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clinical problem-solving

When Past Is Prologue

Nihar R. Desai, M.D., M.P.H., Susan Cheng, M.D., Anju Nohria, M.D., Florencia Halperin, M.D., and Robert P. Giugliano, M.D., S.M.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows.
From the Department of Medicine (N.R.D.) and the Divisions of Cardiovascular Medicine (S.C., A.N., R.P.G.) and Endocrinology (F.H.), Department of Medicine all at Brigham and Womens Hospital, Boston. Address reprint requests to Dr. Giugliano at the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Womens Hospital, 350 Longwood Ave., 1st Fl. Offices, Boston, MA 02115, or at rgiugliano@partners.org. N Engl J Med 2009;360:1016-22.
Copyright 2009 Massachusetts Medical Society.

A 36-year-old man presented to the emergency department with a 2-week history of lower-extremity edema, progressive fatigue, and exertional dyspnea. Edema reflects a disruption of interstitial-fluid homeostasis and typically indicates a cardiac, renal, hepatic, venous, or lymphatic pathology. Particularly important features on examination would include an estimation of central venous pressure, the presence or absence of pulmonary edema, the location of the edema, and whether the edema is pitting or nonpitting. Fatigue and dyspnea on exertion are nonspecific but may be a consequence of pulmonary edema and raise concern for a cardiac cause. The patients medical history was notable for a fall from a roof 10 months before this presentation. He had traumatic head injury with multiple cranial fractures, including a basal skull fracture, and underwent bifrontal craniotomies. After an extensive rehabilitation period, he achieved almost full functional recovery. Eight months before this presentation, dyslipidemia was diagnosed; the level of total cholesterol was 383 mg per deciliter (9.9 mmol per liter), of low-density lipoprotein 236 mg per deciliter (6.1 mmol per liter), of triglycerides 461 mg per deciliter (5.2 mmol per liter), and of high-density lipoprotein 56 mg per deciliter (1.4 mmol per liter). Metabolic screening tests revealed normal levels of glucose and albumin and normal hepatic and renal function. Atorvastatin was started but then discontinued because of myalgias and elevated levels of creatine kinase (794 U per liter) and aspartate aminotransferase (40 U per liter; normal range, 9 to 30); the alanine aminotransferase level was normal. One month later, his symptoms had improved, but the creatine kinase level had risen to 1200 U per liter. The thyrotropin level was 0.32 mIU per liter (normal range, 0.30 to 5.00), and an antinuclear antibody (ANA) test was negative. The onset of exertional dyspnea, fatigue, and edema led to his presentation at the emergency department before a scheduled rheumatology consultation. He was taking ferrous sulfate, which had been prescribed for anemia at the time of hospital discharge, and a stool softener that was prescribed in association with the iron. He reported that his parents and siblings were in good health, and he reported no use of tobacco, alcohol, or illicit drugs. His marked hyperlipidemia raises concern for a familial or secondary dyslipidemia, as can occur with hypothyroidism, the nephrotic syndrome, or certain medications (e.g., thiazide diuretics, atypical antipsychotic agents, and in women, oral contraceptives containing estrogen), but his laboratory evaluation and history were unrevealing. The new onset of myalgias and documentation of an elevated creatine kinase level while the patient was taking atorvastatin pointed initially to a statin-related myopathy, but the further elevation in the creatine kinase level after the statin was discon-

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tinued suggests an alternative cause. The current presentation, suggestive of heart failure, requires consideration of conditions that can lead to both cardiac and skeletal myopathy. On examination, the patient appeared chronically ill and in mild respiratory distress. The temperature was 36C, the blood pressure 80/60 mm Hg, the heart rate 80 beats per minute, and the respiratory rate 22 breaths per minute. The oxygen saturation was 91% while the patient was breathing ambient air. The jugular venous pressure was 14 cm of water. Rales were noted halfway up the lung fields bilaterally, with dullness to percussion at the bases. The apical impulse was nonpalpable. The heart sounds were distant, accompanied by a soft S3 gallop but no murmurs or rubs. There was no abdominal organomegaly or evidence of ascites. The arms and legs were cool, with 1+ peripheral pulses and 3+ pitting edema in the legs to the level of the knee bilaterally. The neurologic examination was remarkable only for mild weakness of the left arm and leg, which was chronic. The rales, S3 gallop, and elevated jugular venous pressure indicate severe left ventricular dysfunction with volume overload. The constellation of hypotension, narrow pulse pressure, and cool extremities is consistent with what has been described as the cold and wet classification of acute heart failure, which is a type of cardiogenic shock. Car-

