Salus - Journal of Health Sciences, é a revista científica da EMESCAM.
ISSN : 2447-7826   •  Language:
Publications Management System
Advanced search

CARDIOVASCULAR TOXIC EFFECTS OF COPPER

Received on 22 December 2016

Abstract

Objective: To describe the main cardiovascular effects developed by copper. Method: This is a narrative review of the literature. Results: Copper can act as a cofactor for some enzymes that act on the cardiovascular system, having an important role in the development of atherogenesis in the angiogenic control and the development of cardiac hypertrophy. Conclusion: Both the deficiency and contamination with copper can lead to changes in the cardiovascular system. It is undeniable the need for further research that can clarify the effects and mechanisms involved in the changes produced by copper in the heart and blood vessels. However, it is essential that the safe values of the recommended daily intake to be set and define the blood concentrations of this metal to be reviewed. transplantation will be used.

Introduction

Copper (Cu) is an essential element necessary for the maintenance and functioning of living organisms.1 It is the third most abundant metal in the body2 and plays an important role in human metabolism, mainly acting as a cofactor for the activity of several enzymes.3 Among these enzymes, we can highlight the cytochrome C oxidase, necessary for aerobic metabolism; Lysyl oxidase, which participates in the synthesis of collagen and elastin; Dopamine ß-hydroxylase, which plays an important role in the conversion of dopamine to noradrenaline; and superoxide dismutase, an antioxidant enzyme that acts on the conversion of superoxide to hydrogen peroxide.4

Copper homeostasis is essential for enzymatic functioning and proper functioning of the body. Metal deficiency may lead to decreased activity of several enzymes, resulting mainly in the development of oxidative imbalance,5 neurological alterations,6 hepatic and cardiovascular.7-9 In addition, although it is an essential micronutrient for man, Cu is toxic at high levels. An overload of this metal easily activates Fenton reactions, resulting in oxidative cellular damage and cell death. Cu toxicity as a result of dietary excess is generally not considered one of the most important sources of exposure to the metal, probably as a result of Cu10 uptake and excretion control mechanisms.

However, when copper homeostasis is discontinued, pathological conditions can be developed. In addition to metabolic changes, Cu toxicity may result from exposure to excess caused by accident, environmental contamination, the use of bactericidal and fungicidal agents based on copper, and the emission of copper smelting industry.10,11 In general, copper deficiency or toxicity from metabolic disturbances or exposure to metal may result in serious damage to the human body. Considering that loss of copper homeostasis offersrisks to human health, this review seeks to describe the human exposure to copper and its main effects on the cardiovascular system.

 

– Copper metabolism

Absorption of copper occurs mainly in the proximal part of the small intestine, where it is transported to the liver through the portal vein. Several parameters affect the dietary Cu absorption rate, including sex, age, type of food and amount of Cu in the diet. It has been shown that copper absorption is higher in women and children and that there are no differences between young adults and older people.12 After intestinal absorption, 25% of copper remains in the circulation bound to albumin, while the remainder is absorbed by the liver. After absorption into the liver, about 80% of the copper is destined for the blood circulation bound to ceruloplasmin, while the remainder is re-excreted into the gastrointestinal system.13 The half-life of copper in a healthy individual is approximately 26 days14 and most of the excretion occurs via the bile duct. There is no evidence that urinary excretion plays a controlling role in Cu homeostasis in response to changes in metal intake.10

Under normal physiological conditions, in which the concentration of copper in the body is normal, ATP7A is the enzyme responsible for absorbing copper in the intestine and transporting it to the metal-dependent enzymes. However, when total reserves of intracellular copper increase, ATP7A moves to the cell membrane to promote copper efflux.15

In the plasma membrane and in intracellular vesicles, the CTR1 transporter plays a fundamental role in the uptake of copper. This transporter acts to control copper uptake through cellular plasma membranes, whereas extracellular copper elevations induce CTR1 endocytosis to vesicles whereas a decrease in extracellular copper restores CTR1 levels in the plasma membrane.16 After copper entry into the cell, it binds to cytosolic chaperones that then transfer the copper to specific cellular targets.17

