REVIEW ARTICLE

More than 50 Years after Konno’s Development of theEndomyocardial Biopsy
A Review from the Konno Memorial Laboratory and the Cardiac Biopsy Conference
Toshio Nishikawa,1,2 MD, Morie Sekiguchi,2,† MD and Hatsue Ishibashi-Ueda,3 MD
Summary
The endomyocardial biopsy (EMB) method was first developed by Japan’s Dr. Souji Konno in 1962. Since
then, this technique has been used worldwide in clinical cardiology for the recognition and diagnosis of cardiomyopathies, arrhythmias, and other heart conditions. Many studies relating to the EMB have been published at
the global level, including a large review by Cooper, et al.,1) wherein a limited selection of Japanese papers
were cited despite considerable pioneering work on the EMB having been done in Japan. Following this, theCardiac Biopsy Conference (CABIC) organization, which was founded in Japan in 1979, conducted a nationwide survey of the English language literature on the EMB. Among the collection of 500 studies compiled, approximately 40 abstracts have been selected by the co-editors in CABIC for further discussion. This report aims
to supplement Cooper’s work and bring to light other prominent contributions of Japanese researchers on the
EMB.
(Int Heart J 2017; 58: 840-846)
Key words: Cardiomyopathy, Histopathological diagnosis, Electric disturbance type cardiomyopathy, Japanesestudies

ifty years have passed since Dr. Souji Konno, ayoung cardiac surgeon, developed the catheter-type
endomyocardial biopsy (EMB) method in 1962. As
Professor Shigeru Sakakibara was the chairman of cardiac
surgery at the Heart Institute of Japan at that time,
Konno’s paper was published by these two authors.2,3) Although the use of this invention was considered to be asafe and dependable method, the EMB was not immediately adopted outside of Japan.4) Eventually, however, theprocedure was found to be clinically useful for the recognition of rejection phenomena by taking a tissue sampleof the transplanted heart. This particular technique was introduced by the Stanford group, where heart transplantation was begun, using a short-sheath bioptome inserted
into the internal jugular vein.5) It was after then that modified methods with the use of a bioptome emerged andwere more widely applied in clinical cardiology care forthe recognition and diagnosis of cardiomyopathies, arrhythmias, and other cardiac conditions. The utility of
Konno’s EMB method through proper interpretation of biopsy findings was introduced into the English literature byProfessor Morie Sekiguchi,6-8) who had performed extensive basic studies to devise a practical guide on the systematic interpretation of biopsy results. During his stay inFGermany in 1970-71, he promoted the EMB in Europe
and became the chairman of the International Society andFederation of Cardiology (ISFC) Cardiomyopathy Sectionin 1987. Recently, a large review of the EMB was released by Cooper, et al., entitled the role of endomyocardial biopsy in the management of cardiovascular disease,that was compiled following gatherings of the American
Heart Association (AHA), the American College of Cardiology, and the European Society of Cardiology, which incorporated 13 Japanese papers into the list of 162 articles.1) However, several essential findings published in
English by Japanese investigators were not cited; it is forthis reason that Japanese studies have been selected as thefocus of this review so as to complete the global recognition of biopsy work to date.

Histopathological Diagnosis by EMB
Sekiguchi first reported his foundational work on the
EMB method in 1969 in which he analyzed 126 cases anddescribed that the EMB was capable of diagnosing several
specific myocardial diseases, such as glycogen storage
disease, sarcoidosis, and myocarditis.6) As there had been
so few reports on the EMB at the time, most specimens

From the 1Department of Surgical Pathology, Tokyo Women’s Medical University, 2Department of Konno Memorial Cardiac Pathology Laboratory, Japan
Research Promotion Society for Cardiovascular Diseases, Tokyo and 3Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka,
Japan.
†Deceased, October 10, 2016
Address for correspondence: Toshio Nishikawa, MD, Department of Surgical Pathology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku,
Tokyo 162-8666, Japan.. E-mail: nishikawat@twmu.ac.jp
Received for publication July 8, 2016. Revised and accepted November 14, 2016.
Released in advance online on J-STAGE November 8, 2017.
doi: 10.1536/ihj.16-316
All rights reserved by the International Heart Journal Association.
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841

Figure 1. Representative micrographs of the bizarre myocardial hypertrophy with disorganization(BMHD) that characterizes hypertrophic cardiomyopathy. Grading of BMHD (-), (+), (++), and (+++) is presented.

showed non-contributory findings at first glance, but
through his analysis, he developed a systemic histopathological classification system that considered hypertrophy of cardiomyocytes, degeneration, disarrangement and/or fragmentation of muscle bundles, interstitial fibrosis,
and endocardial thickening.

