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Trace Elements and Coronary Artery Disease
Chapter 26
Trace Elements and Coronary Artery Disease Ayşegül Bayir Faculty of Medicine, Emergency Department, Selçuk University, Konya, Turkey
INTRODUCTION Coronary artery disease is the most common cause of mortality and morbidity in developed and developing countries. Risk factors such as hypertension, hypercholesterolemia, and smoking dependence are present in less than 50% of the patients diagnosed with coronary artery disease. Free oxygen radicals are responsible for degenerative diseases such as coronary artery disease. Peroxidation of low-density lipoproteins (LDL) increases free radicals. This is an important factor for increased foam cell formation and atherosclerosis. Most trace elements have antioxidant properties that inhibit or reduce the formation of free oxygen radicals. It has been known for many years that trace element levels are important factors in the development and course of many diseases such as cardiovascular diseases, especially coronary artery disease. Numerous studies have reported that there is a relationship between low serum zinc (Zn) level, low copper (Cu) level, low selenium (Se) level, and high iron (Fe) levels and coronary artery disease development. In this section, the relationship between trace elements and coronary artery diseases will be explained.
THE IMPACT OF TRACE ELEMENTS ON CORONARY ARTERY DISEASES Arterial thickness is an independent predictor of cardiovascular mortality in general population. Wall elasticity of the large elastic arteries depends on extracellular matrix proteins such as elastin and collagen. Depending on aging and some diseases, the elastic fibrils degrade and break up. Most trace elements have been found to be important in the pathogenesis of atherosclerosis. Elements such as magnesium (Mg), cobalt (Co), lithium (Li), and manganese (Mn) are considered to have a positive effect on cardiovascular diseases, whereas cadmium (Cd), lead (Pb), and silver (Ag) have a negative effect on atherosclerosis [1]. It has been reported that serum trace elements can be used as diagnostic and prognostic markers in coronary artery diseases. Serum zinc (Zn) and copper (Cu) levels in patients with myocardial infarction have been reported to vary with time. In addition, there is a relation between serum Cu and Fe levels and death from coronary artery disease. Cu and Fe play an important role in oxidative stress that is an important factor in the pathogenesis of ischemic heart diseases. Zn, Cu, and Fe, on the other hand, act as cofactors for superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are major antioxidant enzymes in the body [2]. Supporting this information, plasma Zn levels in female patients diagnosed with acute coronary syndromes (ACS) were found to be significantly lower than in the healthy control group. It has also been reported that plasma malondialdehyde (MDA) levels, which are indicative of lipid peroxidation level in female patients with ACS, are significantly higher than in the healthy control group. In conclusion, it is emphasized that lipid peroxidation and Zn levels are important in patients with ACS and should be monitored during diagnose and treatment period [3]. Jain found that the serum level of Cu increased in the postinfarction from 24th hour and the Zn level decreased in the patients who had acute myocardial infarction [4]. It was determined in the study that both Cu and Zn levels returned to normal in 14 days after acute myocardial infarction. Altekin et al. [2] investigated the relationship between serum Cu, Fe, Se, and Zn levels and cardiac troponins and CK-MB levels in patients with ACS. As a result of the study, there was a positive correlation between cardiac troponins and serum Cu and Fe levels and negative correlation between serum Zn and Se levels. Serum trace element levels were correlated with myocardial injury grade. Lifestyle in Heart Health and Disease. https://doi.org/10.1016/B978-0-12-811279-3.00026-4 © 2018 Elsevier Inc. All rights reserved.
