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Case 6: Lower Extremity Edema and Dyspnea
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Patient Presentation
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History
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Physical Exam
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Initial Studies
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Differential Diagnosis
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Conclusive Studies
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Diagnosis
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Treatment and Clinical Course
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Learning Points
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Discussion
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References
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Patient Presentation
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A 30-year-old man presented to Mulago Hospital in Kampala, Uganda, with lower extremity edema and shortness of breath.

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History
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The patient was in his usual state of health until 3 months before presentation, when he noted the onset of bilateral lower extremity edema and dyspnea. Since then, his symptoms have progressed to include fatigue, orthopnea, paroxysmal nocturnal dyspnea, and, for the last month, a cough productive of clear sputum. His exercise tolerance has decreased from several kilometers to 10-20 meters at a walking pace. His leg swelling is exacerbated by long periods of sitting required by his job as a truck driver. He denies having fevers, chest pain, palpitations, abdominal pain or swelling, hemoptysis, rash, or urinary symptoms. The patient denies use of alcohol, drugs, or medications and believes he eats a fairly typical Ugandan nonvegetarian diet. He recalls several weeklong febrile episodes of cough and "flu" in the past 4 years, all of which have responded to antimalarial medications and oral antibiotics from his local infirmary. He denies having any other past medical conditions, including diabetes, rheumatic fever, and notable childhood illness. He reports 8-10 female sex partners over the past few years including his wife and multiple sex workers, and denies prior HIV testing.

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Physical Exam
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General: slightly built male with mild pallor, sitting upright and able to speak full sentences with some respiratory effort

Vital Signs: temperature--36.6°C; blood pressure--105/70 mmHg; pulse--105 beats per minute; respiratory rate--25 breaths per minute; oxygen saturation--93% on room air

Head: pale conjunctivae; anicteric sclera; moist mucous membranes; oral thrush was present

Neck: jugular venous pulse was to angle of jaw (>20 cm); no thyromegaly or palpable lymphadenopathy were noted

Chest: rales halfway up both lungs; dullness to percussion at the bilateral bases with decreased tactile fremitus

Heart: tachycardia with regular rhythm; right-sided and left-sided S3 heart sounds were present; no murmurs, clicks, or rubs were noted; point of maximal impulse was displaced 3 cm laterally and diffuse

Abdomen: liver was enlarged and tender with a pulsatile edge 4 cm below the costal margin; bowel sounds were present; spleen was not palpable

Extremities: bilateral radial and dorsalis pedis pulses were palpable, but 1+ in intensity; 3+ lower extremity edema was present to the thighs symmetrically

Skin: mild pallor; hemosiderosis of bilateral shins; no other rashes noted; no stigmata of liver disease were noted

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Initial Studies
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Laboratory tests: hemoglobin count was 7.5 g/dL; HIV test was ordered

Electrocardiogram: sinus tachycardia at 110 beats per minute; normal axis and intervals; evidence of left-axis deviation, left ventricular hypertrophy, and biatrial enlargement; diffuse T-wave changes; J-point elevation in V2-V4

Chest X ray: severely enlarged cardiac silhouette; bilateral small effusions and pulmonary vascular congestion

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Differential Diagnosis
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This patient's constellation of lower extremity edema and shortness of breath, with evidence of pulmonary congestion on examination and chest X ray, was most indicative of biventricular cardiac failure. The patient's sexual history and evidence of oral thrush in the setting of a high-risk demographic in an endemic area made HIV infection very probable.

Etiologies of dyspnea and lower extremity edema that were considered in this case included:

  1. Biventricular heart failure:
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    • Dilated cardiomyopathy (DCM) (see Table 1).

    • Valvular disease: Given high tropical prevalence of rheumatic disease, mitral stenosis and aortic disease were both considered, but auscultatory exam did not reveal any murmurs. The patient did not meet the Duke criteria for infective endocarditis.(1)

    • Acute myocarditis (from HIV or other viral etiologies): Although this may have been the historical etiology of cardiac dysfunction, lack of acuity and absence of chest pain made this less likely as an acute presentation.

    • High output failure in setting of chronic anemia, thyrotoxicosis, or nutritional deficiency (eg, wet beriberi from thiamine deficiency): The patient appeared well nourished and without signs of thyroid dysfunction, though he did have evidence of moderate anemia.

    • Endomyocardial fibrosis: This also represents a local etiology of diffuse edema, but has no association with HIV.

    • Congenital disease: Eisenmenger syndrome can present at a later stage in life and does have increased prevalence with vertical transmission of HIV.

    • Ischemia: Though this is the most common cause of heart failure in the developed world, it is less likely to be so in Uganda, especially given the age of this patient.