Hypertrophic Cardiomyopathy (HCM)
It was firstly described by Sekiguchi, et al. that myocyte hypertrophy and disorganization of muscle bundles
were frequently found in EMB specimens from patientswith HCM and named this characteristic finding bizarre
myocardial hypertrophy with disorganization (BMHD)9)(Figure 1). Nunoda, et al. reported that while BMHD was
observed in the EMB samples of 71% of HCM patients,
this finding was rarely present in those of patients withhypertensive heart disease.10) They calculated a sensitivityof 71%, predictive accuracy of 83%, and specificity of
89% of this finding in HCM patients. Takemura, et al. described that the expression of atrial natriuretic peptides inthe EMB specimens of patients with HCM was related to

myocyte hypertrophy, BMHD, and fibrosis.11) Morimoto,et al. have presented several important concepts regarding
the BMHD in apical hypertrophic cardiomyopathy (AH).12)
From the standpoint of clinical cardiology, AH differsfrom HCM with asymmetrical septal hypertrophy (ASH),
and it is unclear whether AH represents a distinct form ofHCM. The presence or absence and extent of BMHD
were compared between patients with ASH or AH, inwhom EMB was performed from the LV apex and fromthe interventricular septum. In the ASH group, BMHD ofvarious degrees was observed in 86% of cases, whereas
this finding was absent or at most limited to a very small
area in the AH group (P < 0.0001). This comparative
analysis led to the conclusion that AH differed from usual
HCM with ASH from both clinical and EMB standpoints.12)

Dilated Cardiomyopathy (DCM)
Sekiguchi, et al. evaluated numerous EMB specimens
obtained from patients with DCM and developed a systematic method of histopathological assessment that in-

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Figure 2. Examples of serial histopathologic endomyocardial biopsy findings. A, B, and C are taken froma case with acute myocarditis on whom serial biopsies were performed on the 9th (A), 17th (B), and 29th (C)day after disease onset.

cluded quantitative evaluation.9) Ogasawara, et al. established the histopathologic contractility failure index(HCFI) through the EMB and evaluated the prognostic
factors of DCM that included HCFI, ECG, and hemodynamics.13) They concluded that a low HCFI score was related with a poor prognosis in DCM. The ultrastructuralchanges in EMB samples have also been analyzed by several investigators.14,15) Mitochondrial degeneration, widening and increase in sarcotubular systems, fragmentationand scarcity of myofibrils, and widened intercalated discs
are frequently disclosed in DCM.14)

sis. The description “arrhythmia-conduction disturbancetype of cardiomyopathy” was considered to be appropriate
for this category of myocardial disease. However, due tothis finding appearing only in the monograph book entitled Cardiomyopathy Update 3”,17-20) it was not included
in Cooper’s description but merits attention on a global
level. Then, Sekiguchi, et al. published additional studies
on this disease and proposed the simpler term of ECM.21)
In a series of 573 cardiomyopathy biopsies, 46% were hypertrophic, 30% were dilated, and 15% were classified as
ECM.

Electric Disturbance Type Cardiomyopathy (ECM)

Myocarditis

There have been cases of cardiomyopathy that were
not easily classifiable into hypertrophic or dilated types,that often showed ventricular arrhythmia, right or left bundle branch block, intraventricular conduction disturbance,
atrioventricular conduction disturbance, or sinus node dysfunction (i.e., sick sinus syndrome).16) The EMB in suchcases revealed advanced myocardial degeneration or fibro-

The histopathological diagnosis of acute, subacute, orconvalescent myocarditis was established by Sekiguchi, etal. in accordance with the histopathological findings of
myocarditis (HFMC) by the EMB.22) They constructed alist of HFMC, in which it was noted the pertinent findingsthat characterized each stage of myocarditis development,i.e., acute, subacute, convalescent, and healed, through se-Int Heart J
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Fifty Years after Konno’s Development of Biopsy

Figure 3. Model for histopathologic categorization of the presence or absence of postmyocarditic change.
It is advisable to classify biopsy findings into the most appropriate category in the absence of any clinical information. H indicates highly suggestive; S, slightly suggestive; D, doubtful; and N, not suggestive.

