High Blood Pressure & Cardiovascular Prevention https://doi.org/10.1007/s40292-018-0295-7 ORIGINAL ARTICLE Association of Vitamin D Deficiency with Chronic Stable Angina: A Case Control Study Eman Raslan1 · Saeed S. Abduljalil Soliman1 · Zeinab A. Nour1 · Dalia Ahmed1 · Nagwa Eid Sobhy Saad1 Received: 17 October 2018 / Accepted: 10 December 2018 © Italian Society of Hypertension 2018 Abstract Introduction Coronary heart disease is a major cause of death worldwide. Although the relationship between vitamin D status and cardiovascular diseases is not clearly understood, vitamin D deficiency could be a potentially modifiable and underestimated risk factor for ischemic heart diseases. This study aims to assess and compare vitamin D status between patient group with chronic stable angina and matched control group. Methods A case-control study was conducted on chronic stable angina patients and matched controls attending family medicine/internal medicine clinics at Cairo University Hospitals. Forty two adult patients with chronic stable angina and forty two matched controls were studied. Detailed medical history, examination, and laboratory tests (vitamin D, fasting lipid profile, and blood sugar) were collected from study participants of both groups. Results Severe vitamin D deficiency was found in 78.6% and 7.1% of cases and controls, respectively. Vitamin D level was found to be a significant predictor of chronic stable angina. Every unit (ng/ml) increase in vitamin D level decreases the chance of the subject to have chronic stable angina by 0.30 times. Conclusion There is a significant association between vitamin D deficiency and the occurrence of chronic stable angina. Keywords Vitamin D · Angina · Ischemic heart disease · Coronary artery disease 1 Introduction Vitamin D is a group of fat-soluble vitamins with classic actions of regulating mineral ion homeostasis and bone metabolism [1]. However, after the discovery of the fact that the vitamin D receptors (VDR) are expressed in most of the body tissues, other roles of vitamin D beyond its established role in the maintenance of bone health and serum calcium levels have been explored. This leads to finding that vitamin D has several important homeostatic functions not related to calcium homeostasis [2]. Vitamin D deficiency is now recognized as a pandemic. The main cause of vitamin D deficiency is the lack of knowledge that sun exposure is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy vitamin D requirements [3]. * Saeed S. Abduljalil Soliman saeed.salah@medicine.cu.edu.eg 1 Faculty of Medicine, Cairo University, Giza, Egypt Risk factors for vitamin D deficiency include: old age, dark skin, obesity, smoking, kidney or liver disorders, diseases affecting fat absorption, and bariatric surgeries [4]. A circulating level of 25-hydroxyvitamin D of more than 75 mmol/L, or 30 ng/mL is required to maximize vitamin D’s beneficial effects for health [3]. Vitamin D insufficiency is defined as 20–30 ng/mL and vitamin D deficiency is defined as < 20 ng/mL [5]. Cardiovascular disease (CVD) has a significant impact on healthcare systems worldwide and over 23 million individuals are expected to succumb to the disease by 2030 [6]. Chronic stable angina is the main symptomatic manifestation of myocardial ischemia, caused by an imbalance between myocardial blood supply and oxygen demand [7]. Angina is associated with significant morbidity and mortality. A patient with angina consults a general practitioner two to three times a year and has a threefold increased risk of developing unstable angina, myocardial infarction or cardiac death within two years of the first presentation. Almost half of these deaths are sudden [8]. Vitamin D deficiency may be more prevalent in patients with cardiovascular risk factors and in those with coronary Vol.:(0123456789) E. Raslan et al. artery disease (CAD) [9]. The mechanism by which vitamin D can influence the risk of cardiovascular disease has not been clearly understood [10]. The proposed mechanisms include: endothelial dysfunction, microvascular dysfunction, insulin resistance, inflammation, and activation of the RAAS, leading to smooth muscle and myocardial hypertrophy [9]. Very few studies have been done to find any association between vitamin D deficiency and stable CAD [5]. This study hypothesizes that vitamin D deficiency is associated with the presence of chronic stable angina. The aim of this study is to test for vitamin D status and assess the relation between vitamin D and the occurrence of chronic stable angina. 