Selenium is an essential micronutrient for the human body [1Small-Howard AL, Berry MJ. Unique features of selenocysteine incorporation function within the context of general eukaryotic translational processes. Biochemical Society Transactions Portland Press Limited 2005; 33(): 1493-7.] since it is required for the synthesis of selenocysteine (Sec), which is needed for the synthesis of selenoproteins. Selenoproteins have important pleiotropic biological activities including antioxidant activity, anti-inflammatory activity, and deiodinase activity (which is required for the synthesis of active thyroid hormone) [2Berry MJ, Tujebajeva RM, Copeland PR, et al. Selenocysteine incorporation directed from the 3'UTR: Characterization of eukaryotic EFsec and mechanistic implications. Biofactors 2001; 14(1-4): 17-24.
[http://dx.doi.org/10.1002/biof.5520140104] [PMID: 11568436] ]. The process of selenoprotein synthesis involves numerous steps. It begins with serylation of tRNA^Sec by seryl-tRNA synthetase to yield seryl-tRNA^Sec. The seryl-tRNA^Sec is phosphorylated by a phosphoseryl-tRNA^Sec kinase to yield phosphoseryl(Sep)-tRNA^Sec. The Sec-tRNA^Sec is synthesized by Sep-tRNA:Sec-tRNA synthase using the phosphoseryl-tRNA^Sec and selenophosphate [1Small-Howard AL, Berry MJ. Unique features of selenocysteine incorporation function within the context of general eukaryotic translational processes. Biochemical Society Transactions Portland Press Limited 2005; 33(): 1493-7.]. The Sec-tRNA^Sec acts as the Sec donor for the incorporation of Sec into a nascent selenoprotein, as determined by a Sec-specific UGA codon, during translation [3Bellinger FP, Raman AV, Reeves MA, Berry MJ. Regulation and function of selenoproteins in human disease. Biochem J 2009; 422(1): 11-22.
[http://dx.doi.org/10.1042/BJ20090219] [PMID: 19627257] ].

The prototype selenoprotein is GPx (glutathione peroxidase), which was characterized as a selenocysteine in 1978 [4Forstrom JW, Zakowski JJ, Tappel AL. Identification of the catalytic site of rat liver glutathione peroxidase as selenocysteine. Biochem 1978; 17(13): 2639-44.
[http://dx.doi.org/10.1021/bi00606a028] [PMID: 678534] ]. Since, other selenoproteins with important biological functions have been discovered, including thioredoxin reductases (TRxR) [5Arnér ESJ, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 2000; 267(20): 6102-9.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01701.x] [PMID: 11012661] ], methionine sulfoxide reductase A [6Moskovitz J. Methionine sulfoxide reductases: Ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases. Biochim Biophys Acta 2005; 1703(2): 213-9.
[http://dx.doi.org/10.1016/j.bbapap.2004.09.003] [PMID: 15680229] ], deiodinases [7Bianco AC, Kim BW. Deiodinases: Implications of the local control of thyroid hormone action. J Clin Invest 2006; 116(10): 2571-9.
[http://dx.doi.org/10.1172/JCI29812] [PMID: 17016550] ], selenoprotein P [8Schomburg L, Schweizer U, Holtmann B, Flohé L, Sendtner M, Köhrle J. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 2003; 370(Pt 2): 397-402.
[http://dx.doi.org/10.1042/bj20021853] [PMID: 12521380] ], selenoprotein N [9Hwang DY, Cho JS, Oh JH, et al. Differentially expressed genes in transgenic mice carrying human mutant presenilin-2 (N141I): Correlation of selenoprotein M with Alzheimer’s disease. Neurochem Res 2005; 30(8): 1009-19.
[http://dx.doi.org/10.1007/s11064-005-6787-6] [PMID: 16258850] ], selenoprotein M [10Zorzato F, Jungbluth H, Zhou H, Muntoni F, Treves S. Functional effects of mutations identified in patients with multiminicore disease. IUBMB Life 2007; 59(1): 14-20.
[http://dx.doi.org/10.1080/15216540601187803] [PMID: 17365175] ], selenoprotein T [11Grumolato L, Ghzili H, Montero-Hadjadje M, et al. Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion. FASEB J 2008; 22(6): 1756-68.
[http://dx.doi.org/10.1096/fj.06-075820] [PMID: 18198219] ] and selenoprotein S [12Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 2004; 429(6994): 841-7.
[http://dx.doi.org/10.1038/nature02656] [PMID: 15215856] ]. The important functions of representative selenoproteins are listed in Table 1. Furthermore, studies of animals and humans have linked deficiencies of various selenoproteins and polymorphisms in selenoprotein genes with a medley of diseases including muscle and cardiovascular disorders, hypothyroidism, and epilepsy [3Bellinger FP, Raman AV, Reeves MA, Berry MJ. Regulation and function of selenoproteins in human disease. Biochem J 2009; 422(1): 11-22.
[http://dx.doi.org/10.1042/BJ20090219] [PMID: 19627257] ].