Copper homeostasis is essential for the functioning of the body. Changes in copper metabolism are characteristic of some genetic diseases such as Menkes Disease and Wilson’s Disease. Menkes disease is characterized by copper deficiency. The main characteristic of Menkes Disease is the low activity of the copper-dependent enzyme (ATPA7). Wilson’s disease is characterized by the copper toxicity that normally affects the severely hepatic and nervous systems.18 In Wilson’s disease, a compromise exists in biliary excretion of copper leading to an accumulation of metal in the liver. When hepatic storage capacity is exceeded, cell death begins, with the release of copper in plasma resulting in hemolysis and copper deposition in extrahepatic tissues.19

 

– Human exposure to copper

In nature, copper emission occurs from natural sources such as dust carried by the wind, volcanoes, forest fires and through the release of copper mines. Cu is one of the most important metals for commercial and industrial application. It is used as a metal alloy for the manufacture of machines, in constructions, in the transport industries and military weapons.20,21 In addition, it is an important component of white gold and other alloys used for costume jewelry, dental products and cosmetics. It can also be used as an additive in paints, plastics, lubricants and metal coatings. In Africa it is traditionally used in medicinal practices.22 Due to its high commercial and industrial demand, copper-based products are produced on a large scale and it is believed that this production will expand in the coming years.23

In addition to the use of copper in the industrial sectors mentioned above, it is also widely used in bactericidal and fungicidal products in many agricultural crops, which consequently leads to contamination of soils and food that are produced.24,25 In addition, copper may also be present in potable water and its concentration may vary depending on domestic plumbing systems and groundwater composition. An increase in the acidity of the water may lead to corrosion in copper plating and increase the concentration of the metal in the water.26

The concentration of Cu in food varies according to local conditions. Most diets contain enough Cu (1-5 mg) to prevent a deficiency and not enough to cause toxicity. There is little information available on Cu intake and adequacy in populations with specific diets, such as vegetarians and vegans. However, it has been shown that daily Cu intake is 27% higher in vegetarian women than in omnivorous women.10

 

– Recommended daily intake and safe blood concentration

 

Although copper is recognized as an essential element for the body’s functioning, the uncertainties remain over reference values of daily intake for humans. The Recommended Daily Intake in the United States and Canada is 0.9 mg/day, with a tolerable intake level of 10 mg/day for adults aged 19 years or older.27

It has been demonstrated that the daily intake of copper can interfere in the body water balance. Daily intake doses below 0.8 mg/day may lead to net losses, while doses above 2.4 mg/day may lead to water retention.10

The usual concentration of copper in human plasma is between 0.3-2.1 μg/mL for the intake of 1.4 to 2.0 mg of copper/day.28 Population studies have shown copper concentrations in healthy individuals of approximately 1 μg/mL.29,30 A study performed with the Brazilian population showed serum copper concentration of 0.8 μg mL in men and 1.4 μg/mL in women.30 This difference between the sexes is expected, since it is well known that women, especially those in the 20-60 age group, increased the absorption of copper. Estrogens also directly influence the metabolism of copper, contributing to the increase of plasma levels of this metal. The effects of estrogens on copper levels are also more evident in pregnant women, as they tend to have even higher concentrations.31

– Effects of intoxication and deficiency on the human body

 

As mentioned, copper is an essential metal and its intake in food is important. However, in addition to exposure related to food intake, the population is still exposed to metal because of its occurrence in the environment and its industrial use. Copper concentrations in the body are tightly controlled under physiological conditions so that their excess or deficiency is harmful to the body. In inflammatory conditions, serum copper levels are increased and trigger oxidative stress responses that activate inflammatory responses. Interestingly, changes in copper metabolism, oxidative stress and inflammation are commonly present in several chronic diseases.32

Inhalation is one of the most important routes of copper intoxication. Therefore, lung tissue toxicity is of great concern. In vitro studies have indicated that Cu can induce cytotoxicity, oxidative stress and genetic toxicity in cultured human lung cells. Some studies have shown that intratracheal instillation of Cu induces oxidative stress, inflammation and neoplastic lesions in rats.23

In addition to pulmonary manifestations, chronic copper toxicity has been known to cause hepatotoxicity and hepatic cirrhosis. As observed in Wilson’s disease and in certain metal intoxication conditions, increased copper concentration has contributed to the development of Alzheimer’s disease.33

