328 Original research
The relationship between vitamin D levels and saphenous vein graft patency Fatih Sena, Samet Yilmaza, Kevser G. Balcia, Ömer Senb, Murat Güla, Serkan Çaya, Serkan Topaloglua and Sinan Aydogdua Objective A growing body of evidence supports an association between vitamin D and cardiovascular diseases. Coronary artery bypass grafting surgery is a treatment modality for suitable patients with coronary artery disease; however, patency rates of saphenous vein grafts (SVGs) are low. In this study we aimed to determine the association between vitamin D levels and the SVG disease. Methods The study population included 180 patients who had undergone a primary coronary artery bypass grafting surgery with at least one SVG and later had a control angiography because of clinical indications. Patients were divided into two groups: 100 patients with SVG disease and 80 of them with patent SVG. Results The mean age of 180 patients was 57.4 ± 8.8 years, and 64.4% of the study population were men. The total number of SVGs was 364, and the mean number of SVGs to each patient was 2.02 ± 0.61. Vitamin D levels were higher in the patent SVG group than in the SVG disease group (36.2 ± 10.7 and 21.1 ± 10.4, respectively; P < 0.001). C-reactive protein levels were significantly higher in the
Introduction Ischemic heart disease is an important health problem because of its associated morbidity and mortality. In this regard, coronary artery bypass grafting (CABG) is an available option to reduce the untoward consequences of coronary heart disease (CHD). Both arterial and venous conduits can be used in this procedure, but patency rates of saphenous vein grafts (SVGs) are lower compared with arterial conduits. Stenosis rates of SVGs are 15% at the end of first year and nearly 50% at the end of 10th year, after CABG surgery [1]. Most common mechanisms for SVG occlusion are thrombosis (first month), neointimal hyperplasia (1–12 months), and atherosclerosis (>12 months) [2]. Vitamin D deficiency is a highly prevalent condition in patients with coronary artery disease and also in the general population [3]. Growing evidence shows that people who are deficient to 25-hydroxyvitamin D [25 (OH)D] have higher risks for several cardiovascularrelated conditions such as obesity, diabetes mellitus (DM), hypertension, peripheral vascular diseases, myocardial infarction, and heart failure [4–6]. Prospective studies have demonstrated that vitamin D deficiency affects vascular functions and augments atherosclerosis, and also treatment with vitamin D has favorable effects 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
SVG disease group (8.3 vs. 6.5 mg/dl, P = 0.001). In a multivariate regression analysis, current smoking, diabetes mellitus, target artery diameter less than 1.5 mm, bypass time duration, and vitamin D levels remained as independent factors associated with SVG disease. Conclusion Lower vitamin D levels are associated with occlusion of SVGs in patients with coronary artery disease. Coron Artery Dis 26:328–332 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:328–332 Keywords: coronary artery disease, saphenous vein graft, vitamin D a Cardiology Clinic, Turkey Yuksek Ihtisas Education and Research Hospital, Ankara and bCardiology Clinic, Adana Numune Education and Research Hospital, Adana, Turkey
Correspondence to Samet Yilmaz, MD, Cardiology Clinic, Turkey Yuksek Ihtisas Education and Research Hospital, Kizilay sok. Sihhiye, 06100 Ankara, Turkey Tel: + 90 507 5883; fax: + 90 312 310 1010; e-mail: [email protected] Received 11 December 2014 Revised 3 February 2015 Accepted 6 February 2015
on endothelial function [7,8]. Recent studies have clarified that vitamin D might play a role in the pathogenesis of cardiovascular disease (CVD) through an involvement in the process of plaque formation and progression [9]. Furthermore, vitamin D deficiency promotes stimulation of systemic and vascular inflammation, whereas in-vitro data suggest that the biologically active form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) has several immunomodulatory functions [10]. In this study we aimed to determine the association between 25 (OH)D levels and the SVG disease. In addition, we hypothesized that 25 (OH)D would also be inversely associated with inflammatory markers such as C-reactive protein (CRP), and that the postulated antiinflammatory properties of vitamin D may be one mechanism for potential CVD risk reduction.
