CLINICO-PATHOLOGICAL CONFERENCE
A case of dilated cardiomyopathy with end-stage heart failure
treated by prolonged continuous hemodiaﬁltration
Satoshi Ogawa, Shin-ichiro Matsumura, Tsutomu Yoshikawa, Toru Satoh, Hiroo Kumagai, Hideo Mitamura,1Shiro Iwanaga2 and Akihiro Umezawa3
Departments of Internal Medicine, 1The Suntory Fund for Advanced Cardiac Therapeutics,
2Laboratory Medicine, 3Pathology, School of Medicine, Keio University, Tokyo, Japan(Received for publication on February 27, 2002)

Abstract. A 55-year-old Asian man ﬁrst visited to our hospital with complaining of exertional dyspnea eight years ago, and was diagnosed as having idiopathic dilated cardiomyopathy. One of his siblings also suffered from idiopathic dilated cardiomyopathy. His symptoms became worse gradually, andhe was hospitalized again because of disturbance of consciousness on February 21, 2001. Hemodynamic
monitoring with a Swan-Ganz catheter was started, which revealed that the cardiac index was 1.1 L/
min/BSA, cardiac output 1.8 L/min, and pulmonary artery pressure 43/33 mmHg. The echocardiographic observation showed that the left ventricular ejection fraction was 32%, and serum BNP waselevated to 5,411 pg/mL. Multi-organ failure including renal and hepatic dysfunction developed because of the low cardiac output status. Continuous hemodiaﬁltration (CHDF) was introduced to reducethe volume overload, improve renal failure, and eliminate adverse cytokines. Although his hemodynamic status was temporarily improved after starting CHDF, weaning from CHDF was difﬁcult and heﬁnally died from cardiogenic shock after two month of intensive therapy. The autopsy showed thinningof the left ventricular wall, and histological examination revealed diffuse ﬁbrous hyperplasia and myocardial ﬁber deﬁcit in the ventricular myocardium. CHDF was effective in reducing the volume overload and improving renal function; however, heart transplantation is inevitable for the patients withsevere heart failure due to dilated cardiomyopathy. (Keio J Med 51 (3): 165–177, September 2002)
Key words: dilated cardiomyopathy, continuous hemodiaﬁltration, autopsy, heart failure, unconsciousness

Dr. Ogawa (Moderator): I declare the 1042nd
clinico-pathological conference (CPC) open. The casefor discussion in today’s CPC is a patient who died from
gradual worsening of his cardiac function over a courseof approximately 8 years. The physician-in-charge, Dr.
Matsumura, will ﬁrst describe the clinical course of thispatient.
Dr. Matsumura (Internal Medicine): The patientpresented complaining of exertion-related dyspnea onclimbing stairs or walking up a slope since March 1993.
He visited the Cardiopulmonary Division at our hospital in April 1993. After he was admitted to the hospital,
cardiac catheterization and left ventriculography were
performed, and revealed contractile dysfunction of theleft ventricle, which was manifested by diffuse hypo-kinase and a reduced ejection fraction (EF, 11%). A
myocardial biopsy further revealed hypertrophy of
myocardial cells and interstitial ﬁbrosis. There was noevident infectious, metabolic, systemic, or hereditary
etiology. The patient was diagnosed as having dilated
cardiomyopathy (DCM). Treatment with an anticoagulant (Warfarin1), digitalis glycoside, an angiotensinconverting enzyme (ACE) inhibitor, and furosemide
was started. The patient was then discharged from thehospital and treatment was continued on an outpatientbasis.
In the months of June and October of 1997, the patient developed acute exaggeration of his heart failure,
precipitated by a common cold, and he was admitted toour hospital. Oral administration of pimobendan was

This is a record of the 1042nd CPC of Keio University Hospital, held on January 30, 2002.
Reprint requests to Dr. Satoshi Ogawa, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan
165