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298 PART | IV Social, Population, and Family Effects on the Heart and Arteries
Cu homeostasis is tightly balanced. The excess of Cu in the body is also associated with severe diseases as much as Cu inadequacy. The relationship between Cu metabolism and cardiovascular diseases is contradictory. Sidhu reported that chelation therapy in patients with stable coronary artery disease and a history of acute myocardial infarction prevented poor cardiovascular outcome [5]. Grammer investigated the relationship between serum ceruloplasmin and Cu levels in all patients with angiographic coronary artery disease and deaths due to cardiovascular causes and all causes in a LURIC study (the Ludwigshafen Risk and Cardiovascular Health study) conducted with a total of 3253 participants. Studies have shown that high ceruloplasmin and Cu levels are associated with both death risk due to all causes and cardiovascular death risk [6]. In another study with 2233 participants, there was a positive correlation between serum Cu level and 10-year coronary risk. In the same study, it was also reported that there was a strong and inverse correlation between serum Cu/Zn ratio and 10-year coronary risk [7]. In a study investigating the relationship between serum Zn and Cu levels and development of ischemic cardiomyopathy, serum Cu levels of patients diagnosed with ischemic cardiomyopathy were found to be significantly higher than in the healthy control group. According to the New York Heart Association (NYHA) classification, patients with NYHA III had higher serum Cu levels, lower Zn levels, and lower Zn/Cu levels than NYHA II patients. It has been stated that serum Cu levels play a role in the development of ischemic cardiomyopathy, the symptoms of ischemic cardiomyopathy can be reversed, and the progress can be stopped by using a chelator, which requires more extensive clinical studies [8]. Besides these studies, there are also experimental and clinical studies investigating the effects of trace element support on oxidative stress and cardiac dysfunction after acute myocardial infarction. Experimental myocardial infarction was performed with isoproterenol in rats pretreated with 0.1 mg/kg Se, 400 μg/kg chromium (Cr), and 30 mg/kg Zn for 28 days. It was reported in an experimental myocardial infarction model performed with subcutaneous isoproterenol (85 mg/day) for 2 days in rats given trace element support [9] that the levels of enzymes such as SOD, catalase (CAT), and GPx decreased; cardiac necrosis factor-α (TNF-α) level increased; and vascular endothelial growth factor (VEGF) decreased. Al-Rasheed reported that cardiac enzymes after myocardial infarction in the Se-supplemented rats, lipid peroxidation, SOD, CAT, GPx, TNF-α, and VEGF levels were within normal limits but dyslipidemia did not improve. In the rats given Cr supplementation, significant improvement was detected in the levels of markers except VEGF together with the lipid profile. Zn supplementation was found to have more positive effects on dyslipidemia angiogenesis [9]. As a result, trace elements given daily trace element support have been reported to have positive effects on myocardial performance by preventing oxidative damage, providing angiogenesis, antiinflammatory, and antihyperlipidemic effects. The lack of Fe is has been reported to be a risk factor for cardiovascular diseases in recent years. Fe deficiency independent of anemia is an effective factor for prognosis in patients with heart failure. Regardless of the increased hemoglobin level in patients with heart failure, intravenous (IV) iron treatment has been found to increase functional capacity. There are few studies investigating the prevalence and clinical significance of Fe deficiency in patients with ischemic coronary syndrome. In a study conducted by Meroño, the relationship between iron deficiency, 30-day mortality, readmission to hospital, functional capacity, and quality of life was investigated in patients diagnosed with ACS [10]. It was found in the study that the lack of Fe was fairly frequent in patients with ACSs, it had no effect on cardiovascular mortality and morbidity in the medium term (30 days), but it was associated with poorer functional recovery, worse functional capacity, and quality of life. Since iron is an important element in the formation of reactive oxygen species, the relationship between high iron levels and atherosclerotic heart diseases has also been investigated. Free Fe or catalytic Fe, free of transferrin or ferritin in circulation, has the potential to produce high levels of reactive oxygen products. In a study of 1701 patients diagnosed with ACS, the relationship between catalytic iron levels and all-cause mortality, recurrent acute myocardial infarction, recurrent ischemia, heart failure, and bleeding was investigated for a mean follow-up of 10 months [11]. Catalytic Fe levels were found to be significantly higher in dying patients than in survivors. It was concluded that high catalytic Fe level was correlated with increased mortality rates due to all causes. However, in this study, there was no significant relationship between catalytic Fe level and recurrent myocardial infarction, recurrent ischemia, heart failure, and bleeding. It has also been reported that catalytic Fe is not useful as an adjunct to biochemical markers for risk stratification of ischemic events. In a study conducted by Huang [12], serum levels of Fe and inflammatory markers, interleukin 6 (IL) levels were examined independent of the anemia at the eighth hour before and after intervention in patients having acute myocardial infarction and undergoing percutaneous coronary intervention (PCI). In addition, patients were assessed by echocardiography within the first 2 days and 6 months after PCI. In the study, it was found that when the serum Fe level of the patients decreased, the TIMI risk score increased—there was a significant negative correlation between them—and when the serum Fe level was lower, the serum IL 6 level increased. Lower serum Fe levels before PCI have been reported to have adverse effects on the improvement of left ventricular systolic function after 6 months of PCI. At the end of the study, it was reported
Trace Elements and Coronary Artery Disease Chapter | 26 299