rial endomyocardial biopsies (Figure 2). The Dallas criteria for the histopathological diagnosis of myocarditis, on
the other hand, were created by pathologists dealing withmyocarditis.23,24) The important point in using the Dallas
criteria is that the clinician must perform repeated EMB
procedures to arrive at an appropriate diagnosis. However,this is not always feasible in routine practice, which is thereason why we have adopted the HFMC that can be utilized for patients receiving only one biopsy during thecourse of the disease25) (Figure 3). Therefore, the terms“ongoing” and healing myocarditis have been replaced
by “acute,” “subacute”, “convalescent”, and “healed.” Figure 3 represents a useful guide for determining HFMC.
Chronic Myocarditis
As chronic myocarditis lacks a concise definition, theterm chronic myocarditis has been adopted to describe its
various conditions. The Dallas criteria for myocarditis do
not address this issue.23,24) Thus, the Japanese Circulation
Society organized a taskforce committee in order to establish appropriate guidelines.26) EMB diagnosis of chronic
myocarditis can be summarized as accumulation or infiltration of large and/or small round cells in the myocardium associated with myocytolysis or necrosis of adjacent
myocytes. Diffuse interstitial fibrosis, irregular replace-ment of myocardial fibrosis, and fatty infiltration are also
observed. It was the committee’s hope that these definitions would be applied in both the clinical and histopathological recognition of this disease.

Sarcoidosis
It has been indicated that the ability for detecting
non-caseating epithelioid granulomas by EMB is rather
limited.27) Only 22.2% of patients in whom the presenceof cardiac sarcoidosis was strongly suspected due to otherclinical features showed positive findings (granuloma) in
their EMB samples.28) Uemura, et al. revealed in a prospective analysis of 26 cases that the diagnostic settlementof cardiac sarcoidosis through the detection of granulomas
amounted to approximately 19.2% of the cases studied.29)
Meanwhile, Yoshida, et al. reported that cardiac sarcoidosis was frequently found in patients with advanced atrioventricular block; 10 of 89 patients (11.2%), which could
not be diagnosed without the EMB.30) It was reported byMikami, et al. that the electron microscopic study disclosed basal lamina layering (BLL) of the capillaries inthe skeletal muscle of sarcoidosis patients.31) Sekiguchi, etal. found BLL in EMB specimens from 77.8% of patients

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with sarcoidosis.28) They concluded that sarcoidosis withmicroangiopathic processes could exist and these were an
important element of the disease. Morimoto, as a memberof the Japanese Circulation Society Joint Working Group,
established an EMB study team and has since postulated
several key findings in the field of sarcoidosis.32)

Electron Microscopic Studies
Sekiguchi described various findings of electron microscopy (EM) in the Bulletin of the Heart Institute during his pioneer work on the EMB.33) Some characteristics,
such as mitochondriosis, size variation, and degenerativechanges, were noteworthy findings reflecting the metabolic retardation of the myocytes. Later, fibrillar disarray
was considered to represent the nature of hypertrophic
cardiomyopathy, which became a topic of EM work outside of Japan. The ultrastructural contractility failure index(UCFI) has been proposed for evaluating the hemodynamic disability and prognosis of patients.34) As it is difficult to objectively evaluate the severity of interstitial pathology by means of ultrastructural evaluation, it can besaid that intracellular, as well as capillary, changes can atleast be assessed semi-quantitatively for EM evaluation of
the diseased myocardium. According to the UCFI, there
are six factors which interfere with the contraction of cardiac myocytes: 1) fragmentation of the myofibrils; 2)swelling of the mitochondria, and especially lysis of thecristae; 3) intracellular edema; 4) widening of the intercalated discs; 5) swelling of the capillary endothelium; and6) accumulation of degenerating substance. When changes
in the above-described 6 factors are semi-quantitatively
evaluated, the sum of each grading may be regarded as an
estimation of contractile phenomenon of cardiac mechanical performance. The UCFI was well correlated with left
ventricular ejection fraction and mean circumferential
shortening rate, and a high UCFI value was closely associated with increased mortality.34) Some other EM papers
were presented.15,35,36)

EMB Recognition of Pediatric Diseases
We earlier described an infant in whom myocarditis
was confirmed by EMB.37) Sekiguchi, et al. analyzed theultrastructural aspects of EMB samples from pediatric patients with endocardial fibroelastosis and identified a relationship with long-term prognosis.38) Lastly, we proposed a
grading system for the degree of myocyte hypertrophy inbiopsy specimens at various pediatric ages, which may be
useful for EMB assessment of pediatric cases.39)

Cardiac Biopsy After Heart Transplantation
The EMB is a well-known an essential method in theevaluation of acute rejection following heart transplantation. As the first such transplant was not well received inJapan due to medico-legal reasons, the progress of hearttransplantation was long delayed until 2008. Accordingly,
Japanese reports on the subject are fewer in number.40,41)

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Complications of the EMB Procedure
Hiramitsu, et al. reported the results of a national
survey concerning the EMB procedure conducted at Japanese health institutions, wherein 19,964 cardiac biopsies at
134 centers were assessed for major EMB complications.42) The rate of right or left ventricular perforation
was 0.7% (147 cases), while the mortality rate due to ventricular perforation was 0.05% (10 cases). Mortality
showed no statistically significant difference between rightand left ventricular perforations (P = 0.22).