It has also been hypothesized that copper accumulation may be related to cognitive decline and changes in the production of humoral and cellular factors of the immune system.10 Cu-deficient animals show reduced neutrophil and T cell populations, decreased phagocyte and B10 lymphocyte activity. The production of antibodies by splenocyte T cells is also reduced. In humans, the relationship between Cu intake and immune function is poorly documented.10

In addition to the changes in the described systems, intoxication and copper deficiency are also capable of triggering cardiovascular changes. Experimental and epidemiological studies have demonstrated a relationship between exposure to metal and the emergence of some diseases of the cardiovascular system. Some of these relationships and their mechanisms will be described below.

 

– Effects on the cardiovascular system

Several studies have shown that high copper concentrations are associated with the development of cardiovascular diseases.34-37 Among these diseases, atherosclerotic disease is one of the most important causes of mortality in the world,38 characterized by persistent vascular inflammation,39 low density lipoprotein (LDL) oxidation and free radical formation. In this context, copper (Cu) is an essential micronutrient for the functioning of enzymes that catalyze oxidation reactions of LDL and have been implicated in atherogenesis through mechanisms that involve the signaling pathways of NF-kB activation.38,40 It has been demonstrated that serum Cu concentration is higher in patients with atherosclerosis, and increases with the severity of the disease.38 In addition, it has been shown that copper chelation in apoE- mice effectively inhibits the development of atherosclerotic lesion and improves inflammation in the cardiovascular system.40

Copper seems to play an important role in controlling the activity of the enzymes nitric oxide synthase (NOS) and guanylate cyclase (GC).41 In addition to the development of inflammatory reactions in the body and the control of vascular tone.41 Copper increases the conversion rate of L-arginine to L-citrulline, depending on the presence of extracellular calcium. Extracellular calcium concentration is a prerequisite for the activation of eNOS by agonists. Thus, Cu can affect the intracellular mobilization of Ca and alter the functioning of eNOS.42

In addition to regulate the eNOS function, Cu is essential for the functioning of another important enzyme for the control of vascular tone, Cu / Zn superoxide dismutase (SOD).43 It regulates the activity of this enzyme in order to control the vasoconstriction caused by oxygen free radicals. Since copper is a cofactor for the functioning of SOD, increased concentrations of the metal could increase the enzymatic activity, while diminished concentrations could lead to a decrease in SOD activity and consequent increase in superoxide production. It has been demonstrated in experimental studies that copper could prevent the development of peripheral vasospasm44 and that incubation with submicromolar concentrations              of Cu impair endothelium-dependent vasorelaxation probably because of the intracellular generation of O2.45

Copper is characterized as a required cofactor in all angiogenic signaling cascades, so much so that a metal deficiency causes neovascularization to decrease. In addition, progression of various angiogenic pathologies (eg, diabetes, cardiac hypertrophy, and ischemia) can be traced by measurement of serum copper levels, which are increasingly viewed as a useful prognostic marker.46 Copper stimulates factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), which is required for the activation of hypoxia-induced factor-1 (HIF-1), an important transcription factor that regulates Expression of VEGF. The essential role of copper in the production of VEGF makes it important, for example, in anti-angiogenesis therapy, such as the application of copper chelating agents in cancer therapy. However, suppression of angiogenesis is involved in the progression of cardiac hypertrophy, so much so that copper supplementation improves hypertrophic cardiac disease conditions.47

In addition to participating in the control of vascular functioning, copper is also essential for cardiac functioning. It has been shown that Cu supplementation restores chronic cardiac hypertrophy induced by pressure overload. The pressure overload generated by constriction of the ascending aorta causes a decrease in Cu levels in the heart along with the development of hypertrophic cardiomyopathy.48 Overload causes homocysteine ​​buildup in the heart, which is accompanied by copper depletion through the formation of copper-homocysteine ​​complexes and the excretion of the complexes. Copper supplementation recovers cytochrome c oxidase activity and promotes myocardial angiogenesis, along with regression of cardiac hypertrophy and recovery of contractile function.49 As previously mentioned, Cu increases VEGF levels and promotes angiogenesis in hypertrophic hearts, improving the parameters of cardiac activity.48