that higher serum Fe levels were cardioprotective and serum Fe levels could be used as a biomarker for post-ST elevated acute myocardial infarction complications and could be used for follow-up after a therapeutic approach. Experimental studies have shown that reactive oxygen species produced during ischemia/reperfusion injury can be reduced with Se support. Se is a trace element that is responsible for the synthesis activity of certain antioxidant enzymes such as GPx and selenoprotein synthesis known to be protective against oxidative stress. Inadequate GPx activity is associated with atherosclerosis and poor prognosis in patients with coronary artery disease. In studies investigating the effects of Se deficiency on long-term prognosis in patients with ACS and stable angina pectoris (SAP), the hypothesis is based on increased plaque rupture and/or ischemia/reperfusion injury rates. In a study involving a total of 1731 ACS and SAP patients [13], participants were followed for cardiac death for 6 years. During the study period, a total of 190 patients died of cardiac causes. Mean serum Se levels of the patients with ACS who died were significantly lower than the mean serum Se levels of survivors. There was no significant correlation between serum Se levels and cardiovascular outcomes in SAP patients. There are some studies reporting that there is a negative relationship between dietary intake of low Se or the level of Se and the risk of developing cardiovascular disease. However, studies of Se support in preventing cardiovascular disease do not support this hypothesis [14]. Some studies carried out in patients with STEMI and NSTEMI have reported that there is a positive correlation between peak troponin I (TnI) levels and serum Ser levels, indicating the degree or extent of myocardial damage [15]. In contrast, a similar study of patients with ACS diagnosed by Bayır et al. found different results [16]. In this study, it was reported that there was a negative correlation between serum TnI levels and Se, Zn, and Cu levels in patients diagnosed with ACS and low Se, Zn, and Cu levels could be a risk factor for ACS. In another study conducted by Islamoğlu et al., serum Zn and Cu levels of 67 patients with atherosclerosis were compared with the healthy control group. As a result of this study, serum Zn and Cu levels of patients with atherosclerosis were significantly lower than those of healthy control group. However, it was stated that serum Zn and Cu levels did not determine the degree of atherosclerosis [17]. Magnesium (Mg) is another element that has been investigated for the prognosis in patients with ACS. In a study of patients who underwent stenting after ACS, serum Mg levels and major cardiovascular events were investigated for a mean of 24 months after stenting. There was no significant relationship between serum Mg levels and major cardiovascular events in patients with UAP in the study. In contrast, low serum Mg levels have been reported to be a strong predictor of major cardiovascular events in patients with acute myocardial infarction [18]. There are many studies in different parts of the world reporting that there is a relationship between drinking water Mg concentration and coronary artery disease. In the Atherosclerosis Risk in Communities (ARIC) study [19], 13,922 healthy participants without coronary artery disease were followed for 4–7 years, and participants with lower serum Mg levels were found to have a higher risk of coronary artery disease. Similarly, the study of the National Health and Nutrition Examination Survey Epidemiologic Follow-up has demonstrated a significant inverse association between serum Mg levels and coronary heart disease and all-cause mortality [20]. The fact that Mg may have a preventive effect of cardiovascular diseases is partly explained with the reduction of inflammatory response. The clinical inflammatory syndrome characterized by leukocyte and macrophage activation, the release of inflammatory cytokines and proteins, and the release of dense free oxygen radicals were observed in experimental animals developed hypomagnesemia. While increase in Mg level in extracellular fluid reduces inflammation, decrease in Mg level causes the activation of phagocytes and endothelial cells. Similarly, in experimental hypomagnesemia studies, inflammation has been shown to cause proatherogenic changes in the hypertriglyceridemia and lipoprotein profile [21]. Magnesium has negative effects on myocardial infarction, infarct size, cardiac arrhythmia, endothelial platelet aggregation, coagulation system, vascular tone, and lipid metabolism. Experimental studies have shown that Mg has antiplatelet effects, inhibits thrombus formation and reocclusion in coronary vessels, and facilitates fibrinolysis-related recanalization [22,23]. In placebo-controlled randomized double-blind studies with Mg, it was determined that infarct size was reduced in patients receiving IV Mg supplementation compared with placebo group. It was reported in Killip class I patients who underwent acute myocardial infarction that infarct area was reduced by 20% and inhospital mortality was reduced with Mg supplementation [24]. In a large, placebo-controlled study, congestive heart failure, all-cause mortality in 28 days, and deaths due to ischemic heart disease during a 4.5-year follow-up were found to be reduced by 25%, 24%, and 20%, respectively, in patients receiving IV magnesium [25]. Inhospital mortality was reduced by 50% in patients given 22 g IV Mg for 48 h after infarction and the patients with an acute myocardial infarction and who were not suitable for the treatment of reperfusion [26]. In another study conducted by Zhang et al. [27], another study conducted with 58,615 healthy participants aged 40–79 years, Mg intake in the diet was questioned, and patients were followed for an average of 14.7 years in terms of cardiovascular disease mortality. At the end of follow-up period, 2690 deaths due to cardiovascular diseases were detected.
300 PART | IV Social, Population, and Family Effects on the Heart and Arteries
As a result, magnesium intake in the diet was found to be inversely related to cardiovascular disease-related mortality, especially in female participants. As can be seen, keeping the trace elements at a certain limit in the body is very important for the prevention of cardiovascular diseases, especially coronary artery diseases and death rates due to coronary artery diseases. There are also some studies reporting that the frequency of coronary artery disease decreases with the supplement of these elements.