    • Cardiac tumors (eg, atrial myxoma or cardiac Kaposi sarcoma): These are rarely seen.

  2. Constrictive pericarditis/effusion: Infectious etiologies (tuberculin, fungal, parasitic, or HIV associated) predominate as causes of constrictive pericarditis in Uganda.(2) Malignancy, such as lymphoma in the setting of HIV or autoimmune diseases, also was possible. In regard to constrictive disease, however, there was no evidence of pulsus paradoxus or Kussmaul sign upon examination. An auscultatory examination was notable for easily audible Korotkoff sounds without a rub, and an electrocardiogram (EKG) was unrevealing.

  3. Pulmonary hypertension: Etiologies considered include schistosomiasis, HIV, rheumatic disease, portal hypertension, and congenital cardiac disease.

  4. Cirrhosis: Etiologies of cirrhosis common to Uganda include hepatitis B, alcohol use, aflatoxin poisoning (for hepatocellular cancer development), schistosomiasis, and granulomatous disease.(3) However, physical examination revealed no stigmata of liver disease, and there was no history of alcohol use. Serum albumin was checked to rule out other etiologies of hypoalbuminemia (eg, protein-losing enteropathy and kwashiorkor).

  5. Renal failure: Although the nephrotic syndrome and tubular/interstitial kidney disease can lead to volume overload, the patient showed no evidence of renal dysfunction. He continued to have excellent urine output with normal-appearing urine and a good response to diuretics.

Table 1. Common Etiologies of DCM in Uganda (4,5,6)
Rheumatic heart disease
Infection (myocarditis or autoimmune process):
  • Viral: HIV, hepatitis, Coxsackievirus, cytomegalovirus, Epstein-Barr virus

  • Bacterial: streptococcal rheumatic fever, brucellosis, Salmonella-related typhoid fever

  • Mycobacterial

  • Parasitic: toxoplasmosis, schistosomiasis

  • Coccidioidal

Hypertension (untreated)
Alcohol use and thiamine deficiency
Drugs:
  • Antiretroviral medications (zidovudine, didanosine, zalcitabine)

  • Chloroquine

  • Chemotherapeutics

Ischemia
Secondary hemosiderosis (eg, via Bantu beer)
Hypo/hyperthyroidism
Peripartum cardiomyopathy
Sarcoidosis
Genetic predisposition
Diabetes
Uremia
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Conclusive Studies
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  1. An EKG did not show any signs of ischemia (as mentioned above).

  2. A chest radiographic image taken 3 years earlier, which the patient brought with him, showed an enlarged cardiac silhouette, suggesting that a chronic process was causing his heart failure.

  3. HIV serology was positive. A CD4 count of 160 cells/µL was reported.

  4. Echocardiogram showed severely dilated ventricles with moderately depressed left and right ventricular function and bilateral dilated atria. There was no evidence of pericardial effusion or pulmonary hypertension by estimation. Nor was there any evidence of aortic or mitral valvular abnormalities.

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Diagnosis
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  • DCM with biventricular failure, presumptively caused by HIV infection

  • Anemia, likely secondary to HIV, contributing to symptoms of fatigue and dyspnea

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Treatment and Clinical Course
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The patient's dyspnea and lower extremity edema responded well to treatment of his congestive heart failure and anemia. He received an intravenous (IV) loop diuretic (furosemide, 60 mg twice a day) for 4 days with a total diuresis of >7 liters. He was transitioned to an oral diuretic (furosemide, 40 mg daily) and was started on an angiotensin-converting enzyme (ACE) inhibitor (captopril, 6.25 mg orally twice a day). The patient received a transfusion of 2 units of packed red blood cells. Thrush was treated with oral clotrimazole lozenges 2-3 times a day. He was started on a daily multivitamin and trimethoprim-sulfamethoxazole prophylaxis at the time of discharge, with follow-up in the hospital's cardiology clinic and the Infectious Disease Institute for consideration for antiretroviral (ARV) therapy.

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Learning Points
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  • The incidence of heart failure in patients with HIV is quite high. Patients with HIV who develop heart failure have a high mortality rate.

  • The contribution of HIV to the pathogenesis of cardiomyopathy is unclear. Myocarditis in the setting of HIV infection is one of the leading theories for the development of DCM in HIV-infected patients.

  • Therapy for DCM in the setting of HIV involves medications that are used routinely in DCM secondary to other causes. IV immunoglobulin shows some promise in preliminary studies for the treatment of HIV-associated cardiomyopathy.