Methods In this cross-sectional study, we enrolled 315 patients who had undergone a primary CABG surgery with at least one SVG and later had a control angiography because of clinical indications, including symptoms of angina and abnormal noninvasive test results (either treadmill exercise tests or myocardial perfusion scintigraphy) between DOI: 10.1097/MCA.0000000000000240
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Vitamin D and saphenous graft patency Sen et al. 329
June 2014 and September 2014 at Turkey Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey. Patients with acute coronary syndrome, significant valvular heart disease, decompensated heart failure, chronic renal (glomerular filtration rate < 60 ml/min) or liver disease (aspartate transaminase/alanine transaminase > three times normal), or other known malignant disease, and patients on vitamin D or calcium supplementation or with hyperparathyroidism or hypercalcemia were excluded from study. Finally, 180 patients were divided into two groups on the basis of the presence of SVG disease. Of all participants, 100 patients had SVG disease and 80 of them had patent SVG. SVG disease was accepted as the presence of at least 50% stenosis in at least one SVG. Patients with less than 50% stenosis in each of the SVGs were accepted as free from SVG disease. The local ethics committee approved the study protocol. Patients’ clinical and demographic characteristics, encompassing age, sex, history of arterial hypertension, DM, tobacco use, and the left ventricular ejection fraction, were noted. In addition, serum levels of fasting blood glucose, hemoglobin, CRP, and lipid panel, including LDL-cholesterol, HDLcholesterol, and triglyceride levels, were also recorded. Hyperlipidemia was defined as total cholesterol greater than 200 mg/dl or treatment with a lipid-lowering agent. SVG age was accepted as the duration between CABG surgery and coronary angiography in years. The study was performed in Ankara, Turkey, which has a continental climate, with cold, snowy winters (December, January, February) and hot, dry summers (June, July, August). Rainfall occurs mostly during spring and autumn. The average temperature is 28°C (82°F) in summer and temperatures as high as 42°C (108°F) were recorded. Blood samples were collected after 12 h of fasting between 8:00 and 10:00 a.m. Complete blood count, biochemistry, and cholesterol panels were recorded. Serum concentrations of 25 (OH)D were measured in aliquots of serum samples stored at − 80°C until testing. A radioimmunoassay procedure was used to measure 25 (OH)D (DiaSorin, Stillwater, Minnesota, USA). LC-MS/MS is widely regarded as the best available technique for 25 (OH)D quantification. The increased analytical specificity provided by the tandem mass spectrometry detection offers the potential for high accuracy and overcomes many of the difficulties associated with immunoassays [11]. A radioimmunoassay by DiaSorin also has a measuring range of 3.8–250 nmol/l and has been shown to have good agreement with LC-MS/MS methods in studies [12,13]. CRP levels were immunologically determined with the immunoturbidimetric method (Abbott Aeroset 1600 autoanalyzer; Abbott reagents, Wiesbaden, Germany). The Judkins technique was used for visualization of coronary arteries and coronary bypass grafts. Each vessel was visualized in at least two different plane images. When it was indicated, visualization of the aortic root was also
performed with aortic root angiography. At least two cardiologists, who were blinded to patients’ characteristics, evaluated the coronary angiograms. Finally, presence of 50% or greater stenosis in at least one SVG according to both cardiologists was accepted as SVG disease. Analyses were performed using SPSS, version 21.0 statistical software (SPSS Inc., Chicago, Illinois, USA). Continuous data were presented as mean ± SD. To test the distribution pattern, the Kolmogorov–Smirnov test was used. Student’s t-test was used to compare groups’ data showing normal distribution. The Mann–Whitney U-test was applied to compare the data without a normal distribution. Categorical variables were summarized as percentages and compared with the χ2-test. Effects of different variables on SVG disease were calculated in univariate analysis for each. Variables that had unadjusted P value less than 0.10 in logistic regression analysis were identified as potential risk markers and included in the full model. We reduced the model using stepwise multivariate logistic regression analyses and eliminated potential risk markers using likelihood ratio tests. A P value less than 0.05 was considered statistically significant, and the confidence interval was 95%.