diogenic shock may be caused by an acute fulminant process or decompensation of a subacute or chronic cardiomyopathy. Elements of the presentation, including a minimal oxygen requirement and profound edema, suggest a subacute or chronic cardiomyopathy. Despite the absence of a pericardial knock, this constellation of findings could also be consistent with constrictive pericardial disease. The first priority is to stabilize the patient. The white-cell count was 6800 per cubic millimeter with a normal differential count, the hemoglobin level 13.0 g per deciliter, and the platelet count 150,000 per cubic millimeter. The serum sodium level was 129 mmol per liter, the potassium level 3.4 mmol per liter (13.3 mg per deciliter), the blood urea nitrogen level 10 mg per deciliter (3.6 mmol per liter), the creatinine level 1.6 mg per deciliter (141 mol per liter) (elevated from a previous baseline value of 0.8 to 1.2 mg per deciliter [71 to 106 mol per liter]), the aspartate aminotransferase level 109 U per liter, and the alanine aminotransferase level 61 U per liter (normal range, 7 to 52). The creatine kinase level was 1110 U per liter with a creatine kinase MB value of 12 ng per milliliter; troponin I was undetectable. The erythrocyte sedimentation rate was 8 mm per hour. The initial 12lead electrocardiogram (ECG) showed sinus rhythm, low voltage in the limb leads, a prolonged QT interval, poor R-wave progression across the precordial leads, and diffuse T-wave flattening (Fig. 1). The

Figure 1. Initial 12-Lead Electrocardiogram. The initial 12-lead electrocardiogram was notable for low voltage in the limb leads, a prolonged QT interval, poor R-wave progression across the precordial leads, and diffuse T-wave flattening.
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2nd 1 FIGURE 3rd CASE TITLE Revised n engl j med 360;10 nejm.org march 5, 2009 EMail Line 4-C SIZE Enon ARTIST: mst H/T H/T FILL 33p9 Combo Downloaded from www.nejm.org by JOAN LLEVADOT MD on March 9, 2009 . Copyright 2009 Massachusetts Medical AUTHOR, PLEASE NOTE: Society. All rights reserved. Figure has been redrawn and type has been reset. Please check carefully.

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Figure 2. Chest Radiograph. The presenting chest radiograph was notable for cardiomegaly with a globular cardiopericardial silhouette, pulmonary edema, and bilateral pleural effusions. RETAKE 1st AUTHOR Giugliano ICM
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Line 4-C chest radiograph revealed cardiomegaly with SIZE pulEnon ARTIST: mst H/T H/T monary effusions FILL edema and bilateral Combo pleural 16p6 (Fig. 2). An echocardiogram revealed a moderate AUTHOR, PLEASE NOTE: Figure effusion, has been redrawn and type has abnormalities, been reset. pericardial no valvular Please check carefully. and a globally hypokinetic, dilated left ventricle with JOB: an ejection 15% (Fig. 36010 fraction of 10 to 3-5-09 3). ISSUE:

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The presence of hyponatremia and pleural effusions further suggests that the patients cardiomyopathy reflects a subacute process rather than an acute fulminant process. This distinction is helpful, since an acute fulminant process may require placement of a ventricular assist device and prompt evaluation for possible cardiac transplantation, whereas a subacute process is more likely to respond to aggressive medical therapy. The low voltages on ECG in combination with a delayed transition point across the precordial leads suggest a dilated cardiomyopathy with apical displacement, as confirmed by the echocardiogram. The broad differential diagnosis for a dilated cardiomyopathy includes ischemic heart disease; toxic, metabolic, and endocrine causes; infectious and inflammatory processes; familial and genetic causes; and tachycardia-induced cardiomyopathy. The patients elevated creatine kinase level and normal creatine kinase MB and troponin levels (as well as a disproportionate rise in aspartate aminotransferase as compared with alanine aminotransferase) are features that continue to suggest a skeletal myopathy. Aggressive treatment with inotropes, diuretics,