Table 1
Normal functions of representative selenoproteins relevant to the cardiovascular system and their corresponding clinical deficient features.

There is a clinical association between selenium deficiency and epilepsy [3Bellinger FP, Raman AV, Reeves MA, Berry MJ. Regulation and function of selenoproteins in human disease. Biochem J 2009; 422(1): 11-22.
[http://dx.doi.org/10.1042/BJ20090219] [PMID: 19627257] ]. Thus, infants with intractable epilepsy have significant lower levels of selenium compared with the normal control group (p < 0.05) [13Ashrafi MR, Shabanian R, Abbaskhanian A, et al. Selenium and intractable epilepsy: Is there any correlation? Pediatr Neurol 2007; 36(1): 25-9.
[http://dx.doi.org/10.1016/j.pediatrneurol.2006.09.001] [PMID: 17162193] ]. In animal studies, it has been demonstrated that a selenium deficient diet increased the susceptibility of rats to kainite-induced epileptic seizures [14Savaskan NE, Bräuer AU, Kühbacher M, et al. Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity. FASEB J 2003; 17(1): 112-4.
[http://dx.doi.org/10.1096/fj.02-0067fje] [PMID: 12424220] ], and neurological seizures were observed in selenoprotein P knockout mice when they were raised on selenium restricted diet [8Schomburg L, Schweizer U, Holtmann B, Flohé L, Sendtner M, Köhrle J. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 2003; 370(Pt 2): 397-402.
[http://dx.doi.org/10.1042/bj20021853] [PMID: 12521380] , 15Hill KE, Zhou J, McMahan WJ, et al. Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem 2003; 278(16): 13640-6.
[http://dx.doi.org/10.1074/jbc.M300755200] [PMID: 12574155] ].