Results The mean age of 180 patients was 57.4 ± 8.8 years and 64.4% of the study population were men. The study population comprised 100 patients with SVG disease and 80 patients with patent SVG. Basal characteristics of the groups are presented in Table 1. The mean number of SVGs to each patient was 2.02 ± 0.61 (range 1–4 grafts; total 364 SVGs). The number of saphenous veins grafted to each of the target coronary arteries was as follows: the left anterior descending artery, eight (4.4%); diagonal artery, 42 (23.3%); circumflex-obtuse marginal artery, 153 (85%); posterior descending artery, 20 (11.1%); and right coronary artery, 141 (78.3%). There were 95 internal mammary grafts (IMAs) in the SVG disease group and 77 IMA grafts in the patent SVG group. All of the arterial grafts were patent in the patent SVG group, and there was only one diseased IMA graft in the SVG disease group. Patients in the SVG disease group had a higher incidence of DM (P = 0.001), hypertension (P = 0.003), and current smokers (P < 0.001). The number of target artery diameter less than 1.5 mm and the duration of surgery time were also higher in patients with SVG disease (P = 0.026 and 0.04, respectively). Laboratory parameters of the patients are given in Table 2. Hemoglobin and creatinine levels, platelet count, and lipid parameters were similar between the two groups. The 25 (OH)D level was higher in the patent SVG group than in the SVG disease group (36.2 ± 10.7 and 21.1 ± 10.4, respectively; P < 0.001) (Fig. 1). CRP levels were significantly higher in the SVG disease group (mean CRP levels, 8.3 vs. 6.5 mg/dl, P = 0.001). There
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Table 1
Baseline characteristics of study groups
Fig. 1
Saphenous vein graft disease group (n = 100)
Patent saphenous vein graft group (n = 80)
P value
57.4 ± 8.9 69 (69.0) 51 (51.0) 79 (79.0) 78 (78.0) 49 (49.0) 40 (40.0) 49.3 ± 7.2 7.9 ± 4.2 2.00 ± 0.61
57.5 ± 8.6 47 (58.7) 24 (30.0) 45 (56.2) 39 (48.7) 33 (41.2) 28 (35.0) 48.1 ± 9.2 5.5 ± 3.2 2.05 ± 0.63
0.943 0.102 0.003 0.001 < 0.001 0.188 0.298 0.965 0.038 0.443
94 (94)
76 (95)
Age (years) Male (%) Hypertension (%) Diabetes mellitus (%) Current smoking (%) Hyperlipidemia (%) Family history (%) Ejection fraction (%) Age of SVG (years) Number of SVGs (mean) Patent internal mammary artery graft (%) Target artery diameter < 1.5 mm (%) Duration of surgery (min) Postoperative medications Aspirin (%) Statin (%) ACEI/ARB (%) β-Blocker (%)
19 (19.0) 101 (75–125)
8 (10.0) 92 (76–105)
60.00
40.00
20.00
0.836
0.026
0.00
0.040
Patent SVG group 95 76 68 71
(95.0) (76.0) (68.0) (71.0)
78 59 52 62
(97.5) (73.7) (65.0) (77.5)
0.862 0.753 0.734 0.556
ACEI, angiotensin converting enzyme inhibitor; ARB, aldosterone receptor blocker; SVG, saphenous vein graft.
Diseased SVG group
Comparision of 25 (OH)D levels between the two groups. 25 (OH)D, 25-hydroxyvitamin D; SVG, saphenous vein graft.
Fig. 2
20.00
In univariate logistic regression analyses, SVG age, target artery diameter less than 1.5 mm, current smoking, DM, duration of surgery, and 25 (OH)D level were all significantly associated with SVG disease. When these six variables were included in a multivariate regression analysis, current smoking, DM, target artery diameter less than 1.5 mm, duration of surgery, and 25 (OH)D level remained as independent factors associated with SVG disease (Table 3).
15.00 C-reactive protein
was a significant inverse correlation between 25 (OH)D levels and CRP levels (r = − 0.168, P = 0.024) (Fig. 2).
F
10.00
5.00
0.00
Discussion In the present study, we found a significant inverse association between serum 25 (OH)D levels and SVG disease. To the best of our knowledge, this is the first report to assess the relationship between serum 25 (OH) D level and SVG disease.
Table 2
0.00
20.00
40.00 Vitamin D
60.00
Correlation between C-reactive protein and vitamin D levels (r = − 0.168, P = 0.024).
Comparision of baseline laboratory findings
Hemoglobin (g/dl) White blood cell count (×109/l) Platelet count (×109/l) Glucose (mg/dl) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglycerides (mg/dl) Creatinine (mg/dl) 25 (OH)D level (ng/ml) C-reactive protein (mg/dl)
Saphenous vein graft disease group (n = 100)
Patent saphenous vein graft group (n = 80)
P value
13.1 ± 1.80 11.0 ± 3.24 239 ± 82 122.2 ± 46.9 186.8 ± 40.1 129.4 ± 33.2 37.3 ± 8.1 171.5 ± 78.2 1.19 ± 0.29 21.1 ± 10.4 8.3 ± 3.9
13.6 ± 1.95 10.2 ± 2.75 254 ± 60 114.1 ± 51.1 182.5 ± 39.2 118.1 ± 30.3 36.7 ± 7.6 167.7 ± 69.5 1.12 ± 0.24 36.2 ± 10.7 6.5 ± 2.8
0.335 0.130 0.440 0.057 0.227 0.390 0.720 0.336 0.510 < 0.001 0.001
25 (OH)D, 25-hydroxyvitamin D.