A New Approach to analyze EMB Samples: Molecular Biological Investigation
Pathogenesis of cardiomyopathy has been elucidated
by detection and analysis of some proteins or gene formation. Several investigators disclosed that virus genome was
detected in EMB samples from DCM patients and suggested a link between viral myocarditis and DCM.43,44)
Moreover, Seko, et al. analyzed the expression of T cell
receptor genes as well as enterovirus genomes by PCR using EMB samples from DCM patients.45) They suggested
that a cell-mediated autoimmune mechanism triggered byvirus infection may play a role in the pathogenesis of
DCM. Another several studies have been reported on theinvestigation of pathogenesis by analyzing some proteinsor genes including dystrophin, tenacin C, troponin T,
myosin heavy chain and glycolipid in EMB samples.46-50)

The Difference Between Japan and OtherCountries in the Attitude Toward EMB and
Cardiomyopathies
As the EMB method was first developed in Japan,
this technique has been widely used for the diagnosis ofcardiomyopathies in clinical cardiology in our country.2)
The EMB is actively employed as a useful diagnostic toolfor cardiomyopathies in Japan,7,32) while it may be prudently applied for these diseases except for transplanted
heart to recognize rejection phenomena in United Statesor European countries.8,51) As regarding the differences ofthe disease concept, chronic myocarditis is defined in Japan and European countries as the condition which indicates chronic heart failure with prolonged inflammation of
the myocardium,26,52) but there is no notion of this disease
in United States.23,24) Further, the term “dilated-phase
HCM” is used in Japan for the condition that indicatesdilatation of cardiac ventricles in certain patients with
HCM,53) but this term is unused in United States andEuropean countries in which “end stage HCM” isadopted.54,55)
At any rate, however, it is common understandingthat EMB is important for recognition of cardiomyopathies.

Forming a Nationwide Study Group on EMB
In 1979, Sekiguchi organized a study group on clinical cardiac biopsy, tentatively named the Clinical Biopsy

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Study Group, and thereafter a Cardiac Biopsy Conference
has been held every year in Japan. The name of this special conference is now called the Cardiac Biopsy Conference, abbreviated as CABIC. Approximately 200 participants from all over Japan attend the meeting, which covers all aspects of EMB study. Recently, the conference’s
format has been changed to not only describe the histopathological aspects of EMB, but also to analyze correlating
work with the use of MRI and PET. CABIC now maintains its initial principle of cardiac biopsy study in addition to including the modern aspects of non-biopsy diagnosis and assessment of heart muscle disease. This groupof professionals is now spreading to a wider field in thatthe diagnosis of cardiomyopathies should not be restricted
to histopathological diagnosis; for example, the value ofhistopathological determination by EMB was only usefulin 20% of cardiac sarcoidosis patients studied.28) Indeed,
CABIC members are involved in the study of many othercategories of cardiomyopathic diseases, and numerous reviews have been made by the editing members of this review, as listed on the CABIC homepage.56) We first begancompiling English language EMB papers from Japan in
2008. As the total number of publications has exceeded
500, it was thought to be impossible to review the entirety, and so we selected approximately 40 essential reports in the current review. The titles of the remaining
publications can be found on the CABIC homepage,
which we expect to become a center for EMB-related information.

Acknowledgments
We greatly appreciate the contribution of Drs. Akihiro Hirashiki, Michiaki Hiroe, Fukiko Ichida, Kyoko
Imanaka, Shunji Kawamura, Makoto Kodama, Shin-ichiro
Morimoto, Hiroshi Nakamura, Kazufumi Nakamura,
Makoto Nagata, Shinnichi Nunoda, Yoshiaki Sakai,
Mamoru Sato, Hiroyuki Takano, Genzo Takemura, Toshihiro Takenaka, Fumio Terasaki, Kenta Uto, Yoshikazu
Yazaki, and Tsutomu Yoshikawa as co-editors of this review article. Editorial assistance by Mr. Trevor Ralph isappreciated as well.

Disclosures
Conflict of Interest: The Authors Have No Conflicts ofInterest Regarding the Content of the Manuscript.

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