However, it is sometimes observed that, under chronic ischemic conditions, capillary density is decreased in the heart.50,51 Epidemiological studies have demonstrated a relationship between copper deficiency and ischemic heart disease. The reasons for this observation are not clear, but investigation has suggested that one of the effects produced by ischemia is the loss of copper in the heart.52 Copper supplementation can stimulate the transcription activity of HIF-1 (Hypoxia-Induced Factor) and restore angiogenic capacity, leading to increased capillary density in the heart.53 In addition to the development of cardiac hypertrophy48 copper deficiency leads to mitochondrial, structural cardiac alterations and changes in oxidative phosphorylation.54,55 In situations of changes in copper metabolism, such as Wilson’s disease, cardiac arrhythmias, diastolic dysfunctions, cardiomyopathies and sudden cardiac death are rare complications, but can be seen mainly in children due to the accumulation of copper in cardiac tissue.56

 

Conclusion

Both deficiency and contamination with copper can lead to changes in the cardiovascular system. There is sufficient evidence that copper can act as a cofactor for some enzymes in the human organism and thus can modify cellular functioning in several systems, having an important role in the development of atherogenesis, angiogenic control and the development of cardiac hypertrophy. There is no doubt that further research is needed to clarify the effects and mechanisms involved with the changes promoted by copper in the cardiovascular system. However, it is critical that safe values of recommended daily intake and blood concentrations of this metal be established.

 

References

1.Yunus EU, Mustafa S, Mustafa T, Baki H. Determination of lead, copper and iron in cosmetics, water, soil and food using polyhydroxybutyrate-B-polydimethyl siloxane preconcentration and flame atomic absorption spectroscopy. Anal Lett. 2015;48:1163-79.