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Vitamin D and saphenous graft patency Sen et al. 331
Significant predictors of saphenous vein graft disease in univariable and multivariable logistic regression analysis
Table 3
Univariate Variables Saphenous vein graft age Diabetes mellitus Hypertension Current smoking Target artery diameter < 1.5 mm Duration of surgery 25 (OH)D level C-reactive protein
OR (95% CI) 0.89 (0.91–0.99)
Multivariate P value 0.035
OR (95% CI)
P value
0.94 (0.87–1.012)
0.670
(1.08–2.09) (0.98–1.22) (1.3–2.9) (1.15–2.07)
< 0.001 0.258 < 0.001 < 0.001
1.92 (1.10–2.65)
0.010
2.10 (1.36–3.30) 1.33 (1.15–1.92)
< 0.001 0.002
1.15 (1.02–1.61)
0.009
1.45 (1.32–2.05)
0.015
0.78 (0.70–0.92) 1.04 (0.95–1.12)
< 0.001 0.49
0.84 (0.80–0.88)
< 0.001
1.56 1.12 1.92 1.47
CI, confidence interval; 25 (OH)D, 25-hydroxyvitamin D; OR, odds ratio.
Surgery, when indicated, is a good option for the treatment of CHD. With appropriate indications and appropriate surgery, CABG gives significant mortality and morbidity benefits to the patients with CHD. Both arterial and venous conduits are available, and they have been frequently used in this surgical procedure. Although patency rates for left IMA is excellent, it cannot be used for all stenotic vessels. For this reason, SVGs are frequently preferred counduits in the CABG surgery. Besides its benefits on revascularization, higher rates of graft occlusion remain a challenging issue. It is known that there are ∼50% occlusion rates for saphenous grafts after 10 years of CABG surgery [1]. The mean age of saphenous grafts in patients with SVG disease was about 7.9 years compared with 5.5 years in patients with patent grafts in our study. Patients with SVG disease underwent surgery at earlier ages compared with those without SVG disease. This may be attributed to their higher potential to suffer from atherosclerosis, as they have more cardiovascular risk factors such as smoking, diabetes, hypertension, and hyperlipidemia. They have lower levels of vitamin D and it might also contribute to development of atherosclerosis in those ages. Recent prospective studies identified 25 (OH)D insufficiency as a significant risk factor for cardiovascular events. Vitamin D exerts a variety of favorable effects on endothelial dysfunction, vascular smooth muscle cell proliferation and migration, and calcification, as well as on the inflammatory/immune process of atherosclerosis; moreover, it exerts beneficial effects against systemic conditions that promote atherosclerosis, such as insulin resistance, β-cell dysfunction, dyslipidemia, and hypertension [9]. Low 25 (OH)D levels have been reported in patients suffering from stroke and CVD, and low levels of 25 (OH)D are associated with cardiovascular mortality and peripheral arterial disease [5,14–16]. Vitamin D receptor is found in most tissues and cells, which includes vascular smooth muscle cells [17], macrophages [18], cardiomyocytes [19], endothelium [20], and lymphocytes [21]. Vitamin D stimulates the production of prostacyclin by vascular smooth muscle cells, which prevents
thrombus formation, cell adhesion, and smooth muscle cell proliferation [22]. In addition, Al Mheid et al. [23] reported that vitamin D insufficiency was associated with increased arterial stiffness and endothelial dysfunction in healthy humans. It was recently demonstrated that vitamin D supplementation significantly improves endothelial function, both in patients with diabetes [8] and in healthy vitamin D-insufficient adults [7]. However, there are no conclusive clinical studies on whether supplementation of vitamin D affects outcome from CVDs. The Women’s Health Initiative study [24] randomized 36 000 women to receive 1 g calcium plus 400 U vitamin D3 daily for 7 years. No difference was seen in either myocardial infarction, death, stroke, or new onset DM. Trivedi et al. [25] randomized 2286 older people to receive 100 000 IU oral vitamin D or placebo every 4 months for 5 years; the relative risk of both cardiovascular death (0.84) and overall mortality (0.88) was nonsignificantly lower in the treatment arm. The role of low-grade inflammation in the pathogenesis of atherosclerosis and its acute complications are well determined, and several biological markers of inflammation predict cardiovascular risk [26,27]. Another mechanism explaining the effects of vitamin D and its metabolites on SVG disease may be its anti-inflammatory actions [21]. Several studies have shown an inverse relationship between vitamin D levels and inflammation markers [28–30]. In our study we also found an inverse relationship between 25 (OH)D and CRP levels. Our study has several limitations such as the crosssectional and observational nature of our study does not allow us to determine cause and effect relationships. Moreover, the study population comprised patients from only one geographical region with a limited number of participants, it cannot be generalized to all of the patients with saphenous graft disease. Vitamin D levels vary with geography, seasonality, latitude, and altitude presumably as a result of sunlight exposure, and vitamin D levels may change throughout the day and season of the year. A single measurement of vitamin D may not reflect lifetime status and atherosclerosis progresses over many years.