166

started on October. From October 1998, his dyspnea onexertion (DOE) became progressively worse, and in
April 2000, he developed the symptom of chest oppression at night. Holter ambulatory ECG recording
performed in January 1999 revealed non-sustained
ventricular tachycardia (max. 11 beats in a run). At 5:00
a.m. on February 21, 2001, his wife, who was sleeping
beside him, noticed that he was breathing hard. He did
not respond to her calls, and she immediately called for
an ambulance. He was taken to Nihon University Surugadai Hospital. On initial examination, dyspnea andcyanosis were observed. His consciousness level was
slightly below normal, and systolic blood pressure wasabout 70 mmHg. Following endotracheal intubation,
artiﬁcial ventilation, and intravenous infusion of dobutamine and furosemide, the patient’s consciousness improved rapidly. He was transferred to our hospital on
February 27.
Dr. Ogawa: So, the clinical course of the patient’s
illness was as follows: The patient ﬁrst presented withthe clinical features of heart failure in 1993, and he wasclinically diagnosed as having DCM. Despite intensive
therapy, however, the heart failure became worse gradually and progressively. At one point, he was admittedwith loss of consciousness to another hospital. Thereafter, he was again admitted to our Keio University
Hospital for thorough examination and treatment.
Echocardiography performed in 1994 revealed enddiastolic and end-systolic left ventricular diameters of
5.9 cm and 4.4 cm, respectively, and cardiac pool scintigraphy (MUGA) revealed a left ventricular EF of
about 40%. These dimensions improved slightly to 5.2
cm and 4.2 cm, respectively, in the year 1996, but they
increased again in 1998 and 1999; in particular, the endsystolic diameter increased to 5.2 cm, indicating that thecontractile function of the left ventricle had decreased
considerably.
The patient ﬁrst presented with dyspnea on exertionin March 1993. Are there data from earlier medical
examinations?
Dr. Matsumura: There is one earlier mention ofright axis deviation on ECG; however, no other ECGchanges were recorded. The patient was apparently ingood health in 1982, when he was involved in a trafﬁc
accident in the State of Kuwait and underwent surgery
on his right lung. Subsequently, he developed slightdyspnea on exertion. The symptom worsened rapidly in
1993, and he was referred to our hospital.
Dr. Ogawa: As for the 11 beat run of non-sustained
ventricular tachycardia revealed by the Holter ECG in
1999, was his morbid condition relatively stable during
the period when the tachycardia was observed? Or was
the non-sustained ventricular tachycardia associatedwith worsening of his heart failure?
Dr. Matsumura: In 1993, his symptoms of heart fail-Ogawa S, et al: A case of DCM treated by prolonged CHDF

ure were relatively mild, classiﬁed as New York Heart
Association (NYHA) functional class II. A little later,
he presented with worsening of the heart failure due toa common cold, and he was admitted to our hospital.
On admission, the NYHA functional class found tohave worsened from Class II to Class III. When thisimproved again to Class II (IIM), he was discharged
from our hospital. The symptoms thereafter graduallyworsened again, and runs of non-sustained ventriculartachycardia were observed on the Holter ECG recording associated with worsening of the heart failure.
Dr. Ogawa: Was the treatment of the tachycardia
detected by Holter ECG undertaken on an outpatientbasis?
Dr. Matsumura: Yes, it was.
Dr. Ogawa: If so, can we understand that the Holter
monitoring was not performed speciﬁcally during theperiod when his heart failure had become worse?
Dr. Matsumura: Yes, we can. Holter ECG monitoring was performed routinely and was not related to theworsening of his heart failure.
Dr. Ogawa: We can therefore say that the nonsustained ventricular tachycardia was incidentally detected.
The patient’s chief compliant seems to have been
consciousness disturbance; when his wife, who was lying
beside him in bed, called out to him at 5:00 a.m. in themorning, she noticed that he did not respond. Is thatright?
Dr. Matsumura: Yes, it is.
Dr. Ogawa: I wonder if the ambulance personnel
detected any abnormalities in his vital signs that could
be responsible for the consciousness disturbance onthat occasion? Is there any record?
Dr. Matsumura: His consciousness level was slightly
below normal, but it was apparently returning to normal when he was taken into the ambulance. The ECG
recorded then also did not show any ventricular tachycardia or ventricular ﬁbrillation. The possibility of low
cardiac output due to DCM, or transient arrhythmias,such as spontaneously converted ventricular tachycardia that terminated spontaneously having caused thesyncope, cannot, however, be ruled out.
Dr. Ogawa: How was the control of his coagulation
parameters with the dose of Warfarin1 during this period? Was he taking an appropriate dose of Warfarin1?
Dr. Matsumura: The thrombotest was supported
to 10–20%, which suggests favorable control by the
Warfarin1. Nor did echocardiography show any evidence of intracardiac thrombus during his course. Thisechocardiographic ﬁnding, together with the appropriate control by Warfarin1, indicate that it is unlikely that
cerebral embolism may have been responsible for this
syncopal episode. A brain CT was not conducted because the patient was in poor general condition.