Figure 3. Initial Transthoracic Echocardiogram. The initial transthoracic echocardiogram revealed biventricular enlargement, severely depressed systolic RETAKE 1st Giugliano AUTHOR ICM with function an estimated ejection fraction of 15%, 2nd REG F FIGURE 3 a&b effusion. The apical fourand a moderate pericardial 3rd CASE TITLE chamber views are shown in diastole (Panel A) and Revised EMail Line 4-C systole (Panel B), with left ventricular end-diastolic and SIZE Enon ARTIST: mst measuring H/T H/T end-systolic diameters 59 mm and 46 mm, FILL Combo 16p6 respectively. LA denotes left atrium, LV left ventricle, AUTHOR, PLEASE PE pericardial effusion, RA right NOTE: atrium, and RV right Figure has been redrawn and type has been reset. ventricle. Please check carefully.
JOB: 36010 ISSUE: 3-5-09

and vasodilators is warranted. I would favor performing cardiac catheterization, during which the hemodynamic profile can be further characterized and mechanical ventricular support may be initiated. Despite the absence of regional wallmotion abnormalities on the echocardiogram, it is not unreasonable to perform coronary angiography. Endomyocardial biopsy can be helpful in a newly diagnosed cardiomyopathy, particularly if we suspect a fulminant process or a cause that might require specific therapy (e.g., immunosuppression). The patient underwent cardiac catheterization. Angiography revealed normal epicardial coronary arteries. Right heart catheterization revealed a

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right atrial pressure of 15 mm Hg, a right ventricular pressure of 43/14 mm Hg, a pulmonary-artery pressure of 40/28 mm Hg, a mean wedge pressure of 32 mm Hg, and a cardiac index of 1.8 liters per minute per square meter of body-surface area. An intraaortic balloon pump was placed and dobutamine and dopamine were started for inotropic support. The patient had several episodes of polymorphic and monomorphic ventricular tachycardia that required multiple cardioversions. The right heart catheterization reveals elevated filling pressures and compromised forward flow, consistent with the examination findings of leftsided heart failure and cardiogenic shock. Reduction of afterload and augmentation of cardiac output can be achieved with placement of an intraaortic balloon pump and inotropic support. Ventricular ectopy and tachyarrhythmias are common in this context and often respond to amiodarone or lidocaine. As the patient is being medically stabilized, ongoing investigations of the underlying disease process should continue to focus on possible causes of both his clinically evident cardiomyopathy and a skeletal myopathy, given his elevated creatine kinase level. This differential diagnosis includes inflammatory myopathies, drug-induced myopathies, infectious myopathies (including those caused by human immunodeficiency virus [HIV], coxsackievirus, cytomegalovirus, echovirus, and Lyme disease), and metabolic myopathies (particularly disorders of fatty acid metabolism), as well as muscular dystrophies and endocrinopathies. The age at onset lessens the likelihood of dystrophies, and there is no reported history of alcohol or illicit-drug use. Since inflammatory and infectious myopathies and endocrinopathies remain in the differential diagnosis, I would repeat an ANA test and thyroid-function studies and also order viral studies, serum and urine protein electrophoresis to assess for AL amyloidosis, and iron studies, although hemochromatosis is not likely given the unremarkable family history. Serologic tests for HIV; Lyme disease; hepatitis A, B, and C viruses; EpsteinBarr virus; cytomegalovirus; and coxsackievirus were all negative. Serum protein electrophoresis with immunofixation was normal, as were iron studies. An ANA test was