Multiminicore, a form of congenital muscular dystrophy, characterized by a distinct loss of muscle fiber organization, has been associated with selenium deficiency and/or selenoprotein defects [16Jungbluth H. Multi-minicore disease. Orphanet J Rare Dis 2007; 2: 31.
[http://dx.doi.org/10.1186/1750-1172-2-31] [PMID: 17631035] ]. The etiology has been attributed to mutations in selenoprotein N and ryanodine receptors [10Zorzato F, Jungbluth H, Zhou H, Muntoni F, Treves S. Functional effects of mutations identified in patients with multiminicore disease. IUBMB Life 2007; 59(1): 14-20.
[http://dx.doi.org/10.1080/15216540601187803] [PMID: 17365175] ]. Ryanodine receptors are transmembrane proteins in the endoplasmic reticulum and are responsible for releasing calcium from the intracellular stores [17Zalk R, Lehnart SE, Marks AR. Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 2007; 76: 367-85.
[http://dx.doi.org/10.1146/annurev.biochem.76.053105.094237] [PMID: 17506640] ]. It appears that selenoprotein N associates with and facilitates the ryanodine receptors to function properly [18Jurynec MJ, Xia R, Mackrill JJ, et al. Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle. Proc Natl Acad Sci USA 2008; 105(34): 12485-90.
[http://dx.doi.org/10.1073/pnas.0806015105] [PMID: 18713863] ]. It was demonstrated in a zebra fish model that selenoprotein N knockout resulted in disorganized muscle fibers, the hallmark of multiminicore disease [19Deniziak M, Thisse C, Rederstorff M, Hindelang C, Thisse B, Lescure A. Loss of selenoprotein N function causes disruption of muscle architecture in the zebrafish embryo. Exp Cell Res 2007; 313(1): 156-67.
[http://dx.doi.org/10.1016/j.yexcr.2006.10.005] [PMID: 17123513] ]. Besides selenoprotein N, selenoproteins M and T also play a vital role in the regulation of calcium-mediated signaling: selenoprotein M attenuates calcium signaling in response to oxidative stress [20Reeves MA, Bellinger FP, Berry MJ. The neuroprotective functions of selenoprotein M and its role in cytosolic calcium regulation. Antioxid Redox Signal 2010; 12(7): 809-18.
[http://dx.doi.org/10.1089/ars.2009.2883] [PMID: 19769485] ], whereas, selenoprotein T increases it [11Grumolato L, Ghzili H, Montero-Hadjadje M, et al. Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion. FASEB J 2008; 22(6): 1756-68.
[http://dx.doi.org/10.1096/fj.06-075820] [PMID: 18198219] ]. Thus, selenoproteins N, M and T are important regulators of calcium signaling relevant to muscular health and function.

Deiodinases are selenoproteins that play an essential role in thyroid hormone metabolism and function [7Bianco AC, Kim BW. Deiodinases: Implications of the local control of thyroid hormone action. J Clin Invest 2006; 116(10): 2571-9.
[http://dx.doi.org/10.1172/JCI29812] [PMID: 17016550] ]. The biologically active thyroid hormone 3,5,3′-triiodothyronine (T3) is activated by deiodinase from its precursor thyroxine (T4). Specifically, deiodinases types I and II convert T4 to T3 whereas the deiodinase type III inactivates both T4 and T3 by removing specific iodine atoms from T3 and T4 [7Bianco AC, Kim BW. Deiodinases: Implications of the local control of thyroid hormone action. J Clin Invest 2006; 116(10): 2571-9.
[http://dx.doi.org/10.1172/JCI29812] [PMID: 17016550] ]. Since thyroid hormone regulates a plethora of organs metabolic functions including the heart, dysregulation of thyroid hormone levels due to deficiencies of selenium and/or defects in deiodinases increases the risk of pathological cardiovascular perturbations [21Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001; 344(7): 501-9.
[http://dx.doi.org/10.1056/NEJM200102153440707] [PMID: 11172193] ].