Keio J Med 2002; 51 (3): 165–177
Table 1

167

Vital Signs and Acute Clinical Settings

NormalPeripheral Artery Occlusion
Coma
Apnea
Choke
Shock
Cardiac Arrest

Consciousness

BreathingPulsation

þ
þ


G
G


þ
þ
þ


þ


þ

þ
þ
þ
G


Dr. Ogawa: What do you think of this case, Dr.
Mitamura?
Dr. Mitamura (The Suntory Fund for Advanced
Cardiac Therapeutics): I would like to make a few
points. As for the labored breathing and absence of response to verbal commands, I doubt whether we canrefer to the patient’s state here as ‘‘syncope’’. When we
use the term ‘‘syncope’’, it usually refers to a conditionof complete muscular weakness associated with unconsciousness; labored breathing therefore is not characteristic of syncope. Syncope in this sense generally
results from a transient and steep fall of blood pressure.
It is also important to know how long the laboredbreathing was sustained in the patient. To sum up,
rather than suffering from an episode of ‘‘syncope,’’this patient was probably taken to the hospital in a socalled state of shock with sustained moderate hypotension, or the main cause of the patient’s condition
may have been dysfunction of the central nervous system (Table 1).
The following possibilities should be considered inthis circumstance, other than DCM: (1) The possibilityof ventricular tachycardia having spontaneously terminated when the patient was taken to the hospital should
be considered as the most likely; (2) and, despite thefavorable control of warfarinization, there is still thepossibility of cerebral infarction having occurred due toa cerebral embolism derived from an intraventricularthrombus because of poor left ventricular function; (3)there is also the probability of cerebral hemorrhage
having occurred due to an excess dose of Warfarin1;(4) the possibility of hemorrhagic shock having beencaused by gastrointestinal hemorrhage or hemorrhage
from other sites; and (5) the possibility of pulmonary
embolism, in which condition the blood pressure ofpatients with very poor cardiac function who are bedridden over a long period of time, suddenly declines.
Dr. Ogawa: Thank you very much. How about his
family history?
Dr. Matsumura: The patient’s younger brother wasdiagnosed as having DCM at the age of 45 years.
Dr. Tsuji (5th-year medical student): Could the history of pulmonary contusion on the right side in 1982 berelated to the slight decrease in respiratory sound on
the right side?
Dr. Matsumura: As is evident from the chest X-rays,
the patient had developed thoracic deformity and collapse of the right lung consequent to the pulmonary
contusion. This is probably the cause for the muted respiratory sound on the right side.
Dr. Ogawa: What was the nature of this pulmonary
injury? Could you explain it in greater detail?
Dr. Matsumura: When he was driving, his car collided head-on with another car. At that time, two otherpeople who were in the car with him died instantly, so
the accident was apparently a major trafﬁc accident.
Dr. Ogawa: I wonder how we can correlate his morbid condition, DCM, with the accident. For instance, it
has been reported that myocardial injury of the rightventricle or tricuspid regurgitation can occur following
steering wheel injury. The patient, however, had notbeen detected as having any signiﬁcant physical abnormalities in medical check-ups undertaken subsequent tothe accident. Am I right?
Dr. Matsumura: Yes, that’s right.
Dr. Ogawa: There is no history to suggest that thepatient was a habitual drinker. The presence of adrinking history is very important in making a differential diagnosis. Now, will you please describe thepatient’s clinical condition on admission to our hospital?
Dr. Matsumura: The blood pressure was 110/80
mmHg, and the pulse was 100 beats per minute. The
respiratory rate was 26 per minute. He was fully conscious. The external jugular vein was distended. In regard to the heart sounds, P2 was loud, and 3rd and 4thheart sounds were audible. A systolic murmur could beheard between the cardiac apex and the 4th intercostal
space at the left margin of the sternum. Breath sounds
were decreased on the right side of the chest, and there
were no added sounds. The liver was palpable by 3
QFB and there was some tenderness below the rightcostal margin. There was no pretibial edema.
Laboratory examination revealed normocytic normochromic anemia and increase in the serum levels ofﬁbrinogen and ﬁbrin degradation products. The BUN
and CRTNN levels were elevated, which was considered to be related to the administration of diuretics.
The serum UA and K levels were also elevated; the serum K was 5.6 mEq/L. Furthermore, the serum levels of
LDH, GOT, and GPT were elevated. Serum CPK was
slightly increased. Serum CRP was increased to 4.56
mg/dL. Thyroid functions were normal. The serum
concentration of digoxin was slightly high. BNP was
revealed to be considerably elevated to 5,410.8 pg/mL.
Dr. Ogawa: Will you please explain the reason forthe distended jugular vein observed in this patient on
admission?