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Discussion
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DCM is defined by cardiac dilatation, impaired contractility of the left ventricle, a left ventricular ejection fraction of <40%, and a fractional shortening measurement of <25%.(5) DCM, hypertension, and rheumatic heart disease represent the most common causes of heart failure in Africa.(7) In the United States, coronary artery disease accounts for 50-75% of DCM in which an etiology is found. The most common causes of DCM in Africa (see Table 1) are often ill defined; however, it is clear that atherosclerotic disease plays a lesser role in the development of DCM in the developing world.(4) In one Ugandan case series chronicling patients referred to the echocardiography department at Mulago Hospital, endomyocardial fibrosis accounted for nearly 20% of the cases.(8)

The occurrence of symptomatic heart failure in HIV-infected patients is quite high, with the 2- to 5-year incidence ranging from 4% to 28%.(9) The prevalence of HIV-associated cardiomyopathy is estimated to be between 10-30% in echocardiographic and autopsy studies.(10,11,12,13) Interestingly, symptomatic DCM was strongly associated with a CD4 count of <100 cells/µL.(9,14)

Although the pathogenesis of DCM in HIV is unclear, several hypotheses have been proposed. Secondary left-ventricle dysfunction may result from viral myocarditis, caused by HIV itself or by coinfection with other viral opportunists such as Coxsackievirus (17%), cytomegalovirus (6%), and Epstein-Barr virus (3%).(10,11,15) In Nigeria, Toxoplasma gondii also has been implicated in the development of HIV-associated DCM.(16) HIV can infect cardiac interstitial cells, but not cardiac myocytes, and an increased number of infected interstitial cells are seen in patients with myocarditis. It is thought that increased tumor necrosis factor-alpha and interleukin in patients with HIV-associated myocarditis can lead to myocyte necrosis and damage. In one study, HIV-infected patients with DCM had a much higher incidence of myocarditis than HIV-uninfected patients with DCM.(17)

HIV-associated cardiomyopathy may have an autoimmune basis: cardiac-specific autoantibodies (anti-alpha myosin autoantibodies) are found in up to 15% of HIV-infected patients with cardiomyopathy compared with 3.5% in HIV-uninfected patients with cardiomyopathy.(18) In addition, HIV leads to upregulation of cytokines, including tumor necrosis factor-alpha and interleukin-6, and nitric oxide, which have shown to be damaging to the myocardium.(17,19,20) HIV-associated intestinal malabsorption of vitamin B12 and trace elements such as selenium, as well as electrolyte imbalances, also can contribute to cardiomyopathy.(21) Finally, ARVs such as zidovudine and chemotherapeutics such as doxorubicin (eg, for treatment of Kaposi sarcoma) have been associated with the development of DCM.(22,23)

The treatment of DCM in the setting of HIV includes standard heart failure therapy, such as diuretics, digoxin, beta-blockers, aldosterone antagonists, and ACE inhibitors.(24) Unfortunately, no randomized controlled trials of these medications have been conducted specifically among HIV-infected patients. The only treatment modality to have been studied in HIV-associated DCM is IV immunoglobulin, which previously had shown some benefit for HIV-negative patients presenting with myocarditis.(25) Researchers studying HIV-infected children have found increases in left ventricular wall thickness and reductions in wall stress after the administration of IV immunoglobulin. Therapy with immunoglobulin may be effective by removing cardiac autoantibodies or dampening the effects of cytokines and growth factors. Although there are no prospective trials showing that ARVs improve HIV-associated cardiomyopathy, retrospective analyses do suggest that prevention of opportunistic infections and maintenance of immunocompetence decrease the overall incidence of cardiomyopathy.(26,27,28)

Currently, standard evaluation and treatment of HIV-associated cardiomyopathy includes left and right heart catheterization with or without biopsy to identify infectious causes of failure. Nutritional status should be evaluated and deficiencies should be addressed when found. In resource-poor settings, where evaluation may be difficult, it is reasonable to supplement patients' diets with carnitine, selenium, and multivitamins.(29,30)

The development of DCM in HIV-infected patients portends a poor outcome, with one study documenting a median survival of 101 days among patients with AIDS and DCM vs 472 days among patients at a similar stage of AIDS without DCM.(9) This increased mortality appears independent of CD4 count, age, sex, and risk group.(9) In another study, patients with HIV-associated DCM had an average survival of 10.8 months compared with 15.6 months among patients with idiopathic cardiomyopathy (95% confidence interval: 1.53-8.07).(20)