Reactive oxygen species are known to cause injury to all cell types including the vascular endothelial cells and cardiac myocytes [22Lum H, Roebuck KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 2001; 280(4): C719-41.
[http://dx.doi.org/10.1152/ajpcell.2001.280.4.C719] [PMID: 11245588] ]. GPx uses glutathione to detoxify hydroperoxides into water, thereby providing cells anti-oxidant protection [23Arthur JR. The glutathione peroxidases. Cell Mol Life Sci 2000; 57(13-14): 1825-35.
[PMID: 11215509] ]. Studies of mice showed that GPx1 inhibited ischemia induced apoptosis of cardiac myocytes [24Maulik N, Yoshida T, Das DK. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. Mol Cell Biochem 1999; 196(1-2): 13-21.
[http://dx.doi.org/10.1023/A:1006905910140] [PMID: 10448898] ], and that targeted deletion of GPx1 gene lead to heart and vascular dysfunction [25Forgione MA, Cap A, Liao R, et al. Heterozygous cellular glutathione peroxidase deficiency in the mouse: Abnormalities in vascular and cardiac function and structure. Circulation 2002; 106(9): 1154-8.
[http://dx.doi.org/10.1161/01.CIR.0000026820.87824.6A] [PMID: 12196344] ]. Other forms of GPx, GPx3 and GPx4, provide protection against thrombosis [26Kenet G, Freedman J, Shenkman B, et al. Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke. Arterioscler Thromb Vasc Biol 1999; 19(8): 2017-23.
[http://dx.doi.org/10.1161/01.ATV.19.8.2017] [PMID: 10446087] ] and atherosclerosis [27Guo Z, Van Remmen H, Yang H, et al. Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL-induced apoptosis in mouse aortic cells. Arterioscler Thromb Vasc Biol 2001; 21(7): 1131-8.
[http://dx.doi.org/10.1161/hq0701.092092] [PMID: 11451741] ]. The positive correlation between selenium and GPx activities/expression alludes to selenium’s indirect cardiovascular protective role. For example selenium supplementation increases GPx1 and GPx4 activities in vascular endothelial cells, resulting in reduced oxidative stress [28Miller S, Walker SW, Arthur JR, et al. Selenite protects human endothelial cells from oxidative damage and induces thioredoxin reductase. Clin Sci (Lond) 2001; 100(5): 543-50.
[http://dx.doi.org/10.1042/cs1000543] [PMID: 11294695] -31Thomas JP, Geiger PG, Girotti AW. Lethal damage to endothelial cells by oxidized low density lipoprotein: Role of selenoperoxidases in cytoprotection against lipid hydroperoxide- and iron-mediated reactions. J Lipid Res 1993; 34(3): 479-90.
[PMID: 8468531] ]. Conversely, long term selenium deficiency leads to decreased GPx expression and activity and cardiovascular damage, which can be reversed by dietary supplementation of selenium [32Huang K, Liu H, Chen Z, Xu H. Role of selenium in cytoprotection against cholesterol oxide-induced vascular damage in rats. Atherosclerosis 2002; 162(1): 137-44.
[http://dx.doi.org/10.1016/S0021-9150(01)00707-9] [PMID: 11947907] , 33Wu Q, Huang K. Effect of selenium compounds on the damage induced by oxysterol on rat arterial walls. Biol Trace Elem Res 2006; 112(3): 273-82.
[http://dx.doi.org/10.1385/BTER:112:3:273] [PMID: 17057266] ].

TRxR is crucial for the control of cellular redox homeostasis because it detoxifies peroxides, prevents deleterious disulfide bonds formation within and between biomolecules, reduces thioredoxin, and regulates the redox state of transcription factors, thereby regulating the redox homeostasis in cells [5Arnér ESJ, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 2000; 267(20): 6102-9.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01701.x] [PMID: 11012661] ]. Studies of mice have demonstrated that systemic inactivation of TRxR resulted in embryonic lethality associated with anemic embryos, thinning of the ventricular heart wall and malformation of the heart [34Conrad M, Jakupoglu C, Moreno SG, et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol 2004; 24(21): 9414-23.
[http://dx.doi.org/10.1128/MCB.24.21.9414-9423.2004] [PMID: 15485910] ]. Mice studies also show that cardiac tissue-selective knockout of the mitochondrial TRxR gene results in fatal dilated cardiomyopathy [34Conrad M, Jakupoglu C, Moreno SG, et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol 2004; 24(21): 9414-23.
[http://dx.doi.org/10.1128/MCB.24.21.9414-9423.2004] [PMID: 15485910] ]. Additionally, cardiomyocyte cell death under ischemic and reperfusion conditions due to failure of thiol regeneration have also been shown in TRxR knockout mice studies [35Horstkotte J, Perisic T, Schneider M, et al. Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection. Circulation 2011; 124(25): 2892-902.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.059253] [PMID: 22144571] ]. In parallel to these findings, studies of humans have established the protective role of TRxR in the cardiovascular system and identified loss-of-function mutations of TrxR that cause dilated cardiomyopathy in patients [36Sibbing D, Pfeufer A, Perisic T, et al. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur Heart J 2011; 32(9): 1121-33.
[http://dx.doi.org/10.1093/eurheartj/ehq507] [PMID: 21247928] ]. In short, loss of mitochondrial TRxR activity in the heart is a pathogenic factor for the development of dilated cardiomyopathy.