168

Ogawa S, et al: A case of DCM treated by prolonged CHDF

Fig. 1 The electrocardiogram has apositive P wave in lead II, and shows a normal sinus rhythm at the rate 60 beats per minute. Although theamplitude of P wave in leads II and III was not high enough to meet the criteria for right atrial overload, peaking of the ﬁrst half of the P wave
in lead VI may be a reﬂection of the overload of the right atrium. The PQ interval was within the normal range. The right axis deviation andclockwise rotation of the QRS complex may be due to right ventricular overload. The width of the QRS complex was 168 msec, and the rS
pattern in V6 with a wide S wave suggests complete right bundle branch block (CRBBB); however, the QRS complex in V1 was not an typical
CRBBB rsR pattern. There was an abnormal Q wave in V1 and V2, which raises the possibility of myocardial necrosis in the ventricular septum. Slight ST depression and biphasic T wave are seen in the left precordial leads.

Dr. Matsumura: The right jugular vein was found to
be distended up to the level of the mandible, and a v
wave was observed.
Dr. Ogawa: The marked distension of the jugularvein indicates that the ﬁlling pressure of the right cardiac system was high, doesn’t it? The respiratory rate
was also increased. How about the cardiac murmur?
Dr. Matsumura: The murmur was pansystolic. Echocardiography suggested the presence of mitral regurgitation (MR) and tricuspid regurgitation (TR), and the
murmur was considered to be associated with theseregurgitations.
Dr. Ogawa: Do you mean that the signs of right heart
failure were rather signiﬁcant?
Dr. Matsumura: Yes, that’s right.
Dr. Ogawa: Will you please present the results ofarterial blood gas analysis?
Dr. Matsumura: Under nasal administaration of 2
L/Min oxygen, the pH was 7.44; Pco2 , 31.4 Torr; Po2 ,144.4 Torr; HCO3  , 24.5 mEq/L; BE 1.5, mEq/L; andthe Sao2 , 99.4%. These ﬁndings are suggestive of compensated respiratory alkalosis from hyperventilation.
Dr. Ogawa: How can we correlate the ﬁndings of themorbid condition reported in this conference with the
ECG ﬁndings? What is your opinion, Dr. Mitamura?
(Fig. 1)
Dr. Mitamura: The ECG fundamentally revealed asinus rhythm. An occasional ventricular extrasystole
was observed in the limb leads.
As to the P wave, the negative portion of P wave inlead V1 did not seem to be so clear. There seemed to besome peaking of the ﬁrst half of the P wave, suggestiveof right atrial overload.
The PQ interval was almost within the normal range.