negative. Electromyography and nerve-conduction studies were unremarkable. The result of a repeat thyrotropin test was low at 0.21 mIU per liter; the serum free thyroxine level was low at 0.3 ng per deciliter (3.9 pmol per liter) (normal range, 0.8 to 1.8 ng per deciliter [10.3 to 23.2 pmol per liter]), and the serum total triiodothyronine was undetectable (normal range, 70 to 170 ng per deciliter [1 to 3 nmol per liter]). The laboratory evaluation is most remarkable for the low thyrotropin level accompanied by low free thyroxine and triiodothyronine levels. These findings raise concern for central hypothyroidism, which can occur from destruction of the pituitary or hypothalamus by tumor, infiltrative disease, infarction, or trauma. However, transient depression of the hypothalamicpituitarythyroid axis in nonthyroidal illness (formerly called euthyroid sick syndrome) is characterized by a similar laboratory profile. Distinguishing between these diagnostic possibilities may be difficult in acutely ill patients. However, the patients history of traumatic brain injury (a recognized cause of hypothalamicpituitary dysfunction) increases my suspicion for central hypothyroidism, a diagnosis that could explain many features of his clinical presentation. The next step in the evaluation should include further assessment of hypothalamicpituitary function with tests of the adrenal, gonadotrophic, and somatotrophic axes. Because the patient continued to require inotropic and mechanical support, further endocrinologic evaluation was undertaken. An evening serum cortisol level was 3.6 g per deciliter (99 nmol per liter) and increased to 9.5 g per deciliter (262 nmol per liter) 60 minutes after the administration of 250 g of cosyntropin. A morning corticotropin level was below 2 pg per milliliter (0.4 pmol per liter) (normal range, 7 to 69 pg per milliliter [1.5 to 15.2 pmol per liter]). The level of follicle-stimulating hormone (FSH) was 0.9 mIU per milliliter (normal range, 3.1 to 12.2), luteinizing hormone 0.5 mU per milliliter (normal range, 1.7 to 8.6), testosterone undetectable (normal range, 1800 to 6650 pg per milliliter [6 to 23 nmol per liter]), prolactin 0.9 ng per milliliter (normal range, 2.6 to 13.1), and insulin-like growth factor I (IGF-I) below 25 ng per milliliter (normal range, 88 to 474). Magnetic resonance imaging of the brain revealed