REFERENCES [1] Subrahmanyam G, Pathapati RM, Ramalingam K, Indira SA, Kantha K, Soren B. Arterial stiffness and trace elements in apparently healthy population – a cross-sectional study. J Clin Diagn Res 2016;10(9):LC12–5. [2] Altekin E, Coker C, Sişman AR, Onvural B, Kuralay F, Kirimli O. The relationship between trace elements and cardiac markers in acute coronary syndromes. J Trace Elem Med Biol 2005;18(3):235–42. [3] Cikim G, Canatan H, Gursu MF, Gulcu F, Baydas G, Kilicoglu AE. Levels of zinc and lipid peroxidation in acute coronary syndrome. Biol Trace Elem Res 2003;96(1–3):61–9. [4] Jain VK, Mohan G. Serum zinc and copper in myocardial infarction with particular reference to prognosis. Biol Trace Elem Res 1991;31(3):317–22. [5] Sidhu MS, Saour BM, Boden WE. A TACTful reappraisal of chelation therapy in cardiovascular disease. Nat Rev Cardiol 2014;11(3):180–3. [6] Grammer TB, Kleber ME, Silbernagel G, Pilz S, Scharnagl H, Lerchbaum E, et al. Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study). Free Radic Res 2014;48(6):706–15. [7] Ghayour-Mobarhan M, Shapouri-Moghaddam A, Azimi-Nezhad M, Esmaeili H, Parizadeh SM, Safarian M, et al. The relationship between established coronary risk factors and serum copper and zinc concentrations in a large Persian cohort. J Trace Elem Med Biol 2009;23(3):167–75. [8] Shokrzadeh M, Ghaemian A, Salehifar E, Aliakbari S, Saravi SS, Ebrahimi P. Serum zinc and copper levels in ischemic cardiomyopathy. Biol Trace Elem Res 2009;127(2):116–23. [9] Al-Rasheed NM, Attia HA, Mohamed RA, Al-Rasheed NM, Al-Amin MA. Preventive effects of selenium yeast, chromium picolinate, zinc sulfate and their combination on oxidative stress, inflammation, impaired angiogenesis and atherogenesis in myocardial infarction in rats. J Pharm Pharm Sci 2013;16(5):848–67. [10] Meroño O, Cladellas M, Ribas-Barquet N, Poveda P, Recasens L, Bazán V, et al. Iron deficiency is a determinant of functional capacity and healthrelated quality of life 30 days after an acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2016;70(5):363–70. [11] Steen DL, Cannon CP, Lele SS, Rajapurkar MM, Mukhopadhyay B, Scirica BM, et al. Prognostic evaluation of catalytic iron in patients with acute coronary syndromes. Clin Cardiol 2013;36(3):139–45. [12] Huang CH, Chang CC, Kuo CL, Huang CS, Chiu TW, Lin CS, et al. Serum iron concentration, but not hemoglobin, correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction. PLoS One 2014;9(8):e104495. [13] Lubos E, Sinning CR, Schnabel RB, Wild PS, Zeller T, Rupprecht HJ, et al. Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study. Atherosclerosis 2010;209(1):271–7. [14] Stranges S, Navas-Acien A, Rayman MP, Guallar E. Selenium status and cardiometabolic health: state of the evidence. Nutr Metab Cardiovasc Dis 2010;20(10):754–60. [15] Kutil B, Ostadal P, Vejvoda J, Kukacka J, Cepova J, Alan D, et al. Alterations in serum selenium levels and their relation to troponin I in acute myocardial infarction. Mol Cell Biochem 2010;345(1–2):23–7. [16] Bayır A, Kara H, Kıyıcı A, Oztürk B, Akyürek F. Levels of selenium, zinc, copper, and cardiac troponin I in serum of patients with acute coronary syndrome. Biol Trace Elem Res 2013;154(3):352–6. [17] Islamoglu Y, Evliyaoglu O, Tekbas E, Cil H, Elbey MA, Atilgan Z, et al. The relationship between serum levels of Zn and Cu and severity of coronary atherosclerosis. Biol Trace Elem Res 2011;144(1–3):436–44. [18] An G, Du Z, Meng X, Guo T, Shang R, Li J, et al. Association between low serum magnesium level and major adverse cardiac events in patients treated with drug-eluting stents for acute myocardial infarction. PLoS One 2014;9(6):e98971. [19] Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 1998;136:480–90. [20] Ford ES. Serum magnesium and ischemic heart disease: findings from national sample of US adults. Int J Epidemiol 1999;28:645–51. [21] Shechter M. Magnesium and cardiovascular system. Magnes Res 2010;23(2):60–72. [22] Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction. Endothelial dysfunction. A marker of atherosclerotic risk. Arteriosc Thromb Vasc Biol 2003;23:168–75. [23] Rukshin V, Santos R, Gheorghiu M, Shah PK, Kar S, Padmanabhan S, et al. A prospective, nonrandomized, open-labeled pilot study investigating the use of magnesium in patients undergoing nonacute percutaneous coronary intervention with stent implantation. J Cardiovasc Pharmacol Ther 2003;8:193–200. [24] Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction. Magnesium 1984;3:346–52. [25] Woods KL, Fletcher S. Long term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1994;343:816–9. [26] Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B. Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol 1995;75:321–3. [27] Zhang W, Iso H, Ohira T, Date C, Tamakoshi A. JACC Study Group. Associations of dietary magnesium intake with mortality from cardiovascular disease: the JACC study. Atherosclerosis 2012;221(2):587–95.