The QRS axis deviated to the right, and as stated earlier, the right axis deviation may be reﬂective of rightventricular overload. However, the axis might be inﬂuenced by a right bundle branch block. The ﬁrst component in leads V1 and V2 in cases of right bundle branch
block is essentially an upright r, but in this case there
was a negative deﬂection, a ‘‘q’’ wave, in these leads.
This matter weighs on my mind. The presence of the‘‘q’’ wave in these two leads may suggest the possibilityof myocardial necrosis in the ventricular septum. Mild
non speciﬁc ST-T changes were observed in the chest
leads.
The patient had a thoracic deformity, and there is
the possibility that this also inﬂuenced the ECGchanges. It would therefore seem difﬁcult to make a
deﬁnitive diagnosis based on the ECG ﬁndings alone inthis patient.
Dr. Ogawa: The presence of abnormal ‘‘q’’ waves inleads V1 and V2 in a case with right bundle branch
block should raise the possibility of cardiac sarcoidosis,
which selectively damages the interventricular septum.
Dr. Matsumura: A chest X-ray taken in the year
2000, when the patient was being followed up as an
outpatient, is shown here. There is thoracic deformity
and collapse of the right lung, which are probably consequent to the trafﬁc accident. The mediastinum isshifted to the left. There is no obvious evidence ofpulmonary venous congestion, such as the presence of
Kerley’s B lines. There is no evidence of pulmonary
venous re-distribution to the upper lung ﬁelds. The tracheal bifurcation angle is approximately 90 , whichsuggests the presence of left atrial dilatation.
In the lateral view, narrowing of the retrosternal
space is observed, which suggests the presence of rightKeio J Med 2002; 51 (3): 165–177

169

Fig. 2 The echocardiography was performed on March 28, 2001. Parasternal long axis view on the left upper panel shows dilation of the left
and right ventricles. Thinning of the left ventricular wall and a small amount of pericardial effusion are also observed on the right upper panel,the parasternal short axis view. The two lower panels are M-mode traces at the mid-ventricular level (left) and mitral valve (right). Both traces
revealed reduced excursion and thinning of the left ventricular wall. The calculated ejection fraction of the left ventricle was 23% by the methodof Pombo, suggesting marked reduction of left ventricular systolic function. B-B0 step of mitral valve on the right lower panel suggests the elevation of left ventricular end-diastolic pressure.

ventricular dilatation. Dilatation of the left ventricle isalso suspected from the point of intersection between
the diaphragm and the inferior vena cava. The costophrenic angles are sharp, and there is no evidence of
pleural effusion.
This X-ray taken on admission to our hospital shows
opacity of the right lung ﬁeld. The cardiothoracic ratio(CTR) is slightly high, and no Kerley’s B lines areevident. These ﬁndings suggest that there was no signiﬁcant pulmonary venous congestion. There is noevidence of pleural effusion. There is also evidence
suggestive of dilatation of the left atrium and rightventricle.
Dr. Ogawa: The left ventricular function was signiﬁcantly compromised in this patient, but ﬁndings ofright heart failure were more remarkable on admission.
There was no evidence of pulmonary congestion, either
clinically or on chest X-ray. Will you present the echocardiographic ﬁndings in this patient and explain hisheart condition as evaluated by this investigation, Dr.
Iwanaga? (Fig. 2)
Dr. Iwanaga (Laboratory Medicine): This videotape
shows the echocardiographic ﬁndings of this patientobtained on March 28. The parasternal long-axis viewshows the right and left ventricles, left atrium, aorta,
mitral valve, and the aortic valve. The short-axis viewshows the right atrium and right ventricle. We can see
a Swan-Ganz catheter inserted. At the level of thepapillary muscle, the interventricular septum is slightly
hyperechoic, which shows little or no wall motion. The
motion of the posterior wall is also poor, and the left
ventricle is dilated. As for the valves, moderate to severe MR is observed. The aortic valve shows atherosclerotic degeneration. The most signiﬁcant ﬁndings are
the dilated left ventricle and the poor contraction of
the interventricular septum and posterior wall. The
mitral regurgitation may be due to dilatation of the left
ventricle and the mitral annulus. The left ventricular