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The patients hemodynamic status stabilized once thyroid, glucocorticoid, and androgen therapy was initiated. Growth hormone supplementation was reasonably withheld while the patient was acutely ill in the hospital but was initiated once growth hormone deficiency was confirmed in the outpatient setting. The continued presence of malignant ventricular arrhythmias necessitating the placement of an implantable cardioverterdefibrillator before hospital discharge was not unexpected, since normalization of left ventricular function in such cases may take several months. The patient The low baseline corticotropin level, together with should continue to have close follow-up including the inadequate cortisol response to exogenous both laboratory testing and echocardiographic corticotropin, is consistent with secondary adre- evaluation to monitor his response to therapy. nal insufficiency. Although FSH, luteinizing hormone, testosterone, and IGF-I levels can be de- Within 9 months after discharge, the patients pressed in patients with critical illness (just as the symptoms of heart failure had completely resolved results of thyroid tests can be depressed), the his- and he had normal creatine kinase, cholesterol, tory of sexual dysfunction and loss of pubic hair free thyroxine, and testosterone levels. His echocarin the context of previous head trauma and other diogram showed a left ventricular ejection fraction pituitary deficiencies is strongly suggestive of ac- of 52% with normal ventricular cavity dimensions. quired hypogonadotrophic hypogonadism. Taken Serial Holter monitoring showed no further ventogether, the clinical presentation and laboratory tricular arrhythmias. At 20 months after disdata are consistent with panhypopituitarism in- charge, his ejection fraction had further improved to 64% (Fig. 4). He remains asymptomatic and duced by traumatic brain injury. clinically well on a multiple-hormonereplaceThe patient was started on hydrocortisone (100 mg ment regimen. intravenously every 8 hours) and levothyroxine (100 g daily), initially intravenously to avoid possible impaired oral absorption in the context of C om men ta r y mucosal edema; his regimen was changed to prednisone (5 mg orally daily) and levothyroxine (125 g Our patient presented with cardiogenic shock in orally daily; equivalent to 1.7 g per kilogram of the context of a dilated cardiomyopathy and a hisbody weight) once he appeared euvolemic. Treat- tory of an elevated creatine kinase level suggesment with testosterone (7.5 g daily of a topical tes- tive of a peripheral skeletal myopathy. On reviewtosterone gel) was also initiated. Growth hormone ing possible common causes of both cardiac and was not initially administered because of his clini- peripheral myopathies,1 the unifying diagnosis cal improvement. Over the course of 2 weeks, he was determined to be multiple hormonal deficienwas successfully weaned from the intraaortic bal- cies arising from panhypopituitarism caused by a loon pump and inotropic supports. Because of re- basal skull fracture, which highlights the imporcurrent episodes of nonsustained ventricular ar- tance of the patients history with respect to the rhythmias despite treatment with amiodarone current presentation. Although panhypopituitarism is a rare conseand ongoing hormone supplementation, an implantable cardioverterdefibrillator was placed. quence of traumatic brain injury,2 the developAfter his discharge, the patient was followed clini- ment of at least one neuroendocrine disorder after cally and with serial echocardiography. Supple- an injury serious enough to cause temporary or mentation with growth hormone was begun once permanent neurologic dysfunction is reported in the deficiency was confirmed by means of provoc- approximately 25% of cases.3 Therefore, routine ative testing with arginine plus growth hormone screening for disorders of the hypothalamicpituitary axis is recommended initially and then 3 to releasing hormone. postsurgical findings consistent with the patients previous partial bifrontal craniotomies and a partially empty sella. On further questioning, he reported decreased sexual drive, impotence, and loss of pubic hair during the preceding 3 months. In addition, serial physical examinations during the initial course of diuresis revealed the presence of nonpitting edema, made more apparent after improvement of superimposed pitting edema. He was also noted to have coarse, dry skin and hair loss involving the lateral eyebrows and the legs.

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Figure 4. Follow-up Transthoracic Echocardiogram. A follow-up transthoracic echocardiogram revealed markedly improved systolic function with an estimated RETAKE 1st Giugliano AUTHOR ICM fraction ejection of 64%. The apical four-chamber REGare F shown 4 a&b (Panel A) and systole 2nd FIGUREin diastole views 3rd CASEB), TITLE (Panel with left ventricular end-diastolicRevised and endEMail Line 4-C systolic diameters measuring 46 mm and 27 mm, reSIZE Enon ARTIST: mst left atrium, H/T H/T spectively. LA denotes LV left ventricle, RA FILL Combo 16p6 right atrium, and RV right ventricle.

6 months after the injury, particularly for persons with JOB: higher-risk 36010 features, including 3-5-09 age or ISSUE: older basal skull fracture.3 Because the thyrotropin level may be in the normal range in patients with central hypothyroidism, a serum thyroxine level must be measured when screening for this condition. Although panhypopituitarism is uncommon, severe cardiomyopathy as a clinical consequence is even rarer. Nevertheless, because of the potential for reversibility, deficiency of thyroid4,5 or adrenal6 hormone, or both, should always be considered in a patient with an unexplained cardiomyopathy. Marked deficiencies of gonadal7 and growth8 hormones may also adversely affect cardiovascular function and contribute to heart failure. Thyroid hormone has widespread effects on cardiovascular function9: triiodothyronine, the