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References

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1.   Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994 Mar;96(3):200-9.?
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2.   Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in Africa. Circulation. 2005 Dec 6;112(23):3602-7. Review.
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3.   Shiratori Y, Yoshida H, Omata M. Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther. 2001 Aug;1(2):277-90. Review.
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4.   Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation. 2005 Dec 6;112(23):3577-83. Review.
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5.   Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J. 1980 Dec;44(6):672-3.
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6.   Cardiomyopathy and AIDS. N Engl J Med. 1987 Apr 30;316(18):1158-60.
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7.   Akinkugbe OO, Nicholson GD, Cruickshank JK. Heart disease in blacks of Africa and the Caribbean. Cardiovasc Clin. 1991;21(3):377-91. Review.
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8.   Freers J, Mayanja-Kizza H, Ziegler JL, et al. Echocardiographic diagnosis of heart disease in Uganda. Trop Doct. 1996 Jul;26(3):125-8.
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9.   Currie PF, Jacob AJ, Foreman AR, et al. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994 Dec 17;309(6969):1605-7.
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10.   Restrepo CS, Diethelm L, Lemos JA, et al. Cardiovascular complications of human immunodeficiency virus infection. Radiographics. 2006 Jan-Feb;26(1):213-31. Review.
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11.   Barbaro G, Di Lorenzo G, Grisorio B, et al. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med. 1998 Oct 15;339(16):1093-9.
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12.   Himelman RB, Chung WS, Chernoff DN, et al. Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study. J Am Coll Cardiol. 1989 Apr;13(5):1030-6.
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13.   Levy WS, Simon GL, Rios JC, et al. Prevalence of cardiac abnormalities in human immunodeficiency virus infection. Am J Cardiol. 1989 Jan 1;63(1):86-9.
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14.   Jacob AJ, Sutherland GR, Bird AG, et al. Myocardial dysfunction in patients infected with HIV: prevalence and risk factors. Br Heart J. 1992 Dec;68(6):549-53.
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15.   Harmon WG, Dadlani GH, Fisher SD, et al. Myocardial and Pericardial Disease in HIV. Curr Treat Options Cardiovasc Med. 2002 Dec;4(6):497-509.
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16.   Falase AO. Infections and dilated cardiomyopathy in Nigeria. Heart Vessels Suppl. 1985;1:40-4.
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17.   Fisher SD, Bowles NE, Towbin JA, et al. Mediators in HIV-associated cardiovascular disease: a focus on cytokines and genes. AIDS. 2003 Apr;17 Suppl 1:S29-35. Review.
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18.   Currie PF, Goldman JH, Caforio AL, et al. Cardiac autoimmunity in HIV related heart muscle disease. Heart. 1998 Jun;79(6):599-604.
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19.   Tinkle BT, Ngo L, Luciw PA, et al. Human immunodeficiency virus-associated vasculopathy in transgenic mice. J Virol. 1997 Jun;71(6):4809-14.
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20.   Barbaro G, Di Lorenzo G, Soldini M, et al. Intensity of myocardial expression of inducible nitric oxide synthase influences the clinical course of human immunodeficiency virus-associated cardiomyopathy. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS (GISCA). Circulation. 1999 Aug 31;100(9):933-9.
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21.   Miller TL, Orav EJ, Colan SD, et al. Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus. Am J Clin Nutr. 1997 Sep;66(3):660-4.
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22.   Barbaro G, Lipshultz SE. Pathogenesis of HIV-associated cardiomyopathy. Ann N Y Acad Sci. 2001 Nov;946:57-81. Review.
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23.   Rerkpattanapipat P, Wongpraparut N, Jacobs LE, et al. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med. 2000 Mar 13;160(5):602-8. Review.
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24.  Bristow MR, Linas S, Port JD. Drugs in the Treatment of Heart Failure. In: Bonow R, Braunwald, E., Libby, P, et al, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine; 7th ed. Philadelphia: W.B. Saunders; 2005:1719-29.
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25.   McNamara DM, Rosenblum WD, Janosko KM, et al. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation. 1997 Jun 3;95(11):2476-8.
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26.   Pugliese A, Isnardi D, Saini A, et al. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000 May;40(3):282-4.
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27.   Barbaro G, Fisher SD, Lipshultz SE. Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis. 2001 Sep;1(2):115-24. Review.
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28.   Lipshultz SE. Dilated cardiomyopathy in HIV-infected patients. N Engl J Med. 1998 Oct 15;339(16):1153-5.
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29.   Dworkin BM, Antonecchia PP, Smith F, et al. Reduced cardiac selenium content in the acquired immunodeficiency syndrome. J Parenter Enteral Nutr. 1989 Nov-Dec;13(6):644-7.
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30.   Kavanaugh-McHugh AL, Ruff A, Perlman E, et al. Selenium deficiency and cardiomyopathy in acquired immunodeficiency syndrome. Parenter Enteral Nutr.
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