170

diameter as measured by M-mode was 6 cm and 5.5 cm
at end-diastole and end-systole, respectively, which
reﬂects signiﬁcant dilatation. A small amount of pericardial effusion is also observed.
The apical four-chamber view shows that the contraction of the interventricular septum is even worse
than that of the free wall, even though there is signiﬁcant thinning of the free wall. The left atrium is dilated.
Wall motion of the free wall is relatively sustained, but,on the whole, left ventricular contractile dysfunction isdiffuse. Based on these echocardiographic ﬁndings, thediagnosis of DCM is suspected. One problem, however,is localization of the wall thinning; the thinning is distributed in the areas supplied by the right coronary andleft anterior descending arteries. Marked ﬁbrosis isevident in these areas. It is impossible to completely
rule out left ventricular contractile dysfunction due toischemic heart disease from this ﬁnding.
Dr. Ogawa: What do you think of the possibility ofcardiac sarcoidosis in this case?
Dr. Iwanaga: In cardiac sarcoidosis, a relatively
localized contractile dysfunction of the left ventricle isobserved, and wall motion remains relatively normal inother areas. Reports of diffuse hypokinesis of the left
ventricle, as observed in the present case, are limited. A
color Doppler image of the apical four chamber view isshown. Severe TR is evident from this image.
Dr. Ogawa: Is there any evidence of an organic legion in the tricuspid valve?
Dr. Iwanaga: The TR could be related to the presence of the Swan-Ganz catheter through the tricuspid
valve and annular dilatation consequent to dilatation of
the right ventricle. The patient had only mild pulmonary hypertension; the pulmonary arterial pressure wasestimated to be 31/21 mmHg. This is reﬂective of postcapillary pulmonary hypertension due to left heart failure.
From the echocardiographic ﬁndings, DCM may besuspected as the ﬁrst differential diagnosis, and in thepresent case, it was presumably severe and associatedwith hemodynamic decompensation. However, in thepresence of thinning of the ventricular wall in the areasof the right coronary artery and left anterior descending
artery, it is difﬁcult to rule out so-called ischemic cardiomyopathy.
Dr. Ogawa: When DCM is suspected, primary DCM
should be differentiated from secondary DCM. The
ischemic DCM just mentioned by Dr. Iwanaga cannot
be ruled out, either. While cardiac sarcoidosis may be
kept in mind, the possibility is rather remote, because
in this case, not only the interventricular septum, inwhich lesions usually develop, but also the free wall of
the left ventricular myocardium, showed signiﬁcant diffuse damage. The presence of a positive family history
also points more towards the possibility of primary or

Ogawa S, et al: A case of DCM treated by prolonged CHDF

hereditary DCM.
Now, Dr. Matsumura, could you please outline thetreatment initiated in this case?
Dr. Matsumura: In 1993, when the patient was ﬁrst
admitted to our hospital, treatment with digitalis,
Warfarin1, an ACE inhibitor, and furosemide wasstarted. Thereafter, the patient was followed up on
outpatient basis. Sometime in mid 1997, the patient was
readmitted with symptoms of a common cold and worsening of his heart failure. On that occasion, administration of a b-blocker was initiated, and when thepatient showed improvement, he was discharged. However, with the continuation of the b-blocker, the symptoms of heart failure, including leg edema and dyspnea
on exertion (DOE), gradually became worse, and administration of the b-blocker was discontinued.
Subsequently, when the patient was admitted once
again with worsening of heart failure, administrationof Acardi1 (pimobendan), a phosphodiesterase (PDE)
inhibitor that also enhances the calcium sensitivity of
myocardial cells, was initiated. In addition, the dose of
the diuretic was increased and spironolactone wasstarted. The subsequent course of the patient was again
monitored on outpatient basis.
Dr. Ogawa: Do you have any comments about thecourse of treatment undertaken so far, Dr. Yoshikawa?
Dr. Yoshikawa (Internal Medicine): The standard
treatment for all cases ranging from asymptomatic left
ventricular dysfunction to severe heart failure includes
administration of ACE inhibitors or angiotensin type I
receptor antagonists. For mild to moderate heart failureclassiﬁed as NYHA functional class II or III, diuretics
are usually added to the treatment regimen, and insome patients, also digitalis. Some reports have shownthat the prognosis is improved by the administration ofa b-blocker in such patients. Furthermore, in severe
heart failure classiﬁed as NYHA functional class III or
IV, further improvement of prognosis has been reported with the addition of spironolactone to the treatment regimen. Although pimobendan does not decrease the mortality rate, clinical studies in Japan haveshown that the drug decreases the number of patients
who are admitted to hospitals due to worsening heart
failure, i.e., it improves the quality of life. With regard
to Warfarin1, there is limited evidence to suggest improvement in the prognosis of these patients, as there
have been no large-scale studies on the treatment ofheart failure with this drug.
Dr. Ogawa: How about digitalis?
Dr. Yoshikawa: Some data have shown that digitalis
signiﬁcantly decreases the mortality associated withworsening heart failure. The overall mortality, however, has been reported to be similar between groups
receiving digitalis and placebo. The reason for this is
unclear, but digitalis probably increases the incidenceKeio J Med 2002; 51 (3): 165–177