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active form of thyroid hormone, enters cardiomyocyte nuclei and modulates calcium flux, betaadrenergicreceptor function, and the transcription of various contractile proteins. Accordingly, hypothyroidism is associated with depressed chronotropy, decreased cardiac output, and increased systemic vascular resistance.10 In addition, severe hypothyroidism is associated with ventricular dysrhythmias, including torsades de pointes.11 As with our patient, thyroid hormone supplementation in hypothyroid-associated cardiomyopathy typically results in recovery of myocardial function.4,5 In this case, hypothyroidism was also associated with dyslipidemia and peripheral myopathy that likewise resolved with thyroid hormonereplacement therapy. Patients with secondary adrenal insufficiency usually present with fatigue and orthostatic hypotension, rather than frank cardiovascular collapse. However, glucocorticoids have been shown to augment cardiac myocyte contraction and relaxation, increase calcium ATPase activity, and stimulate calciumcalmodulindependent protein kinase II in cardiac sarcoplasmic reticulum.12 Moreover, adrenal insufficiency has been reported, in rare cases, to cause a reversible dilated cardiomyopathy.6 Physiologic growth hormone levels are also required to maintain normal cardiac function and structure, primarily through the effects of IGF-I.8 Patients with growth hormone deficiency tend to have at least subtle abnormalities in left ventricular mass and function8; replacement therapy in such patients is associated with increased left ventricular mass, stroke volume, and contractility in addition to improved endothelial function and diminished systemic vascular resistance. Although growth hormone deficiency rarely leads to severe cardiomyopathy, replacement therapy typically leads to rapid clinical improvement.13 Testosterone deficiency is common among patients with long-standing heart failure14; in such patients, androgen levels are inversely related to the severity of heart failure and to mortality.14,15 Furthermore, testosterone replacement in patients who have at least moderately severe left ventricular dysfunction is associated with improved functional capacity,7 perhaps accounted for by the antiinflammatory or vasodilatory effects of testosterone. Fortunately, as this case illustrates, appropri-

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ate treatment of even a severe cardiomyopathy due to the deficiency of one or more hormones carries a good prognosis.4,5 The overall outcome, therefore, relies largely on making the correct diagnosis, often by appreciating that what is past is prologue.
References
1. Abelmann WH. Cardiomyopathies,

Dr. Giugliano reports receiving grant support from ScheringPlough and Merck, and consulting and lecture fees from Pfizer, Merck, and Schering-Plough. No other potential conflict of interest relevant to this article was reported. We thank Dr. Brian Won-Sik Kim for his assistance with the preparation and review of the manuscript.

myocarditis and pericardial disease. In: Abelmann WH, ed. Atlas of heart diseases. Philadelphia: Current Medicine, 1995:1. 2. Bondanelli M, Ambrosio MR, Zatelli MC, De Marinis L, degli Uberti EC. Hypopituitarism after traumatic brain injury. Eur J Endocrinol 2005;152:679-91. 3. Behan LA, Phillips J, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury. J Neurol Neurosurg Psychiatry 2008;79:753-9. 4. Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A 1992;89:5251-5. [Erratum, Proc Natl Acad Sci U S A 1992;89:8856.] 5. MacKerrow SD, Osborn LA, Levy H, Eaton RP, Economou P. Myxedema-associated cardiogenic shock treated with intravenous triiodothyronine. Ann Intern Med 1992;117:1014-5. 6. Eto K, Koga T, Sakamoto A, Kawazoe

N, Sadoshima S, Onoyama K. Adult reversible cardiomyopathy with pituitary adrenal insufficiency caused by empty sella a case report. Angiology 2000; 51:319-23. 7. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006; 27:57-64. 8. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation 2003;108:2648-52. 9. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501-9. 10. Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116:1725-35. [Erratum, Circulation 2008;117(3):e18.] 11. Schenck JB, Rizvi AA, Lin T. Severe primary hypothyroidism manifesting with torsades de pointes. Am J Med Sci 2006; 331:154-6.

12. Rao MK, Xu A, Narayanan N. Gluco-

corticoid modulation of protein phosphorylation and sarcoplasmic reticulum function in rat myocardium. Am J Physiol Heart Circ Physiol 2001;281:H325-H333. 13. Meyers DE, Maddicks-Law J, Seaton DM, Galbraith AJ, Cuneo RC. The role of growth hormone replacement in a growth hormone deficient patient with underlying cardiomyopathy and severe congestive heart failure. J Heart Lung Transplant 2005;24:110-4. 14. Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 2006;114: 1829-37. 15. Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997;96:526-34.
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