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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The relationship between vitamin D levels and saphenous vein graft patency Fatih Sena, Samet Yilmaza, Kevser G. Balcia, Ömer Senb, Murat Güla, Serkan Çaya, Serkan Topaloglua and Sinan Aydogdua Objective A growing body of evidence supports an association between vitamin D and cardiovascular diseases. Coronary artery bypass grafting surgery is a treatment modality for suitable patients with coronary artery disease; however, patency rates of saphenous vein grafts (SVGs) are low. In this study we aimed to determine the association between vitamin D levels and the SVG disease. Methods The study population included 180 patients who had undergone a primary coronary artery bypass grafting surgery with at least one SVG and later had a control angiography because of clinical indications. Patients were divided into two groups: 100 patients with SVG disease and 80 of them with patent SVG. Results The mean age of 180 patients was 57.4 ± 8.8 years, and 64.4% of the study population were men. The total number of SVGs was 364, and the mean number of SVGs to each patient was 2.02 ± 0.61. Vitamin D levels were higher in the patent SVG group than in the SVG disease group (36.2 ± 10.7 and 21.1 ± 10.4, respectively; P < 0.001). C-reactive protein levels were significantly higher in the
Introduction Ischemic heart disease is an important health problem because of its associated morbidity and mortality. In this regard, coronary artery bypass grafting (CABG) is an available option to reduce the untoward consequences of coronary heart disease (CHD). Both arterial and venous conduits can be used in this procedure, but patency rates of saphenous vein grafts (SVGs) are lower compared with arterial conduits. Stenosis rates of SVGs are 15% at the end of first year and nearly 50% at the end of 10th year, after CABG surgery [1]. Most common mechanisms for SVG occlusion are thrombosis (first month), neointimal hyperplasia (1–12 months), and atherosclerosis (>12 months) [2]. Vitamin D deficiency is a highly prevalent condition in patients with coronary artery disease and also in the general population [3]. Growing evidence shows that people who are deficient to 25-hydroxyvitamin D [25 (OH)D] have higher risks for several cardiovascularrelated conditions such as obesity, diabetes mellitus (DM), hypertension, peripheral vascular diseases, myocardial infarction, and heart failure [4–6]. Prospective studies have demonstrated that vitamin D deficiency affects vascular functions and augments atherosclerosis, and also treatment with vitamin D has favorable effects 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
SVG disease group (8.3 vs. 6.5 mg/dl, P = 0.001). In a multivariate regression analysis, current smoking, diabetes mellitus, target artery diameter less than 1.5 mm, bypass time duration, and vitamin D levels remained as independent factors associated with SVG disease. Conclusion Lower vitamin D levels are associated with occlusion of SVGs in patients with coronary artery disease. Coron Artery Dis 26:328–332 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:328–332 Keywords: coronary artery disease, saphenous vein graft, vitamin D a Cardiology Clinic, Turkey Yuksek Ihtisas Education and Research Hospital, Ankara and bCardiology Clinic, Adana Numune Education and Research Hospital, Adana, Turkey
Correspondence to Samet Yilmaz, MD, Cardiology Clinic, Turkey Yuksek Ihtisas Education and Research Hospital, Kizilay sok. Sihhiye, 06100 Ankara, Turkey Tel: + 90 507 5883; fax: + 90 312 310 1010; e-mail: [email protected] Received 11 December 2014 Revised 3 February 2015 Accepted 6 February 2015
on endothelial function [7,8]. Recent studies have clarified that vitamin D might play a role in the pathogenesis of cardiovascular disease (CVD) through an involvement in the process of plaque formation and progression [9]. Furthermore, vitamin D deficiency promotes stimulation of systemic and vascular inflammation, whereas in-vitro data suggest that the biologically active form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) has several immunomodulatory functions [10]. In this study we aimed to determine the association between 25 (OH)D levels and the SVG disease. In addition, we hypothesized that 25 (OH)D would also be inversely associated with inflammatory markers such as C-reactive protein (CRP), and that the postulated antiinflammatory properties of vitamin D may be one mechanism for potential CVD risk reduction.