Given the fact that GPx and TRxR are selenoproteins, selenium nutrition plays an important role in the antioxidant systems in the human body. Hence deficiencies of GPx, TRxR and deoidenases secondary to selenium deficiency can result in the pathogenesis of cardiovascular diseases. Thus, the classic demonstration of diseases caused by selenium deficiency is the Keshan disease, which was originally discovered in China with clinical features that are characteristic of dilated cardiomyopathy: cardiogenic shock, cardiac arrhythmias, ECG changes, enlarged heart, and/or congestive heart failure [37Chen J. An original discovery: Selenium deficiency and Keshan disease (an endemic heart disease). Asia Pac J Clin Nutr 2012; 21(3): 320-6.
[PMID: 22705420] ]. Epidemiological and population-based intervention studies in China established a causal relationship between dietary deficiency of selenium and the development of Keshan disease [37Chen J. An original discovery: Selenium deficiency and Keshan disease (an endemic heart disease). Asia Pac J Clin Nutr 2012; 21(3): 320-6.
[PMID: 22705420] ]. Subsequent case-controlled studies in other countries, such as the one in Finland [38Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982; 2(8291): 175-9.
[http://dx.doi.org/10.1016/S0140-6736(82)91028-5] [PMID: 6123886] ], established an inverse relationship between the serum selenium level and incidence of myocardial infarction and cardiovascular death. Specifically, a low level of serum selenium (< 45 μg/L) was associated with 2-3 times of increased risk for death due to cardiovascular diseases [38Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982; 2(8291): 175-9.
[http://dx.doi.org/10.1016/S0140-6736(82)91028-5] [PMID: 6123886] ]. However, certain epidemiological features of Keshan disease could not be explained solely by selenium deficiency because there are other factors involved [39Levander OA, Beck MA. Interacting nutritional and infectious etiologies of Keshan disease. Insights from coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E. Biol Trace Elem Res 1997; 56(1): 5-21.
[http://dx.doi.org/10.1007/BF02778980] [PMID: 9152508] ]. For example, selenium deficiency increases the susceptibility of mice to myocarditis induction by Coxsackie B virus infection [40Beck MA. Nutritionally induced oxidative stress: Effect on viral disease. Am J Clin Nutr 2000; 71(6)(Suppl.): 1676S-81S.
[http://dx.doi.org/10.1093/ajcn/71.6.1676S] [PMID: 10837315] ]. Nevertheless, it is likely that selenium deficiency predisposes an individual to Keshan disease that can be precipitated by other etiological factors and that these factors are likely to act synergistically with selenium deficiency to cause Keshan disease.

At the molecular level, it seems that the best explanation for cardiomyopathy secondary to selenium deficiency is that selenium deficiency causes myopathy as a result of the depletion of GPx and TRxR that protect cardiomyocytes from oxidative damage. Although it is intuitive that selenium deficiency can occur in individuals with malabsorption and/or malnutrition or living in a selenium-deficient environment, there has been no, to the best of our knowledge, systemic review of the published clinical case reports for etiologies of selenium deficiency in relationship to the development of cardiomyopathy. Therefore, in an effort to understand how patients who do not live in selenium deficient areas acquire selenium deficiency and develop selenium-responsive cardiomyopathy, we researched the biomedical literature to identify and review cardiomyopathy cases in which selenium deficiency plays a causative role.

A systematic search of the published biomedical literature was conducted in PubMed, Scopus, Embase, and Science Direct Library databases for studies investigating cardiomyopathy associated with selenium deficiency. For optimal identification of relevant studies, the search criteria used the following keywords alone and in combination: selenium deficiency, diet, malabsorption, cardiomyopathy, and heart failure. There were no date restrictions applied to the search. For consistency, the same criteria were implemented across all databases. Study selection entailed screening for studies in which selenium deficiency played a role in the etiology of a cardiomyopathy, which was validated on the basis of cardiomyopathy symptoms resolution or reduction after repletion of selenium or selenium deficient level findings postmortem. Pertinent information from each article was recorded in Tables 2 and 3 without altercation of information or conversion of any selenium values and units reported. Non-English written articles were excluded due our inability to comprehend the language the manuscripts were composed in.

