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The discrepancies between clinical and histopathological diagnoses of cardiomyopathies in patients with stage D heart failure undergoing heart transplantation

Thana Lertsuttimetta, Monravee Tumkosit, Peerapat Kaveevorayan, Poonchavist Chantranuwatana, Nonthikorn Theerasuwipakorn, Pairoj Chattranukulchai, Sarinya Puwanant

Abstract

Background

This study aimed to determine the etiology of stage-D heart failure (HF) and the prevalence and prognosis of misdiagnosed cardiomyopathy in patients undergoing heart transplantation.

Introduction

Heart failure is a common clinical syndrome caused by various cardiovascular diseases [1–3]. Evaluation of heart failure etiology is crucial and should be correctly and rapidly identified. An accurate diagnosis provides an opportunity for specific treatment to be delivered that can potentially reverse heart failure and improve overall prognosis. In inherited cardiomyopathy, an accurate diagnosis also helps in prevention and screening all affected family members. Histopathological analysis of the explanted heart can reveal the definite diagnosis of the etiology of heart failure in patients undergoing heart transplantation. The linkages between histopathological examination, patient genotype-phenotype, clinical diagnosis, and findings of cardiac imaging and cardiac investigations is a pivotal pathway to better understand pathophysiology, nature of diseases, caveats in clinical diagnosis, and phenotypic manifestation of the etiologies of heart failure and cardiomyopathies. Previous studies have shown a discrepancy rate between clinical diagnosis and pathological diagnosis ranging between 7% to 23% of explanted heart examinations [4–11]. However, most of the studies were investigated in the years when the performance rate of cardiac magnetic resonance imaging (MRI) was low [4, 5, 9]. Most of these studies were also examined in non-Asian patient populations [4–8, 10]. This study aimed to determine: (1) the etiology of end-stage heart failure, (2) the prevalence of misdiagnosis of cardiomyopathy type and the discrepancy rate between pre-transplant /clinical diagnosis and post-transplant/ histopathological diagnosis, (3) the performance of pre-transplant cardiac investigations in patients with misdiagnoses of the etiology of heart failure, and (4) the post-transplant survival rate of patients with misdiagnosis.

Methods

Study population

The study protocol was approved by the Chulalongkorn University’s Institutional Review Board with a waiver of written informed consent (IRB 796/63). All methods were carried out in accordance with the tenets of the Declaration of Helsinki and the ethical standard guidelines and regulations. We retrospectively reviewed histopathological findings and pre-transplant clinical diagnoses of explanted hearts in consecutive patients with stage D heart failure undergoing heart transplantation in our tertiary center from February 1994 to September 2021. Stage D heart failure was defined as advanced heart failure with one of the following clinical features indicating high mortality: persistent NYHA class III-IV, elevated natriuretic peptide, inotrope dependence, frequent heart failure hospitalizations, end-organ dysfunction, frequent defibrillator shocks, high-dose diuretic requirement, hyponatremia, hypotension, cachexia, intolerance to guideline-directed medical therapy, or low peak oxygen consumption [12–15]. Patients with unavailable or incomplete histopathological specimens for analysis were excluded. Patient demographics and clinical, laboratory, and histopathological data were extracted from medical records. Echocardiography, coronary angiography, cardiac MRI, and nuclear scan were reviewed from the cardiovascular and radiology picture archiving and communication (PAC) system. Pre-transplant/clinical diagnosis was determined by the heart failure and transplant cardiologists using clinical, echocardiographic, cardiac MRI, coronary angiogram, and cardiac endomyocardial (EMB) information before heart transplantation.

Results

From February 1994 to September 2021, 146 patients underwent cardiac transplantation. Of these, 19 patients were excluded because their pathological specimens were not available for analysis. A total of 127 patients were included in the study (mean age, 42 years; 90 [71%], male). All these patients met the criteria of stage D heart failure. Table 1 illustrates baseline patient characteristics. Pre-transplant intravenous inotrope or cardiogenic shock (INTERMACS profile 1–3) were present in 29% of patients. Mechanical circulatory support devices were implanted in 7 patients (6%). The most common (76%) pre-transplant/clinical diagnosis was NISCM.

Discussion

The major findings of our study are: (1) misdiagnosis of the etiology of end-stage heart failure in patients undergoing heart transplantation in our study were found in 6% of patients, (2) the most common etiology of stage D or end-stage heart failure in patients undergoing heart transplantation is NISCM, (3) the misdiagnosis of cardiomyopathy mostly occurred with a clinical/ pre-transplant diagnosis of NISCM, (4) the most common reversible cardiomyopathy with pre-transplant misdiagnoses were cardiac sarcoidosis and hypersensitivity myocarditis, all of these patients did not undergo EMB pre-transplant or received corticosteroid or immunosuppressive agents, (5) pre-transplant EMBs with 8 sampling tissues were found to be negative for amyloid fibril by Congo-red staining and polarized examination in a patient with a clinical diagnosis of transthyretin cardiac amyloidosis, (6) 3% of patients (2 out of 58) with NISCM had additional concomitant significant coronary artery diseases not identified pretransplant, (7) the misdiagnosis rate was not different between patients who underwent both EMB and cardiac MRI and those who did not undergo both cardiac investigations, and (8) survival post-transplant between accurate diagnosis and misdiagnosis were similar. These findings represent the first reported data in Southeast Asian patient population.

Conclusions

Among patients with stage D heart failure undergoing heart transplantation, the most common etiology of heart failure is NISCM. A discrepancy between pre-transplant clinical diagnosis and histopathological diagnosis by explanted heart analysis occurred in 6% of our study patients. Cardiac sarcoidosis and hypersensitivity myocarditis were the most common misdiagnoses followed by noncompacted cardiomyopathy and ARVC/LDAC. Those patients with a pre-transplant misdiagnosis clinically presented as chronic worsening heart failure with typical echocardiographic feature of idiopathic dilated/nonischemic cardiomyopathy, dilated and generalized LV systolic dysfunction with a normal or reduced LV wall thickness, and no echocardiographic clue of specific cardiomyopathies. Our findings underscore that an accurate diagnosis of a newly diagnosed cardiomyopathy, especially non-ischemic type, give an opportunity for specific treatment that can potentially reverse of cardiomyopathy and heart failure. This strategy may minimize the need for advanced heart failure therapy or heart transplantation. With the advent of new techniques in modern echocardiography, cardiac MRI, nuclear cardiology, and coronary artery imaging, improvements in diagnostic accuracy of the etiology of heart failure should follow.

Acknowledgments

We thank the research team of the Department of Medicine, Faculty of Medicine, Chulalongkorn University, for editing the final manuscript. We also thank YongkasemVorasettakarnkij, MD, for his contribution in clinical images of cardiac MRI.

Citation: Lertsuttimetta T, Tumkosit M, Kaveevorayan P, Chantranuwatana P, Theerasuwipakorn N, Chattranukulchai P, et al. (2022) The discrepancies between clinical and histopathological diagnoses of cardiomyopathies in patients with stage D heart failure undergoing heart transplantation. PLoS ONE 17(6): e0269019. https://doi.org/10.1371/journal.pone.0269019

Editor: Joshua M. Hare, University of Miami School of Medicine, UNITED STATES

Received: November 17, 2021; Accepted: May 12, 2022; Published: June 1, 2022

Copyright: © 2022 Lertsuttimetta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data Availability Statement: All relevant data are within the paper and its Supporting information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0269019#abstract0

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