  1. Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J ClinPathol2015;123:125-31.
  2. Harris ED. Copper homeostasis: the role of cellular transporters. Nutr Rev. 2001;59: 281-5.
  3. Osredkar J, Sustar N. Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance. J Clinic Toxicol. 2011. S3:001.
  4. Młyniec K, Gaweł M, Doboszewska U, Starowicz G, Pytka K, Davies CL, et al. Essential elements in depression and anxiety. Part II Pharmacol Rep. 2015;67(2):187-194.
  5. Shimizu N. Copper metabolism and genetic disorders. Nihon Rinsho. 2016 Jul;74(7):1151-5.
  6. Tasić NM, Tasić D, Otašević P, Veselinović M, Jakovljević V, Djurić D, et al. Copper and zinc concentrations in atherosclerotic plaque and serum in relation to lipid metabolism in patients with carotid atherosclerosis. Vojnosanit Pregl. 2015;72(9):801-6.
  7. Gaetke LM, Chow-Johnson HS, Chow CK. Copper: Toxicological relevance and mechanisms Department. Arch Toxicol.2014;88 (11):1929-1938.
  8. Bagheri B, Akbari N, Tabiban S, Habibi V, Mokhberi V. Serum level of copper in patients with coronary artery disease. Niger Med J. 2015;56(1):39-42.
  9. Bost M, Houdart S, Oberli M, Kalonji E, Huneauc J, Margaritis I. Dietary copper and human health: Current evidence and unresolved issues. J Trace Elem Med Biol.2016;35:107–15.
  10. Mortimer M, Kasemets K, Kahru A. Toxicity of ZnO and CuOnanoparticlesto ciliated protozoa Tetrahymenathermophila. Toxicology. 2010;269, 182–9.
  11. Olivares M, Lonnerdal B, Abrams SA, Pizarro F, Uauy R. Age and copper intake do not affect copper absorption, measured with the use of 65Cu as a tracer, in young infants, Am. J. Clin. Nutr.2001;76(3):641–5.
  12. Harvey LJ, Dainty JR, Hollands WJ, Bull VJ, Beattie JH, Venelinov TI, et al., Use of mathematical modeling to study copper metabolism in humans, Am J Clin. Nutr.2005; 81(4):807–813.
  13. Bentur Y, Koren G, McGuigan M. An unusual skin exposure to copper: Clinical and pharmacokinetic evalution. ClinToxicol. 1988;26:371-80.
  14. Monty JF, Llanos RM, Mercer JF, Kramer DR. Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice. J Nutr. 2005;135 (12):2762–6.
  15. Molloy SA, Kaplan JH. Copper-dependent recycling of hCTR1, the human high affinity copper transporter. J Biol Chem. 2009;284(43):29704-13.
  16. Leary SC, Winge DR, Cobine PA. “ Pulling the plug’’ on cellular copper: the role of mitochondria in copper export. Biochim Biophys Acta. 2009;1793(1):146-53.
  17. Kodama H1, Fujisawa C, Bhadhprasit W. Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab. 2012 Mar;13(3):237-50.
  18. Aoki T1. [Genetic disorders of copper transport–diagnosis and new treatment for the patients of Wilson’s disease]. No To Hattatsu. 2005 Mar;37(2):99-109.
  19. Barceloux DG. Zinc.J Toxicol Clin Toxicol. 1999;37(2): 279-92.
  20. Winge DR, Mehra RK.Host defenses against copper toxicity. Int Rev Exp Pathol. 1990;31:47–83.
  21. Street RA, KaberaGM, Connolly C. Copper sulphate use in South African traditional medicine. Environ Geochem Health. 2016 Apr 8.
  22. Ahamed M, Akhtar MJ, Alhadlaq HA, Alrokayan SA. Nanomedicine (Lond). Assessment of the lung toxicity of copper oxide nanoparticles: current status. 2015;10(15):2365-77.
  23. Chaignon V, Sanchez-Neira I, Herrmann P, Jaillard B, Hinsinger P. Copper bioavailability and extractability as related to chemical properties of contaminated soils from a vine-growing área. Environ. Pollut. 2003;123 (2):229–38.
  24. Ginocchio R, Rodriguez PH, Badilla-Ohlbaum R, Allen HE, Lagos GE. Effect of soil copper content and pH on copper uptake of selected vegetables grown under controlled conditions. Environ. Toxicol.Chem. 2002;21(8):1736–44.
  25. Zietz BP, de Vergara JD, Dunkelberg H. Copper concentrations in tap water and possible effects on infant’s health—results of a study in Lower Saxony, Germany. Environ. Res. 2003;92(2):129–38.
  26. Trumbo P,Yates AA, Schlicker S, and Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. 2001;101:294–301.
  27. Arnal N, de Alaniz MJ, Marra CA. Involvement of Copper Overload in Human Diseases, in: M.S. Giménez (Ed.), Research Signpost/Transworld Research Network, Kerala, India. 2010;1:1-28.
  28. Zhang L, Lu L, PanY, Ding C, Xu D, Huang C, Pan X, Zheng W . Environmental Research. 2015;140:10–17.
  29. Rocha GH, Steinbach C, Munhoz JR, Madia MA, Faria JK, Hoeltgebaum D,et al. Trace metal levels in serum and urine of a population in southern Brazil. J Trace Elem Med Biol.2016;35:61–5.
  30. Klinc M, Coskun A, Bilge F, Imrek S, Atli Y, Serum reference levels ofselenium, zinc and copper in healthy pregnant women at a prenatal screeningprogram in southeastern Mediterranean region of Turkey, J. Trace Elem. Med.Biol. 2010;24:152–6.