Table 2
Clinical cases of selenium-responsive abnormalities associated with ketogenic diet.

Table 3
Selenium deficiency and cardiovascular abnormalities associated with other etiologies.

As shown in Fig. (1), our search strategy yielded a total of 189 studies. We retrieved 31 studies of which 28 met our criteria and were included in our report. Tables 2 and 3 contain relevant information regarding each patient’s gender, age, cause of selenium deficiency, selenium status, symptoms that prompted selenium analysis, form of selenium used for treatment, and length of selenium treatment to resolve symptoms.

Fig. (1) Flowchart of study selection.

Keshan disease is a well-documented dilated cardiomyopathy described as focal myocardial necrosis with normal coronary arteries [64]. It was an endemic disease with high incidence in regions where the soil has little selenium [64]. Dietary sources of selenium include seafood, meat and cereals [65Bergqvist AGC, Chee CM, Lutchka L, Rychik J, Stallings VA. Selenium deficiency associated with cardiomyopathy: A complication of the ketogenic diet. Epilepsia 2003; 44(4): 618-20.
[http://dx.doi.org/10.1046/j.1528-1157.2003.26102.x] [PMID: 12681013] ]. This portends that human selenium levels is contingent on the type of food intake and source of cereal – whether the grains for cereal production are grown in selenium rich soil or deficient in selenium [65Bergqvist AGC, Chee CM, Lutchka L, Rychik J, Stallings VA. Selenium deficiency associated with cardiomyopathy: A complication of the ketogenic diet. Epilepsia 2003; 44(4): 618-20.
[http://dx.doi.org/10.1046/j.1528-1157.2003.26102.x] [PMID: 12681013] ]. The ketogenic diet, which consists mostly of fat in addition to some fish/eggs/meats, has insufficient amounts of selenium compared to a more balanced diet [66National Research Council, Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances 10^th rev. ed.. 1989.]. For example, Bergqvist et al. conducted a retrospective analysis of the ketogenic diet and showed a deficiency in selenium [65Bergqvist AGC, Chee CM, Lutchka L, Rychik J, Stallings VA. Selenium deficiency associated with cardiomyopathy: A complication of the ketogenic diet. Epilepsia 2003; 44(4): 618-20.
[http://dx.doi.org/10.1046/j.1528-1157.2003.26102.x] [PMID: 12681013] ]. In the case report by Bank et al., although they did not report an analysis of their patient’s ketogenic diet, their post mortem cardiomyocyte examination was consistent with findings observed in the context of selenium deficiency [67Bank IM, Shemie SD, Rosenblatt B, Bernard C, Mackie AS. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol 2008; 39(6): 429-31.
[http://dx.doi.org/10.1016/j.pediatrneurol.2008.08.013] [PMID: 19027591] ]. Similarly, although Sirikonda et al. did not report the ketogenic diet content of their patient, their diagnosis of the patient with selenium deficiency-induced cardiomyopathy was supported by the fact that the patient had low serum selenium level and that selenium supplementation and termination of the ketogenic diet resulted in cardiac improvement [68Sirikonda NS, Patten WD, Phillips JR, Mullett CJ. Ketogenic diet: Rapid onset of selenium deficiency-induced cardiac decompensation. Pediatr Cardiol 2012; 33(5): 834-8.
[http://dx.doi.org/10.1007/s00246-012-0219-6] [PMID: 22367552] ].