of sudden death. Accordingly, there has been a gradualtendency towards reduced usage of this drug.
Dr. Ogawa: Dr. Matsumura, could you please describe the course of this patient after admission?
Dr. Matsumura: The blood pressure on admission
was 118/75 mmHg, and frequent non sustained ventricular tachycardia were observed. With a Swan-Ganz
catheter, the pulmonary arterial pressure was determined to be 43/33 mmHg; the right atrial pressure, 19mmHg; the cardiac index, 1.1 L/min/m 2 BSA; and the
cardiac output, 1.8 L/min. Thus, all of these values
were abnormal, and the pulmonary arterial oxygen saturation was markedly decreased to 33%. Intravenous
injections of furosemide and continuous infusion of
dobutamine, which had been initiated for the treatmentof heart failure at the Nihon University Hospital, were
continued. Administration of amiodarone for the treatment of ventricular tachycardia, and also of Adehl1,(colforsin daropate hydrochloride) as an inotropic
agent, was started. The hemodynamic status improved
slightly, the cardiac index and right atrial pressure
improving to 1.4 and 16, respectively, however, oliguria and gradual deterioration of renal function wereobserved.
On March 9, elevation of the BUN/Cr and K levels
to 93.5/6.0 and 6.0, respectively, were observed, andcontinuous hemodiaﬁltration (CHDF) was initiated.
With the start of CHDF, the serum Cr and K levels
decreased gradually to 2.7 and 3.9, respectively, while
the heart rate started increasing.
With stabilization of the serum Cr and K levels,
CHDF was temporarily discontinued on March 27.
However, the patient could not be indeﬁnitely sustained
without CHDF, and the procedure was started again on
March 31. Wide QRS tachycardia began to be observedon this day, and severe hepatic dysfunction was notedon April 3. Hemodialysis (HD) was started to wean thepatient from CHDF, performed once every two days,
and the course of the patient was carefully monitored.
The wide QRS tachycardia and severe hepatic dysfunction improved slightly, but the patient’s general condition continued to deteriorate. On April 14, elevationof the central venous pressure, deterioration of renal
function, and decreased consciousness level were observed, and CHDF was started again.
The consciousness disturbance deteriorated on April
15. On April 17, in deference to the family’s wishes,
CHDF was discontinued. On the evening of the 18th,
the patient started gasping, and developed respiratoryarrest at 18:20 p.m. Thereafter, cardiac arrest occurredat 18:30 p.m., and the patient was declared dead.
Dr. Ogawa: The patient, who had DCM, was referred to our hospital with consciousness disturbance.
He had severe cardiac dysfunction. How should thedata collected with the Swan-Ganz catheter be inter-

