omid Moradi for their contribution to the statistical analysis of this work.
Author contributions
Conceptualization: Laleh Mahmoudi, Peyman Izadpanah, Sara Asadi.
Data curation: Laleh Mahmoudi, Peyman Izadpanah, Sara Asadi.
Investigation: Laleh Mahmoudi, Peyman Izadpanah, Sara Asadi.
Methodology: Laleh Mahmoudi, Sara Asadi.
Supervision: Laleh Mahmoudi, Peyman Izadpanah.
Writing – review & editing: Laleh Mahmoudi, Peyman Izadpanah.
Writing – original draft: Sara Asadi.
Abbreviations:
- CK-MB
- creatine kinase MB
- hs-CRP
- high sensitive C-reactive protein
- MACE
- major adverse cardiovascular events
- PCI
- percutaneous coronary intervention
- PMI
- periprocedural myocardial injury
- VDR
- vitamin D receptor
This study was conducted under the supervision of the Deputy of Research and Technology, Shiraz University of Medical Sciences, Shiraz, Iran as a research project. No external funding support by any other institute or company was received.
The consent for publication of the result of this study was obtained from all of the participants. No personal or contact information of the participants was reported in this study. Only collected data about the study aims were reported.
The study was performed in accordance with the declaration of Helsinki and the study protocol was approved by the board of ethics committee, Shiraz University of Medical Sciences, Shiraz, Iran (IR.SUMS.REC.1398.513). Written informed consent was obtained from all patients before enrollment. The trial was registered in the Iranian registry of clinical trials by the code IRCT20150518022306N3 on 20-08-2020.
The study was registered in the Iranian Registry of Clinical Trials under the registration number IRCT20150518022306N3.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Mahmoudi L, Izadpanah P, Asadi S. The effect of calcitriol and cholecalciferol on inflammatory markers in periprocedural myocardial injury: A randomized controlled trial. Medicine 2025;104:15(e42103).
During the preparation of this work, the author(s) did not use generative artificial intelligence in the writing of the manuscript.
Contributor Information
Laleh Mahmoudi, Email: Mahmoudi_l@sums.ac.ir.
Peyman Izadpanah, Email: Izadpanahpeyman52@gmail.com.
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