Similar to ketogenic diet, PN may also be low in selenium [69Zabel NL, Harland J, Gormican AT, Ganther HE. Selenium content of commercial formula diets. Am J Clin Nutr 1978; 31(5): 850-8.
[http://dx.doi.org/10.1093/ajcn/31.5.850] [PMID: 417618] ]. The amount of selenium provided in PN is typically 20-60 μg/day, which is inadequate [70Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: Recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract 2012; 27(4): 440-91.
[http://dx.doi.org/10.1177/0884533612446706] [PMID: 22730042] , 71Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2011; 35(6): 736-47.
[http://dx.doi.org/10.1177/0148607111413902] [PMID: 21825087] ]. An increase of selenium in PN has been proposed to 60-100 μg/day [70Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: Recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract 2012; 27(4): 440-91.
[http://dx.doi.org/10.1177/0884533612446706] [PMID: 22730042] , 71Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2011; 35(6): 736-47.
[http://dx.doi.org/10.1177/0148607111413902] [PMID: 21825087] ], given selenium requirements are increased in malabsorptive states [71Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2011; 35(6): 736-47.
[http://dx.doi.org/10.1177/0148607111413902] [PMID: 21825087] ]. Regardless of this adjustment, higher doses of selenium in parenteral nutrition might still be warranted for patients with SBS and non-SBS [71Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2011; 35(6): 736-47.
[http://dx.doi.org/10.1177/0148607111413902] [PMID: 21825087] ]. In a study conducted by Milan et al., 68 patients receiving long term care for SBS using parenteral nutrition had significant decline in serum selenium levels [72Dastych M Jr, Šenkyřík M, Dastych M, et al. Trace element status (Zinc, Copper, Selenium, Iron, Manganese) in patients with long-term home parenteral nutrition. Ann Nutr Metab 2016; 69(2): 120-4.
[http://dx.doi.org/10.1159/000450763] [PMID: 27736814] ]. On the contrary, other trace elements, such as zinc, copper and iron, had no significant difference between patients with PN and control subjects [72Dastych M Jr, Šenkyřík M, Dastych M, et al. Trace element status (Zinc, Copper, Selenium, Iron, Manganese) in patients with long-term home parenteral nutrition. Ann Nutr Metab 2016; 69(2): 120-4.
[http://dx.doi.org/10.1159/000450763] [PMID: 27736814] ], suggesting that the selenium provided by the conventional PN is insufficient and explaining why selenium deficiency was observed in a significant number of patients on PN. The cases we reviewed involved patients with lower nutritional status stemming from various etiologies such as lack or reduced selenium in their oral/parenteral diet and numerous gastrointestinal pathologies that resulted in intestinal failure. Given that sick patients tend to have a poor appetite and hence lower nutritional status, poor selenium intake seems an important determinant for the selenium deficiency of the patients in Tables 2 and 3. Thus, it is important to make certain that PN is supplemented with sufficient selenium and that the selenium levels of patients need to be continuously monitored to prevent the development of selenium deficiency related conditions including, but not limited to, cardiomyopathy.

Patients suffering from AIDS are another group of patients who are at risk of selenium deficiency. Some AIDS patients developed HIV associated cardiac abnormalities similar to those found in Keshan disease [73Dworkin BM, Antonecchia PP, Smith F, et al. Reduced cardiac selenium content in the acquired immunodeficiency syndrome. JPEN J Parenter Enteral Nutr 1989; 13(6): 644-7.
[http://dx.doi.org/10.1177/0148607189013006644] [PMID: 2614866] ]. HIV causes impaired systolic function through proinflammatory cytokines such as tumor necrosis factor and IL-1β [55Hsue PY, Waters DD. Heart failure in persons living with HIV infection. Curr Opin HIV AIDS 2017; 12(6): 534-9.
[http://dx.doi.org/10.1097/COH.0000000000000409] [PMID: 28863015] ]. In conjunction with these findings, there are reports of sudden cardiac death in selenium deficiency patients triggered by sepsis [74Lockitch G, Taylor GP, Wong LT, et al. Cardiomyopathy associated with nonendemic selenium deficiency in a Caucasian adolescent. Am J Clin Nutr 1990; 52(3): 572-7.
[http://dx.doi.org/10.1093/ajcn/52.3.572] [PMID: 2168125] ]. However, the pathophysiology of how infections alters the immune systems response in selenium deficient patients leading to cardiomyopathy remains elusive. The change in the immune systems reaction may underlie the susceptibility of cardiomyopathies of individuals with inadequate selenium nutrition.