Methods In this cross-sectional study, we enrolled 315 patients who had undergone a primary CABG surgery with at least one SVG and later had a control angiography because of clinical indications, including symptoms of angina and abnormal noninvasive test results (either treadmill exercise tests or myocardial perfusion scintigraphy) between DOI: 10.1097/MCA.0000000000000240
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Vitamin D and saphenous graft patency Sen et al. 329
June 2014 and September 2014 at Turkey Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey. Patients with acute coronary syndrome, significant valvular heart disease, decompensated heart failure, chronic renal (glomerular filtration rate < 60 ml/min) or liver disease (aspartate transaminase/alanine transaminase > three times normal), or other known malignant disease, and patients on vitamin D or calcium supplementation or with hyperparathyroidism or hypercalcemia were excluded from study. Finally, 180 patients were divided into two groups on the basis of the presence of SVG disease. Of all participants, 100 patients had SVG disease and 80 of them had patent SVG. SVG disease was accepted as the presence of at least 50% stenosis in at least one SVG. Patients with less than 50% stenosis in each of the SVGs were accepted as free from SVG disease. The local ethics committee approved the study protocol. Patients’ clinical and demographic characteristics, encompassing age, sex, history of arterial hypertension, DM, tobacco use, and the left ventricular ejection fraction, were noted. In addition, serum levels of fasting blood glucose, hemoglobin, CRP, and lipid panel, including LDL-cholesterol, HDLcholesterol, and triglyceride levels, were also recorded. Hyperlipidemia was defined as total cholesterol greater than 200 mg/dl or treatment with a lipid-lowering agent. SVG age was accepted as the duration between CABG surgery and coronary angiography in years. The study was performed in Ankara, Turkey, which has a continental climate, with cold, snowy winters (December, January, February) and hot, dry summers (June, July, August). Rainfall occurs mostly during spring and autumn. The average temperature is 28°C (82°F) in summer and temperatures as high as 42°C (108°F) were recorded. Blood samples were collected after 12 h of fasting between 8:00 and 10:00 a.m. Complete blood count, biochemistry, and cholesterol panels were recorded. Serum concentrations of 25 (OH)D were measured in aliquots of serum samples stored at − 80°C until testing. A radioimmunoassay procedure was used to measure 25 (OH)D (DiaSorin, Stillwater, Minnesota, USA). LC-MS/MS is widely regarded as the best available technique for 25 (OH)D quantification. The increased analytical specificity provided by the tandem mass spectrometry detection offers the potential for high accuracy and overcomes many of the difficulties associated with immunoassays [11]. A radioimmunoassay by DiaSorin also has a measuring range of 3.8–250 nmol/l and has been shown to have good agreement with LC-MS/MS methods in studies [12,13]. CRP levels were immunologically determined with the immunoturbidimetric method (Abbott Aeroset 1600 autoanalyzer; Abbott reagents, Wiesbaden, Germany). The Judkins technique was used for visualization of coronary arteries and coronary bypass grafts. Each vessel was visualized in at least two different plane images. When it was indicated, visualization of the aortic root was also
performed with aortic root angiography. At least two cardiologists, who were blinded to patients’ characteristics, evaluated the coronary angiograms. Finally, presence of 50% or greater stenosis in at least one SVG according to both cardiologists was accepted as SVG disease. Analyses were performed using SPSS, version 21.0 statistical software (SPSS Inc., Chicago, Illinois, USA). Continuous data were presented as mean ± SD. To test the distribution pattern, the Kolmogorov–Smirnov test was used. Student’s t-test was used to compare groups’ data showing normal distribution. The Mann–Whitney U-test was applied to compare the data without a normal distribution. Categorical variables were summarized as percentages and compared with the χ2-test. Effects of different variables on SVG disease were calculated in univariate analysis for each. Variables that had unadjusted P value less than 0.10 in logistic regression analysis were identified as potential risk markers and included in the full model. We reduced the model using stepwise multivariate logistic regression analyses and eliminated potential risk markers using likelihood ratio tests. A P value less than 0.05 was considered statistically significant, and the confidence interval was 95%.