2 Methods This is a case-control study conducted on 42 patients aged 18–65 years with a documented diagnosis of chronic stable angina (CSA) as a clinical syndrome of typical chest pain ± ischemic changes in ECG or patients previously diagnosed and known to have ischemic heart disease in addition to 42 matched controls attending family and internal medicine outpatient clinics at Cairo University Hospitals from October 2016 to March 2018. Patients having an acute illness or acute coronary syndrome, history of malignant neoplasm within the past 5 years, renal impairment, parathyroid disease, or vitamin D and/or calcium supplements were excluded. The study protocol was approved by the Ethical Committee of Faculty of Medicine, Cairo University. Participants were informed about the objectives, methods, and possible impact of the study and a written consent was obtained. 2.1 Data Collection Tools and Techniques An interviewing questionnaire covering the following items: Socio-demographic data (age, sex, occupation and residency), lifestyle data (smoking/alcohol habits, physical activity, sun exposure), assessment of angina severity using New York Heart Association Classification for cases, and history of comorbidities with chronic diseases. Clinical data: BMI, waist circumference, pulse and blood pressure. Laboratory testing: 5 ml venous blood were collected from each participant into sterile plane tubes allowed to stand for 30 min at room temperature, centrifuged at 300g (gravitational force) for 5 min. Sera were separated immediately. Fasting blood glucose, complete blood count (CBC), and complete lipid profile were measured, then the rest was stored at − 80 °C until the time of analysis of 25-OH vitamin D3. 2.2 Estimation of Serum 25‑OH Vitamin D3 The Serum 25-OH Vitamin D3 concentration was measured by commercial ELISA kit (ORGENTEC Diagnostika, GmbH, Germany). The ELISA was performed according to the manufacturer’s written protocol. The calculation range of this ELISA assay is 5–120 ng/ml. 2.3 Statistical Design Data were coded and entered using the Statistical Package for the Social Sciences (IBM SPSS Statistics 21) software. Data were summarized using number and percent for qualitative variables, mean, and SD for quantitative variables which are normally distributed. Median and interquartile range (IQR) were used for quantitative variables which are not normally distributed. Comparisons between groups were done using the Chi-square test. Mann–Whitney test was used for quantitative data comparisons. Logistic regression was done to test for significant predictors of the presence of CSA. P value ≤ 0.05 was considered as statistically significant. 3 Results Socio-demographic, lifestyle habits, clinical, and vitamin D categories data of study participants are shown in Table 1. There was no statistically significant difference between cases and controls regarding age, sex, season and residence, daily exposure to sunlight, BMI, family history of diabetes and/or hypertension, and sampling time. The mean age ± SD was 53.7 ± 9.8 years for cases and 50.1 ± 13.5 years for controls, with the difference being statistically insignificant (student t test, P = 0.164). Chronic stable angina group showed statistically significant higher proportion of non-workers, manual workers, diabetes, hypertension, ex-smokers, sedentary life, hypercholesterolemia, and hypertriglyceridemia (Chi-square test, P < 0.05). Severe vitamin D deficiency was observed in 78.1% of cases and 7.1% of controls. This difference was statistically significant (Chi-square test, P < 0.001). Median (IQR) vitamin D level was significantly lower in cases 13 ng/dl (8:18) than in controls 33 ng/dl (25.5:72.5) as shown in Fig. 1, (Mann Whitney U test, P < 0.001). Age, gender, diabetes, hypertension, cholesterol level, and vitamin D level were entered in logistic regression model. Hypertension and vitamin D level were found to be a significant predictors. Hypertensive subjects are about 22 times more likely to have CSA compared to non-hypertensive subjects, while every unit (ng/ml) increase in vitamin D level Association of Vitamin D Deficiency with Chronic Stable Angina Table 1 Demographic and medical data of cases and controls Gender (male) 24–40 years 40–59 years ≥ 60 years Not working Manual worker Professional Urban residence Autumn sampling Winter sampling Daily sunlight exposure Daily physical activity Current smoker Ex-smoker Non-smoker Diabetic Hypertensive Obese Family history of diabetes Family history of hypertension Severe vitamin D deficiency Vitamin D deficiency Vitamin D insufficiency High total cholesterol High triglycerides Cases, n 42 (%) Controls, n 42 (%) P value 21 (50.0) 5 (11.9) 23 (54.8) 14 (33.3) 26 (61.9) 13 (31.0) 3 (7.1) 39 (92.9) 24 (57.1) 18 (42.9) 39 (92.9) 19 (45.2) 10 (23.8) 11 (26.2) 21 (50.0) 18 (42.9) 27 (64.3) 14 (33.3) 11 (26.2) 9 (21.4) 33 (78.6) 9 (21.4) 0 (00.0) 17 (40.5) 18 (42.9) 19 (45.2) 12 (28.6) 16 (38.1) 14 (33.3) 8 (19.0) 5 (11.9) 29 (69.1) 38 (90.5) 24 (57.1) 18 (42.9) 33 (78.6) 31 (73.8) 7 (16.7) 3 (7.1) 32 (76.6) 9 (21.4) 8 (19.0) 12 (28.6) 9 (21.4) 9 (21.4) 3 (7.1) 7 (16.7) 6 (14.3) 5 (12.0) 6 (14.3) 0.662 0.126 *Significant P value Table 2 Predictors of chronic stable angina Hypertension Vitamin D Constant P value Odds ratio 95% C.I. for odds ratio 0.003 < 0.001 0.001 21.9 0.7 373.3 2.8 0.6 172.3 0.9 < 0.001* (NYHA) class I (NYHA) class II (NYHA) class III (NYHA) class IV 0.693 1 12% 19% 0.061 0.011* 0.025* 29% 0.035* < 0.001* 0.609 0.608 1 < 0.001* 40% Fig. 2 Percent of patients in each class of angina severity (NYHA) < 0.001* 0.001* decrease the chance of the subject to have CSA by 0.30 times as shown in Table 2. Using this model can correctly predict 88.1% of controls, 97.6% of cases, and 92.9% of total. All our cases were symptomatic. More than two thirds of cases had angina on effort (AOE)/angina equivalent New York Heart Association (NYHA) class II and III, while the least percent of cases had class IV symptoms, followed by nineteen percent of the patients had class I as shown in Fig. 2. Angina severity subgroup analysis of chronic stable angina group for possible associated factors with severity of angina was performed using chi square test. Diabetes was the only significantly associated factor with the severity of angina, being higher in the severe group. Other factors (sex, residence, occupation, physical activity, daily exposure to sun, hypertension, family history, and vitamin D level) showed no significant association with severity of angina. 4 Discussion Fig. 1 Median vitamin D level among cases and controls Vitamin D deficiency is a global major public health problem worldwide. Our study has revealed a higher prevalence of severe vitamin D deficiency and significantly lower vitamin D level median in chronic stable angina patients E. Raslan et al. compared to control subjects. This study results emphasize the role of vitamin D as an independent cardiovascular risk factor. The results of this study regarding median vitamin D difference between case and control groups agree with results of another study on 100 patients undergoing coronary angiography where mean vitamin D level was 14.8 ± 9.1 ng/ml. In addition, the results reported agree with results of a study in India where the mean vitamin D level among the cases was 15.53 ng/ml. This finding was different from that of a study from Sweden with mean vitamin D 27.6 ± 8.2 ng/ml among cases, this difference may be attributed to the type of the selected cases which came from rural area and most of them were farmers. Regarding vitamin D categories, results of this study are similar to those of Sanjeev Kumar et al. study in which vitamin D deficiency was present in 80% and only 7% had optimal vitamin D levels [11] as well as Raina et al. (2016) study in which 76.2% of cases of CSA were vitamin D-deficient. Our finding stating that vitamin D level is a significant predictor for chronic stable angina agrees with data of National Health and Nutrition Examination Survey (NHANES) 2000–2004. Vitamin D deficiency is associated with increased prevalence of self-reported coronary heart disease, heart failure and peripheral vascular disease [12]. In our study, there was a significant association between vitamin D deficiency and the presence of angina, but there was no association between vitamin D level and the severity of angina. This is similar to results of Raina et al. (2016) which suggested a significant correlation between vitamin D deficiency and chronic stable angina but they found no relationship between the severity of angina and vitamin D level. This study has some weaknesses and limitations. The sample might be partially biased which may not be optimal for a matched case-control study. There is a possibility of selection bias as patients were selected from a tertiary hospital pool. Matching of groups was not perfect, raising the possibility of confounders such as smoking, physical activity, hypertension, and diabetes. 5 Conclusion The results of this study added to the existing evidence suggesting that low vitamin D levels may be an independent and potentially modifiable cardiovascular risk factor. From the results of logistic regression, vitamin D level can be considered as a significant predictor for chronic stable angina. 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