We have identified two cases of cardiomyopathy due to selenium deficiency associated with RDEB reported by Melville et al. [75Melville C, Atherton D, Burch M, Cohn A, Sullivan I. Fatal cardiomyopathy in dystrophic epidermolysis bullosa. Br J Dermatol 1996; 135(4): 603-6.
[http://dx.doi.org/10.1111/j.1365-2133.1996.tb03840.x] [PMID: 8915155] ]. Although, according to the report, the patients involved were malnourished, numerous patients with RDEB (14 to 25 patients) had reduced serum selenium levels without cardiomyopathy [75Melville C, Atherton D, Burch M, Cohn A, Sullivan I. Fatal cardiomyopathy in dystrophic epidermolysis bullosa. Br J Dermatol 1996; 135(4): 603-6.
[http://dx.doi.org/10.1111/j.1365-2133.1996.tb03840.x] [PMID: 8915155] ]. Thus, it is possible that patients with RDBE are at risk of developing selenium deficiency, which, if worsens, can lead to cardiomyopathy. Thus, Melville et al. recommended that patients with severe RDEB should be examined carefully for their nutritional intake including selenium and with regular echocardiographic screening for signs of cardiomyopathy.

It is important to note that the selenium status of the patients in Tables 2 and 3 was determined by serum selenium levels, and that majority of the cases involved sick patients who might have had other unknown confounding factors that cause selenium deficiency. An alternative method of assessing selenium status is measuring intracellular concentrations or the activities of selenoproteins [5Arnér ESJ, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 2000; 267(20): 6102-9.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01701.x] [PMID: 11012661] , 27Guo Z, Van Remmen H, Yang H, et al. Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL-induced apoptosis in mouse aortic cells. Arterioscler Thromb Vasc Biol 2001; 21(7): 1131-8.
[http://dx.doi.org/10.1161/hq0701.092092] [PMID: 11451741] , 33Wu Q, Huang K. Effect of selenium compounds on the damage induced by oxysterol on rat arterial walls. Biol Trace Elem Res 2006; 112(3): 273-82.
[http://dx.doi.org/10.1385/BTER:112:3:273] [PMID: 17057266] ]. Ideally, the selenium status should be monitored by multiple methods that determine not only the serum level but also intracellular level and the activities of selenoproteins, such as glutathione peroxidase in cells. Nevertheless, the fact that the cardiomyopathy symptoms were alleviated after administration of selenium in most patients reviewed suggests that the measurement of serum selenium level is a useful way to determine selenium status of patients with cardiomyopathy symptoms.

The cases of cardiovascular dysfunction listed in Table 2 and 3 represent selenium-responsive cases and furthermore show distinctive patient populations who are at risk of developing cardiovascular dysfunction due to selenium deficiency. However, it is possible that selenium deficiency in populations of patients with these diseases and/or other diseases is underreported because those patients who have yet to present with cardiovascular dysfunction are unlikely to receive selenium status analysis. Therefore, it is important that physicians think about including selenium status analysis for patients with certain diseases (IBS, AIDS, and RDBE, for example) and/or receiving certain treatment, such as ketogenic diet and parenteral nutrition. Doing so is important because physicians can take simple management – selenium supplementation – to prevent the development of cardiovascular dysfunctions, such as cardiomyopathy, in these patients.

These cases in the literature emphasize the need for considering selenium deficiency as a potential cause of the development of cardiomyopathy in patients in various diseases states and treatments. We hope to draw attention to implement preventative measures of selenium deficiency-induced cardiomyopathy in these clinical contexts. Moreover, we hope to spark more investigation into the pathophysiology of selenium induced cardiomyopathy.