Results The mean age of 180 patients was 57.4 ± 8.8 years and 64.4% of the study population were men. The study population comprised 100 patients with SVG disease and 80 patients with patent SVG. Basal characteristics of the groups are presented in Table 1. The mean number of SVGs to each patient was 2.02 ± 0.61 (range 1–4 grafts; total 364 SVGs). The number of saphenous veins grafted to each of the target coronary arteries was as follows: the left anterior descending artery, eight (4.4%); diagonal artery, 42 (23.3%); circumflex-obtuse marginal artery, 153 (85%); posterior descending artery, 20 (11.1%); and right coronary artery, 141 (78.3%). There were 95 internal mammary grafts (IMAs) in the SVG disease group and 77 IMA grafts in the patent SVG group. All of the arterial grafts were patent in the patent SVG group, and there was only one diseased IMA graft in the SVG disease group. Patients in the SVG disease group had a higher incidence of DM (P = 0.001), hypertension (P = 0.003), and current smokers (P < 0.001). The number of target artery diameter less than 1.5 mm and the duration of surgery time were also higher in patients with SVG disease (P = 0.026 and 0.04, respectively). Laboratory parameters of the patients are given in Table 2. Hemoglobin and creatinine levels, platelet count, and lipid parameters were similar between the two groups. The 25 (OH)D level was higher in the patent SVG group than in the SVG disease group (36.2 ± 10.7 and 21.1 ± 10.4, respectively; P < 0.001) (Fig. 1). CRP levels were significantly higher in the SVG disease group (mean CRP levels, 8.3 vs. 6.5 mg/dl, P = 0.001). There
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Coronary Artery Disease 2015, Vol 26 No 4
Table 1
Baseline characteristics of study groups
Fig. 1
Saphenous vein graft disease group (n = 100)
Patent saphenous vein graft group (n = 80)
P value
57.4 ± 8.9 69 (69.0) 51 (51.0) 79 (79.0) 78 (78.0) 49 (49.0) 40 (40.0) 49.3 ± 7.2 7.9 ± 4.2 2.00 ± 0.61
57.5 ± 8.6 47 (58.7) 24 (30.0) 45 (56.2) 39 (48.7) 33 (41.2) 28 (35.0) 48.1 ± 9.2 5.5 ± 3.2 2.05 ± 0.63
0.943 0.102 0.003 0.001 < 0.001 0.188 0.298 0.965 0.038 0.443
94 (94)
76 (95)
Age (years) Male (%) Hypertension (%) Diabetes mellitus (%) Current smoking (%) Hyperlipidemia (%) Family history (%) Ejection fraction (%) Age of SVG (years) Number of SVGs (mean) Patent internal mammary artery graft (%) Target artery diameter < 1.5 mm (%) Duration of surgery (min) Postoperative medications Aspirin (%) Statin (%) ACEI/ARB (%) β-Blocker (%)
19 (19.0) 101 (75–125)
8 (10.0) 92 (76–105)
60.00
40.00
20.00
0.836
0.026
0.00
0.040
Patent SVG group 95 76 68 71
(95.0) (76.0) (68.0) (71.0)
78 59 52 62
(97.5) (73.7) (65.0) (77.5)
0.862 0.753 0.734 0.556
ACEI, angiotensin converting enzyme inhibitor; ARB, aldosterone receptor blocker; SVG, saphenous vein graft.
Diseased SVG group
Comparision of 25 (OH)D levels between the two groups. 25 (OH)D, 25-hydroxyvitamin D; SVG, saphenous vein graft.
Fig. 2
20.00
In univariate logistic regression analyses, SVG age, target artery diameter less than 1.5 mm, current smoking, DM, duration of surgery, and 25 (OH)D level were all significantly associated with SVG disease. When these six variables were included in a multivariate regression analysis, current smoking, DM, target artery diameter less than 1.5 mm, duration of surgery, and 25 (OH)D level remained as independent factors associated with SVG disease (Table 3).
15.00 C-reactive protein
was a significant inverse correlation between 25 (OH)D levels and CRP levels (r = − 0.168, P = 0.024) (Fig. 2).
F
10.00
5.00
0.00
Discussion In the present study, we found a significant inverse association between serum 25 (OH)D levels and SVG disease. To the best of our knowledge, this is the first report to assess the relationship between serum 25 (OH) D level and SVG disease.
Table 2
0.00
20.00
40.00 Vitamin D
60.00
Correlation between C-reactive protein and vitamin D levels (r = − 0.168, P = 0.024).
Comparision of baseline laboratory findings
Hemoglobin (g/dl) White blood cell count (×109/l) Platelet count (×109/l) Glucose (mg/dl) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglycerides (mg/dl) Creatinine (mg/dl) 25 (OH)D level (ng/ml) C-reactive protein (mg/dl)
Saphenous vein graft disease group (n = 100)
Patent saphenous vein graft group (n = 80)
P value
13.1 ± 1.80 11.0 ± 3.24 239 ± 82 122.2 ± 46.9 186.8 ± 40.1 129.4 ± 33.2 37.3 ± 8.1 171.5 ± 78.2 1.19 ± 0.29 21.1 ± 10.4 8.3 ± 3.9
13.6 ± 1.95 10.2 ± 2.75 254 ± 60 114.1 ± 51.1 182.5 ± 39.2 118.1 ± 30.3 36.7 ± 7.6 167.7 ± 69.5 1.12 ± 0.24 36.2 ± 10.7 6.5 ± 2.8
0.335 0.130 0.440 0.057 0.227 0.390 0.720 0.336 0.510 < 0.001 0.001
25 (OH)D, 25-hydroxyvitamin D.
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Vitamin D and saphenous graft patency Sen et al. 331
Significant predictors of saphenous vein graft disease in univariable and multivariable logistic regression analysis
Table 3
Univariate Variables Saphenous vein graft age Diabetes mellitus Hypertension Current smoking Target artery diameter < 1.5 mm Duration of surgery 25 (OH)D level C-reactive protein
OR (95% CI) 0.89 (0.91–0.99)
Multivariate P value 0.035
OR (95% CI)
P value
0.94 (0.87–1.012)
0.670
(1.08–2.09) (0.98–1.22) (1.3–2.9) (1.15–2.07)
< 0.001 0.258 < 0.001 < 0.001
1.92 (1.10–2.65)
0.010
2.10 (1.36–3.30) 1.33 (1.15–1.92)
< 0.001 0.002
1.15 (1.02–1.61)
0.009
1.45 (1.32–2.05)
0.015
0.78 (0.70–0.92) 1.04 (0.95–1.12)
< 0.001 0.49
0.84 (0.80–0.88)
< 0.001
1.56 1.12 1.92 1.47
CI, confidence interval; 25 (OH)D, 25-hydroxyvitamin D; OR, odds ratio.
Surgery, when indicated, is a good option for the treatment of CHD. With appropriate indications and appropriate surgery, CABG gives significant mortality and morbidity benefits to the patients with CHD. Both arterial and venous conduits are available, and they have been frequently used in this surgical procedure. Although patency rates for left IMA is excellent, it cannot be used for all stenotic vessels. For this reason, SVGs are frequently preferred counduits in the CABG surgery. Besides its benefits on revascularization, higher rates of graft occlusion remain a challenging issue. It is known that there are ∼50% occlusion rates for saphenous grafts after 10 years of CABG surgery [1]. The mean age of saphenous grafts in patients with SVG disease was about 7.9 years compared with 5.5 years in patients with patent grafts in our study. Patients with SVG disease underwent surgery at earlier ages compared with those without SVG disease. This may be attributed to their higher potential to suffer from atherosclerosis, as they have more cardiovascular risk factors such as smoking, diabetes, hypertension, and hyperlipidemia. They have lower levels of vitamin D and it might also contribute to development of atherosclerosis in those ages. Recent prospective studies identified 25 (OH)D insufficiency as a significant risk factor for cardiovascular events. Vitamin D exerts a variety of favorable effects on endothelial dysfunction, vascular smooth muscle cell proliferation and migration, and calcification, as well as on the inflammatory/immune process of atherosclerosis; moreover, it exerts beneficial effects against systemic conditions that promote atherosclerosis, such as insulin resistance, β-cell dysfunction, dyslipidemia, and hypertension [9]. Low 25 (OH)D levels have been reported in patients suffering from stroke and CVD, and low levels of 25 (OH)D are associated with cardiovascular mortality and peripheral arterial disease [5,14–16]. Vitamin D receptor is found in most tissues and cells, which includes vascular smooth muscle cells [17], macrophages [18], cardiomyocytes [19], endothelium [20], and lymphocytes [21]. Vitamin D stimulates the production of prostacyclin by vascular smooth muscle cells, which prevents
thrombus formation, cell adhesion, and smooth muscle cell proliferation [22]. In addition, Al Mheid et al. [23] reported that vitamin D insufficiency was associated with increased arterial stiffness and endothelial dysfunction in healthy humans. It was recently demonstrated that vitamin D supplementation significantly improves endothelial function, both in patients with diabetes [8] and in healthy vitamin D-insufficient adults [7]. However, there are no conclusive clinical studies on whether supplementation of vitamin D affects outcome from CVDs. The Women’s Health Initiative study [24] randomized 36 000 women to receive 1 g calcium plus 400 U vitamin D3 daily for 7 years. No difference was seen in either myocardial infarction, death, stroke, or new onset DM. Trivedi et al. [25] randomized 2286 older people to receive 100 000 IU oral vitamin D or placebo every 4 months for 5 years; the relative risk of both cardiovascular death (0.84) and overall mortality (0.88) was nonsignificantly lower in the treatment arm. The role of low-grade inflammation in the pathogenesis of atherosclerosis and its acute complications are well determined, and several biological markers of inflammation predict cardiovascular risk [26,27]. Another mechanism explaining the effects of vitamin D and its metabolites on SVG disease may be its anti-inflammatory actions [21]. Several studies have shown an inverse relationship between vitamin D levels and inflammation markers [28–30]. In our study we also found an inverse relationship between 25 (OH)D and CRP levels. Our study has several limitations such as the crosssectional and observational nature of our study does not allow us to determine cause and effect relationships. Moreover, the study population comprised patients from only one geographical region with a limited number of participants, it cannot be generalized to all of the patients with saphenous graft disease. Vitamin D levels vary with geography, seasonality, latitude, and altitude presumably as a result of sunlight exposure, and vitamin D levels may change throughout the day and season of the year. A single measurement of vitamin D may not reflect lifetime status and atherosclerosis progresses over many years.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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