Trace Elements and Coronary Artery Disease Ayşegül Bayir Faculty of Medicine, Emergency Department, Selçuk University, Konya, Turkey
INTRODUCTION Coronary artery disease is the most common cause of mortality and morbidity in developed and developing countries. Risk factors such as hypertension, hypercholesterolemia, and smoking dependence are present in less than 50% of the patients diagnosed with coronary artery disease. Free oxygen radicals are responsible for degenerative diseases such as coronary artery disease. Peroxidation of low-density lipoproteins (LDL) increases free radicals. This is an important factor for increased foam cell formation and atherosclerosis. Most trace elements have antioxidant properties that inhibit or reduce the formation of free oxygen radicals. It has been known for many years that trace element levels are important factors in the development and course of many diseases such as cardiovascular diseases, especially coronary artery disease. Numerous studies have reported that there is a relationship between low serum zinc (Zn) level, low copper (Cu) level, low selenium (Se) level, and high iron (Fe) levels and coronary artery disease development. In this section, the relationship between trace elements and coronary artery diseases will be explained.
THE IMPACT OF TRACE ELEMENTS ON CORONARY ARTERY DISEASES Arterial thickness is an independent predictor of cardiovascular mortality in general population. Wall elasticity of the large elastic arteries depends on extracellular matrix proteins such as elastin and collagen. Depending on aging and some diseases, the elastic fibrils degrade and break up. Most trace elements have been found to be important in the pathogenesis of atherosclerosis. Elements such as magnesium (Mg), cobalt (Co), lithium (Li), and manganese (Mn) are considered to have a positive effect on cardiovascular diseases, whereas cadmium (Cd), lead (Pb), and silver (Ag) have a negative effect on atherosclerosis [1]. It has been reported that serum trace elements can be used as diagnostic and prognostic markers in coronary artery diseases. Serum zinc (Zn) and copper (Cu) levels in patients with myocardial infarction have been reported to vary with time. In addition, there is a relation between serum Cu and Fe levels and death from coronary artery disease. Cu and Fe play an important role in oxidative stress that is an important factor in the pathogenesis of ischemic heart diseases. Zn, Cu, and Fe, on the other hand, act as cofactors for superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are major antioxidant enzymes in the body [2]. Supporting this information, plasma Zn levels in female patients diagnosed with acute coronary syndromes (ACS) were found to be significantly lower than in the healthy control group. It has also been reported that plasma malondialdehyde (MDA) levels, which are indicative of lipid peroxidation level in female patients with ACS, are significantly higher than in the healthy control group. In conclusion, it is emphasized that lipid peroxidation and Zn levels are important in patients with ACS and should be monitored during diagnose and treatment period [3]. Jain found that the serum level of Cu increased in the postinfarction from 24th hour and the Zn level decreased in the patients who had acute myocardial infarction [4]. It was determined in the study that both Cu and Zn levels returned to normal in 14 days after acute myocardial infarction. Altekin et al. [2] investigated the relationship between serum Cu, Fe, Se, and Zn levels and cardiac troponins and CK-MB levels in patients with ACS. As a result of the study, there was a positive correlation between cardiac troponins and serum Cu and Fe levels and negative correlation between serum Zn and Se levels. Serum trace element levels were correlated with myocardial injury grade. Lifestyle in Heart Health and Disease. https://doi.org/10.1016/B978-0-12-811279-3.00026-4 © 2018 Elsevier Inc. All rights reserved.
297
298 PART | IV Social, Population, and Family Effects on the Heart and Arteries
Cu homeostasis is tightly balanced. The excess of Cu in the body is also associated with severe diseases as much as Cu inadequacy. The relationship between Cu metabolism and cardiovascular diseases is contradictory. Sidhu reported that chelation therapy in patients with stable coronary artery disease and a history of acute myocardial infarction prevented poor cardiovascular outcome [5]. Grammer investigated the relationship between serum ceruloplasmin and Cu levels in all patients with angiographic coronary artery disease and deaths due to cardiovascular causes and all causes in a LURIC study (the Ludwigshafen Risk and Cardiovascular Health study) conducted with a total of 3253 participants. Studies have shown that high ceruloplasmin and Cu levels are associated with both death risk due to all causes and cardiovascular death risk [6]. In another study with 2233 participants, there was a positive correlation between serum Cu level and 10-year coronary risk. In the same study, it was also reported that there was a strong and inverse correlation between serum Cu/Zn ratio and 10-year coronary risk [7]. In a study investigating the relationship between serum Zn and Cu levels and development of ischemic cardiomyopathy, serum Cu levels of patients diagnosed with ischemic cardiomyopathy were found to be significantly higher than in the healthy control group. According to the New York Heart Association (NYHA) classification, patients with NYHA III had higher serum Cu levels, lower Zn levels, and lower Zn/Cu levels than NYHA II patients. It has been