  31. Pereira TC, Campos MM, Bogo MR. Copper toxicology, oxidative stress and inflammation using zebrafish as experimental model. J ApplToxicol. 2016 Jul;36(7):876-85.
  32. Pal A, Prasad R.An overview of various mammalian models to study chronic copper intoxication associated Alzheimer’s disease like pathology. Biometals. 2015 Feb;28(1):1-9.
  33. Ghayour-Mobarhan M, Taylor A, New SA, Lamb DJ, Ferns GA. Determinants of serum copper, zinc and selenium in healthy subjects. Ann ClinBiochem. 2005;42:364-75.
  34. Leone N, Courbon D, Ducimetiere P, Zureik M. Zinc, copper, and magnesium and risks for all-cause, cancer, and cardiovascular mortality. Epidemiology. 2006;17:308-14.
  35. Bo S, Durazzo M, Gambino R, Berutti C, Milanesio N, Caropreso A et al. Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults. J Nutr. 2008;138:305-10.
  36. Tsuboi A, Terazawa M, Kazumi T,Fukuo K. Serum copper, zinc and risk factors for cardiovascular disease in community-living Japanese elderly women. Asia Pac J ClinNutr. 2014;23(2):239-45.
  37. Bagheri B, Akbari N, Tabiban S, Habibi V, Mokhberi V. Serum level of copper in patients with coronary artery disease. Niger Med J. 2015;56(1):39-42.
  38. Lusis AJ. Atherosclerosis.Nature. 2000 Sep 14;407(6801):233-41.
  39. Wei H, Zhang WJ, Mcmillen TS, Leboeuf RC, Frei B. Copper Chelation by Tetrathiomolybdate Inhibits Vascular Inflammation and Atherosclerotic Lesion Development in Apolipoprotein E-deficient Mice. Atherosclerosis. 2012 Aug;223(2): 306–13.
  40. Plane F, Wigmore S, Angelini GD, Jeremy JY. Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aorta Br J Pharmacol.1997;121(2):345-50.
  41. Demura Y, Ameshima S, Ishizaki T, Okamura S, Miyamori I, Matsukawa S. The activation of eNOS by copper ion (Cu2+) in human pulmonary arterial endothelial cells. Free Radic Biol Med. 1998; 25(3):314–20.
  42. Al-Bayati MA, Jamil DA, Al-Aubaidy HA. Cardiovascular effects of copper deficiency on activity of superoxide dismutase in diabetic nephropathy. N Am J Med Sci. 2015 Feb;7(2):41-6.
  43. Gumus E, Adilay U, Gunaldi O, Bayindir C, Kazanci B,Guclu B. The effect of copper on vasospastic femoral artery in rats. Turk Neurosurg. 2014;24(1):25-9.
  44. Chiarugi A, Pitari GM, Costa R, Ferrante M, Villari L, Amico-Roxas M, et al. Effect of prolonged incubation with copper on endothelium- dependent relaxation in rat isolated aorta. Br J Pharmacol. 2002;136:1185-93.
  45. Urso E, Maffia M. Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems. J Vasc Res. 2015;52(3):172-96.
  46. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito RL, Liao R, et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 2005;115(8):2108–18.
  47. Jiang Y, Reynolds C, Xiao C, Feng W, Zhou Z, Rodriguez W, et al. Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice. J Exp Med. 2007 March 19;204(3): 657-66.
  48. Zheng L, Han P, Liu J, Li R, Yin W, Wang T, et al. Role of copper in regression of cardiac hypertrophy. Pharmacol Ther. 2015 Apr;148:66-84.
  49. Hinkel R, TrenkwalderT, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737.
  50. Frangogiannis NG, Entman ML. Chemokines in myocardial ischemia. Trends Cardiovasc Med. 2005;15:163–169.
  51. Chevion M, Jiang Y, Har-El R, Berenshtein E, Uretzky G, Kitrossky N. Copper and iron are mobilized following myocardial ischemia: possible predictive criteria for tissue injury. Proc Natl Acad Sci US. 1993;90:1102–6.
  52. He W, James Kang Y.Ischemia-induced copper loss and suppression of angiogenesis in the pathogenesis of myocardial infarction. CardiovascToxicol. 2013 Mar;13(1):1-8.
  53. GoodmanJR, Warshaw JB, Dallman PR. Cardiac hypertrophy in rats with iron and copper deficiency: quantitative contribution of mitochondrial enlargement. Pediatr Res.1970; 4:244–56.
  54. Kopp SJ, Klevay LM, Feliksik JM.Physiological and metabolic characterization of a cardiomyopathy induced by chronic copper deficiency.Am J Physiol. 1983;245:H855–866.
  55. Karakurt C, Çelik S, Selimoğlu A, Varol I, Karabiber H, Yoloğlu S.Strain and strain rate echocardiography in children with Wilson’s disease. Cardiovasc J Afr. 2016 May 13;271-8.

 

 

Authors

Karolini Zuqui Nunes1, Mirian Fioresi2

1 Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, ES, Brazil.

2 Department of Nursing, Federal University of Espírito Santo, Vitoria, ES, Brazil.

Share

Newsletter

Get news of Salus Journal reported on its e-mail

2024 - SALUS JOURNAL - All rights reserved
Language: