Congestive Heart Failure Endomyocardial biopsy plays a role in diagnosing patients with unexplained cardiomyopathy Hossein Ardehali, MD, PhD,a Atif Qasim, MD,b Thomas Cappola, MD,f David Howard,c Ralph Hruban, MD,d Joshua M. Hare, MD,a Kenneth L. Baughman, MD, FACC,a,e and Edward K. Kasper, MD, FACCa Baltimore, Md, Boston, Mass, and Philadelphia, Pa Background The etiology of cardiomyopathy is usually inferred from clinical information and preliminary labora- tory studies. Patients with unexplained cardiomyopathy may be referred for endomyocardial biopsy (EMBx). It is unknown whether pathological information obtained from EMBx is beneficial or alters the diagnosis established clinically. This study was undertaken to evaluate the utility of EMBx in confirming or excluding a clinically suspected diagnosis. Methods We evaluated 845 patients with initially unexplained cardiomyopathy who underwent EMBx between 1982 and 1997 at The Johns Hopkins Hospital. For each patient, an initial clinical diagnosis, an EMBx diagnosis, and a final diagnosis prior to discharge based on all available data were established. Results The final diagnosis differed from the initial clinical diagnosis in 264 (31%) of these patients; EMBx made the diagnosis in 196 (75%) of these cases. Initial diagnoses most frequently altered were myocarditis (34%) and idiopathic cardiomyopathy (25%). Initial diagnoses least likely to be altered were those in which biopsy was used to confirm or grade a previously documented illness, such as hemochromatosis (11%), amyloidosis (18%), or cardiomyopathy second- ary to doxorubicin toxicity (0%). EMBx was more sensitive than clinical diagnosis in detecting myocarditis and amyloi- dosis, and proved to be very specific in detecting ischemic cardiomyopathy, myocarditis, amyloidosis, and hemochroma- tosis. Conclusions In patients with unexplained cardiomyopathy after a standard evaluation, the clinical assessment of the etiology is inaccurate in 31% of patients. EMBx establishes the final diagnosis in 75% of these patients with a high degree of specificity. (Am Heart J 2004;147:919–23.) and mortality,1 and accounts for a large proportion of See related Editorial on page 759. health care expenditures in developed countries.2 Cardiomyopathy is a common disorder resulting In the developed world, the most common cause of from a variety of causes that lead to impaired cardiac cardiomyopathy is coronary artery disease; however, performance and often results in congestive heart fail- many other causes have been characterized. It is im- ure. Despite recent advances, congestive heart failure portant to identify the cause of cardiomyopathy in or- remains a major cause of morbidity, hospitalizations der to devise an appropriate treatment strategy. The current guidelines recommend that patients with car- diomyopathy undergo a 12-lead EKG, a chest radio- graph, blood chemistry including thyroid and liver From the aDivision of Cardiology, Department of Medicine, The Johns Hopkins Hospi- function test, urine analysis, and cardiac imaging, usu- tal, bJohns Hopkins University School of Medicine, cDepartment of Epidemiology, Johns ally a transthoracic echocardiography.3 Patients with d Hopkins Bloomberg School of Public Health, Department of Pathology, The Johns risk factors for atherosclerosis may be subjected to Hopkins Hospital, Baltimore, Md, eDivision of Cardiology, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass, and fDivision of Cardiovascular Medi- coronary angiography. These studies may help to con- cine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, firm the clinical diagnosis and evaluate selected causes Pa. for the cardiomyopathy. Submitted May 23, 2003; accepted September 9, 2003. Reprint requests: Hossein Ardehali, MD, PhD, Johns Hopkins University, 844 Ross Despite evaluation, there remains a group of patients Building, 720 Rutland Ave, Baltimore, MD 21205. in whom the cause of the cardiomyopathy cannot be E-mail: [email protected] explained. These patients may be referred to a tertiary 0002-8703/$ - see front matter 4 © 2004, Elsevier Inc. All rights reserved. care center for endomyocardial biopsy (EMBx). Al- doi:10.1016/j.ahj.2003.09.020 though this procedure has become a common diagnos- American Heart Journal 920 Ardehali et al May 2004 tic modality in patients with unexplained cardiomyopa- minimum of 5 samples from the right ventricular septum was thy in some centers, it is unknown to what extent the obtained from each patient at the time of biopsy. histologic information obtained from EMBx improves A cardiac pathologist examined all specimens at a mini- diagnostic accuracy. In fact, the recent American Col- mum of four section levels stained with hematoxylin and eo- lege of Cardiology/American Heart Association (ACC/ sin. The Dallas criteria were used to establish a diagnosis of myocarditis.7 In cases of suspected myocarditis, the inflam- AHA) guidelines indicate that EMBx should not be per- matory cells were often further characterized using immuno- formed in the routine evaluation of cardiomyopathy, histochemical labeling for CD3, CD4, CD8, and CD68. The and that it should be performed only when there is “a diagnosis of idiopathic cardiomyopathy was established in strong reason to believe that the results will have a cases with significant myocyte hypertrophy and nuclear en- meaningful effect on subsequent therapeutic deci- largement, and no other explanation for the patient’s heart sions.”3 However, the guidelines also indicate that the failure. To identify the presence of hemochromatosis and overall utility of EMBx in patients with unexplained amyloidosis, Prussian blue and Congo red stains were used, cardiomyopathy is unclear.3,5 respectively. Doxorubicin cardiac toxicity was established In the present study, we evaluated 845 patients who and graded using ultrastructural examination of glutaralde- underwent EMBx at The Johns Hopkins Hospital to hyde fixed samples. Ischemic cardiomyopathy was defined by the presence of focal replacement fibrosis in a patient with determine how often EMBx results changed the initial coronary artery disease. Replacement fibrosis is characterized clinical diagnosis. In addition, we assessed the sensitiv- by the presence of discrete foci of myocyte loss associated ity and specificity of EMBx compared with clinically with fibrosis and pigment-laden macrophages. established diagnoses as a means of evaluating their relative effectiveness as diagnostic tools. Diagnosis of the cause of cardiomyopathy All patients were given three diagnoses. The initial clinical Methods diagnosis was based on the clinical data at the time of refer- ral for biopsy, according to previously published defini- Selection of patients tions.6,8 A biopsy diagnosis was established according to the The study group consisted of 1230 patients who under- results of the EMBx. Final diagnosis was based on all available went EMBx for evaluation of unexplained cardiomyopathy at data (ie, clinical, laboratory, and EMBx data and “other inter- The Johns Hopkins Hospital between December 1982 and ventions”) prior to discharge. “Other interventions” refers to December 1997. Most of these patients were referred for bi- diagnostic means other than the ones already mentioned. For opsy after initial evaluation in a physician’soffice or in an- example, in the case of cardiomyopathy due to amyloidosis, other hospital. Therefore, some common causes of heart fail- the diagnosis of systemic amyloidosis may have been made ure that are more easily identifiable (ie, ischemic heart based on abdominal fat pad biopsy, rectal biopsy, or biopsy disease, hypertension, etc) are underrepresented in this pa- of the tongue. Patients were assigned to one of the following tient group. Since we currently do not have the longitudinal categories for our analysis: idiopathic cardiomyopathy, myo- follow-up of deaths of patients who underwent EMBx after carditis, cardiomyopathy due to ischemic heart disease, drug- December 1997, they were not included in this study. related, infiltrative myocardial disease (ie, hemochromatosis, Patients whose cardiomyopathy had an identified cause amyloidosis), connective tissue disease, or neoplastic heart were excluded from our analysis. These etiologies included disease. peripartum cardiomyopathy, infection with human immuno- deficiency virus, substance abuse, valvular disease, hyperten- sion, endocrine diseases (thyroid disease and pheochromocy- Statistical analysis toma), neuromuscular disease, and congenital and familial For each etiology of cardiomyopathy, the sensitivity and cardiomyopathy. The remaining 845 patients were included specificity of clinical diagnosis and EMBx were computed in our analysis. This is a retrospective review analysis. using final diagnosis as gold standard. The ␬ statistic was cal- A history and physical examination were performed on all culated for both clinical diagnosis and EMBx to evaluate the of the patients, and selected laboratory studies such as thy- overall agreement between each of these and the final diag- roid function tests and antinuclear antibodies were also ob- nosis. Analyses were performed using SAS statistical software tained. All the subjects also underwent right heart catheter- (version 8, SAS Institute, Cary, NC). ization for hemodynamic measurements at the time of EMBx as described previously.6 Those subjects at high risk for hav- ing coronary artery disease underwent coronary angiography. Results The clinical characteristics of this cohort of