stated that serum Cu levels play a role in the development of ischemic cardiomyopathy, the symptoms of ischemic cardiomyopathy can be reversed, and the progress can be stopped by using a chelator, which requires more extensive clinical studies [8]. Besides these studies, there are also experimental and clinical studies investigating the effects of trace element support on oxidative stress and cardiac dysfunction after acute myocardial infarction. Experimental myocardial infarction was performed with isoproterenol in rats pretreated with 0.1 mg/kg Se, 400 μg/kg chromium (Cr), and 30 mg/kg Zn for 28 days. It was reported in an experimental myocardial infarction model performed with subcutaneous isoproterenol (85 mg/day) for 2 days in rats given trace element support [9] that the levels of enzymes such as SOD, catalase (CAT), and GPx decreased; cardiac necrosis factor-α (TNF-α) level increased; and vascular endothelial growth factor (VEGF) decreased. Al-Rasheed reported that cardiac enzymes after myocardial infarction in the Se-supplemented rats, lipid peroxidation, SOD, CAT, GPx, TNF-α, and VEGF levels were within normal limits but dyslipidemia did not improve. In the rats given Cr supplementation, significant improvement was detected in the levels of markers except VEGF together with the lipid profile. Zn supplementation was found to have more positive effects on dyslipidemia angiogenesis [9]. As a result, trace elements given daily trace element support have been reported to have positive effects on myocardial performance by preventing oxidative damage, providing angiogenesis, antiinflammatory, and antihyperlipidemic effects. The lack of Fe is has been reported to be a risk factor for cardiovascular diseases in recent years. Fe deficiency independent of anemia is an effective factor for prognosis in patients with heart failure. Regardless of the increased hemoglobin level in patients with heart failure, intravenous (IV) iron treatment has been found to increase functional capacity. There are few studies investigating the prevalence and clinical significance of Fe deficiency in patients with ischemic coronary syndrome. In a study conducted by Meroño, the relationship between iron deficiency, 30-day mortality, readmission to hospital, functional capacity, and quality of life was investigated in patients diagnosed with ACS [10]. It was found in the study that the lack of Fe was fairly frequent in patients with ACSs, it had no effect on cardiovascular mortality and morbidity in the medium term (30 days), but it was associated with poorer functional recovery, worse functional capacity, and quality of life. Since iron is an important element in the formation of reactive oxygen species, the relationship between high iron levels and atherosclerotic heart diseases has also been investigated. Free Fe or catalytic Fe, free of transferrin or ferritin in circulation, has the potential to produce high levels of reactive oxygen products. In a study of 1701 patients diagnosed with ACS, the relationship between catalytic iron levels and all-cause mortality, recurrent acute myocardial infarction, recurrent ischemia, heart failure, and bleeding was investigated for a mean follow-up of 10 months [11]. Catalytic Fe levels were found to be significantly higher in dying patients than in survivors. It was concluded that high catalytic Fe level was correlated with increased mortality rates due to all causes. However, in this study, there was no significant relationship between catalytic Fe level and recurrent myocardial infarction, recurrent ischemia, heart failure, and bleeding. It has also been reported that catalytic Fe is not useful as an adjunct to biochemical markers for risk stratification of ischemic events. In a study conducted by Huang [12], serum levels of Fe and inflammatory markers, interleukin 6 (IL) levels were examined independent of the anemia at the eighth hour before and after intervention in patients having acute myocardial infarction and undergoing percutaneous coronary intervention (PCI). In addition, patients were assessed by echocardiography within the first 2 days and 6 months after PCI. In the study, it was found that when the serum Fe level of the patients decreased, the TIMI risk score increased—there was a significant negative correlation between them—and when the serum Fe level was lower, the serum IL 6 level increased. Lower serum Fe levels before PCI have been reported to have adverse effects on the improvement of left ventricular systolic function after 6 months of PCI. At the end of the study, it was reported
Trace Elements and Coronary Artery Disease Chapter | 26 299
that higher serum Fe levels were cardioprotective and serum Fe levels could be used as a biomarker for post-ST elevated acute myocardial infarction complications and could be used for follow-up after a therapeutic approach. Experimental studies have shown that reactive oxygen species produced during ischemia/reperfusion injury can be reduced with Se support. Se is a trace element that is responsible for the synthesis activity of certain antioxidant enzymes such as GPx and selenoprotein synthesis known to be protective against oxidative stress. Inadequate GPx activity is associated with atherosclerosis and poor prognosis in patients with coronary artery disease. In studies investigating the effects of Se deficiency on long-term prognosis in patients with ACS and stable angina pectoris (SAP), the hypothesis is based on increased plaque rupture and/or ischemia/reperfusion injury rates. In a study involving a total of 1731 ACS and SAP patients [13], participants were followed for cardiac death for 6 years. During the study period, a total of 190 patients died of cardiac causes. Mean serum Se levels of the patients with ACS who died were significantly lower than the mean serum Se levels of survivors. There was no significant correlation between serum Se levels and cardiovascular outcomes in SAP patients. There are some studies reporting that there is a negative relationship between dietary intake of low Se or the level of Se and the risk of developing cardiovascular disease. However, studies of Se support in preventing cardiovascular disease do not support this hypothesis [14]. Some studies carried out in patients with STEMI and NSTEMI have reported that there is a positive correlation between peak troponin I (TnI) levels and serum Ser levels, indicating the degree or extent of myocardial damage [15]. In contrast, a similar study of patients with ACS diagnosed by Bayır et al. found different results [16]. In this study, it was reported that there was a negative correlation between serum TnI levels and Se, Zn, and Cu levels in patients diagnosed with ACS and low Se, Zn, and Cu levels could be a risk factor for ACS. In another study conducted by Islamoğlu et al., serum Zn and Cu levels of 67 patients with atherosclerosis were compared with the healthy control group. As a result of this study, serum Zn and Cu levels of patients with atherosclerosis were significantly lower than those of healthy control group. However, it was stated that serum Zn and Cu levels did not determine the degree of atherosclerosis [17]. Magnesium (Mg) is another element that has been investigated for the prognosis in patients with ACS. In a study of patients who underwent stenting after ACS, serum Mg levels and major cardiovascular events were investigated for a mean of 24 months after stenting. There was no significant relationship between serum Mg levels and major cardiovascular events in patients with UAP in the study. In contrast, low serum Mg levels have been reported to be a strong predictor of major cardiovascular events in patients with acute myocardial infarction [18]. There are many studies in different parts of the world reporting that there is a relationship between drinking water Mg concentration and coronary artery disease. In the Atherosclerosis Risk in Communities (ARIC) study [19], 13,922 healthy participants without coronary artery disease were followed for 4–7 years, and participants with lower serum Mg levels were found to have a higher risk of coronary artery disease. Similarly, the study of the National Health and Nutrition Examination Survey Epidemiologic Follow-up has demonstrated a significant inverse association between serum Mg levels and coronary heart disease and all-cause mortality [20]. The fact that Mg may have a preventive effect of cardiovascular diseases is partly explained with the reduction of inflammatory response. The clinical inflammatory syndrome characterized by leukocyte and macrophage activation, the release of inflammatory cytokines and proteins, and the release of dense free oxygen radicals were observed in experimental animals developed hypomagnesemia. While increase in Mg level in extracellular fluid reduces inflammation, decrease in Mg level causes the activation of phagocytes and endothelial cells. Similarly, in experimental hypomagnesemia studies, inflammation has been shown to cause proatherogenic changes in the hypertriglyceridemia and lipoprotein profile [21]. Magnesium has negative effects on myocardial infarction, infarct size, cardiac arrhythmia, endothelial platelet aggregation, coagulation system, vascular tone, and lipid metabolism. Experimental studies have shown that Mg has antiplatelet effects, inhibits thrombus formation and reocclusion in coronary vessels, and facilitates fibrinolysis-related recanalization [22,23]. In placebo-controlled randomized double-blind studies with Mg, it was determined that infarct size was reduced in patients receiving IV Mg supplementation compared with placebo group. It was reported in Killip class I patients who underwent acute myocardial infarction that infarct area was reduced by 20% and inhospital mortality was reduced with Mg supplementation [24]. In a large, placebo-controlled study, congestive heart failure, all-cause mortality in 28 days, and deaths due to ischemic heart disease during a 4.5-year follow-up were found to be reduced by 25%, 24%, and 20%, respectively, in patients receiving IV magnesium [25]. Inhospital mortality was reduced by 50% in patients given 22 g IV Mg for 48 h after infarction and the patients with an acute myocardial infarction and who were not suitable for the treatment of reperfusion [26]. In another study conducted by Zhang et al. [27], another study conducted with 58,615 healthy participants aged 40–79 years, Mg intake in the diet was questioned, and patients were followed for an average of 14.7 years in terms of cardiovascular disease mortality. At the end of follow-up period, 2690 deaths due to cardiovascular diseases were detected.
300 PART | IV Social, Population, and Family Effects on the Heart and Arteries
As a result, magnesium intake in the diet was found to be inversely related to cardiovascular disease-related mortality, especially in female participants. As can be seen, keeping the trace elements at a certain limit in the body is very important for the prevention of cardiovascular diseases, especially coronary artery diseases and death rates due to coronary artery diseases. There are also some studies reporting that the frequency of coronary artery disease decreases with the supplement of these elements.
REFERENCES [1] Subrahmanyam G, Pathapati RM, Ramalingam K, Indira SA, Kantha K, Soren B. Arterial stiffness and trace elements in apparently healthy population – a cross-sectional study. J Clin Diagn Res 2016;10(9):LC12–5. [2] Altekin E, Coker C, Sişman AR, Onvural B, Kuralay F, Kirimli O. The relationship between trace elements and cardiac markers in acute coronary syndromes. J Trace Elem Med Biol 2005;18(3):235–42. [3] Cikim G, Canatan H, Gursu MF, Gulcu F, Baydas G, Kilicoglu AE. Levels of zinc and lipid peroxidation in acute coronary syndrome. Biol Trace Elem Res 2003;96(1–3):61–9. [4] Jain VK, Mohan G. Serum zinc and copper in myocardial infarction with particular reference to prognosis. Biol Trace Elem Res 1991;31(3):317–22. [5] Sidhu MS, Saour BM, Boden WE. A TACTful reappraisal of chelation therapy in cardiovascular disease. Nat Rev Cardiol 2014;11(3):180–3. [6] Grammer TB, Kleber ME, Silbernagel G, Pilz S, Scharnagl H, Lerchbaum E, et al. Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study). Free Radic Res 2014;48(6):706–15. [7] Ghayour-Mobarhan M, Shapouri-Moghaddam A, Azimi-Nezhad M, Esmaeili H, Parizadeh SM, Safarian M, et al. The relationship between established coronary risk factors and serum copper and zinc concentrations in a large Persian cohort. J Trace Elem Med Biol 2009;23(3):167–75. [8] Shokrzadeh M, Ghaemian A, Salehifar E, Aliakbari S, Saravi SS, Ebrahimi P. Serum zinc and copper levels in ischemic cardiomyopathy. Biol Trace Elem Res 2009;127(2):116–23. [9] Al-Rasheed NM, Attia HA, Mohamed RA, Al-Rasheed NM, Al-Amin MA. Preventive effects of selenium yeast, chromium picolinate, zinc sulfate and their combination on oxidative stress, inflammation, impaired angiogenesis and atherogenesis in myocardial infarction in rats. J Pharm Pharm Sci 2013;16(5):848–67. [10] Meroño O, Cladellas M, Ribas-Barquet N, Poveda P, Recasens L, Bazán V, et al. Iron deficiency is a determinant of functional capacity and healthrelated quality of life 30 days after an acute coronary syndrome. Rev Esp Cardiol (Engl Ed) 2016;70(5):363–70. [11] Steen DL, Cannon CP, Lele SS, Rajapurkar MM, Mukhopadhyay B, Scirica BM, et al. Prognostic evaluation of catalytic iron in patients with acute coronary syndromes. Clin Cardiol 2013;36(3):139–45. [12] Huang CH, Chang CC, Kuo CL, Huang CS, Chiu TW, Lin CS, et al. Serum iron concentration, but not hemoglobin, correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction. PLoS One 2014;9(8):e104495. [13] Lubos E, Sinning CR, Schnabel RB, Wild PS, Zeller T, Rupprecht HJ, et al. Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study. Atherosclerosis 2010;209(1):271–7. [14] Stranges S, Navas-Acien A, Rayman MP, Guallar E. Selenium status and cardiometabolic health: state of the evidence. Nutr Metab Cardiovasc Dis 2010;20(10):754–60. [15] Kutil B, Ostadal P, Vejvoda J, Kukacka J, Cepova J, Alan D, et al. Alterations in serum selenium levels and their relation to troponin I in acute myocardial infarction. Mol Cell Biochem 2010;345(1–2):23–7. [16] Bayır A, Kara H, Kıyıcı A, Oztürk B, Akyürek F. Levels of selenium, zinc, copper, and cardiac troponin I in serum of patients with acute coronary syndrome. Biol Trace Elem Res 2013;154(3):352–6. [17] Islamoglu Y, Evliyaoglu O, Tekbas E, Cil H, Elbey MA, Atilgan Z, et al. The relationship between serum levels of Zn and Cu and severity of coronary atherosclerosis. Biol Trace Elem Res 2011;144(1–3):436–44. [18] An G, Du Z, Meng X, Guo T, Shang R, Li J, et al. Association between low serum magnesium level and major adverse cardiac events in patients treated with drug-eluting stents for acute myocardial infarction. PLoS One 2014;9(6):e98971. [19] Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 1998;136:480–90. [20] Ford ES. Serum magnesium and ischemic heart disease: findings from national sample of US adults. Int J Epidemiol 1999;28:645–51. [21] Shechter M. Magnesium and cardiovascular system. Magnes Res 2010;23(2):60–72. [22] Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction. Endothelial dysfunction. A marker of atherosclerotic risk. Arteriosc Thromb Vasc Biol 2003;23:168–75. [23] Rukshin V, Santos R, Gheorghiu M, Shah PK, Kar S, Padmanabhan S, et al. A prospective, nonrandomized, open-labeled pilot study investigating the use of magnesium in patients undergoing nonacute percutaneous coronary intervention with stent implantation. J Cardiovasc Pharmacol Ther 2003;8:193–200. [24] Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction. Magnesium 1984;3:346–52. [25] Woods KL, Fletcher S. Long term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1994;343:816–9. [26] Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B. Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol 1995;75:321–3. [27] Zhang W, Iso H, Ohira T, Date C, Tamakoshi A. JACC Study Group. Associations of dietary magnesium intake with mortality from cardiovascular disease: the JACC study. Atherosclerosis 2012;221(2):587–95.