171

preted?
Dr. Matsumura: According to Forrester’s classiﬁcation of hemodynamic disturbance in acute myocardial
infarction, heart failure is classiﬁed as group IV. In thiscategory of patients, not only diuretics, but also an inotropic agents are considered to be indicated.
Dr. Ogawa: Could you please explain the changes in
the ANP and BNP data in relation to the severity of theheart failure?
Dr. Matsumura: The serum level of BNP was 2,356
in 1997, which decreased in subsequent examinations
to 1,557 and 1,217. The level of ANP was 100 to 700,
showing no remarkable changes thereafter. On admission, the BNP level was signiﬁcantly elevated to 5,410,
consistent with deterioration of the heart failure. BNP,
which is a protein discovered from swine brain, is reported to be secreted mainly from the ventricular cardiomyocytes in humans. The normal serum BNP level is
15 or less, and the levels are elevated in heart failure.
Our patient showed markedly elevated levels of BNP.
Dr. Ogawa: Initially, I thought that the present admission may have been directly related to the ventricular arrhythmia. However, judging from the course,
the cardiac failure also seems to have worsened considerably, and there is the possibility that the nonsustained ventricular tachycardia was related to the worsening of the cardiac function. Am I right?
Dr. Matsumura: Yes, Sir.
Dr. Ogawa: What about other possibilities for theventricular tachycardia, such as its being a possible
proarrhythmic effect of one of the drugs used?
Dr. Matsumura: The possibility of pimobendan, an
inotropic agent, having triggered the ventricular tachycardia cannot be ruled out.
Dr. Ogawa: What was the blood level of digoxin?
Dr. Matsumura: It was slightly elevated to 2.2. The
echocardiographic ﬁndings showed that the size of theleft ventricle was almost unchanged, but the short-axis
view revealed deterioration of wall motion and thinningof the wall. These observations suggest the possibility
that the frequent runs of ventricular tachycardia were
triggered by increasing severity of the cardiomyopathy
itself.
Dr. Ogawa: Cardiomyopathy itself in this case had
progressed considerably, and such progression secondarily induced frequent episodes of tachycardia. This
also may have contributed to the worsening of themorbid condition of the patient.
As a last issue regarding the clinical course of thepatient, the serum Cr level in the patient on admission
was 2.6. Thereafter, the renal function deteriorated
rapidly, necessitating the introduction of hemodialysis(HD). I would like to now ask Dr. Kumagai to explain
the patient’s overall pathological ﬁndings in relation to
the changes in the renal function and CHDF.

172

Fig. 3 The principle underlying the commonly performed hemodialysis (HD).

Dr. Kumagai (Internal Medicine): On admission,
serum Cr level of the patient was 2.6 mg/dl and BUN
level was approximately 60 ml/dl, but thereafter, therenal function deteriorated gradually. The deterioration
can be explained by following mechanism: renal blood
ﬂow (RBF) is one-fourth of normal cardiac output despite their small size; it is well known that the RBF
becomes extremely reduced in a situation of low cardiac
output.
The BUN to Cr ratio is usually somewhere between
10 : 1 and 20 : 1. Thus given for a serum Cr level of 2.6,
the corresponding BUN level should have been 30 to
40, whereas it was actually 60 in this patient. To explain this discrepancy, it is important to consider thispatient’s use of a diuretic (furosemide, Lasix1). Diuretics cause dehydration and vasopressin release, whichmakes water reabsorption at the collecting ducts of thekidneys. Vasopressin causes the reabsorption of urea
from the tubules. On the other hand, Cr is ﬁltered onlyat the glomeruli and is not reabsorbed in the renal
tubules. Therefore, even though vasopressin is released,
blood level of Cr does not increase. Since only urea
is reabsorbed, the urea nitrogen level is relatively
increased as compared with serum Cr level when adiuretic is used for the resolution of pulmonary congestion and in the presence of dehydration.

Ogawa S, et al: A case of DCM treated by prolonged CHDF

Fig. 4 A schema of continuous hemodiaﬁltration (CHDF). As in thecommonly performed HD, the HD solution and the patient’s blood
are allowed to ﬂow in reverse directions and to come in contact witheach other; then a supplementary solution is added to the blood.

Although the cardiac function improved somewhat
due to the use of furosemide, the cardiac index still did
not reach 2, and the patient’s renal function continued
to deteriorate, and eventually CHDF became necessary.
In the conventional hemodialysis (HD) shown Fig. 3,
the patient’s blood and HD solution are allowed to ﬂow
as counter currents, and the excess K, urea, Cr, andwater in the patient’s blood are removed from thepatient’s blood into the HD solution. Conversely, substances that are beneﬁcial for the patient (calcium, bicarbonate ion), which are contained in the HD solution,enter the patient’s blood.
In CHDF, shown in Fig. 4, the mechanism is basicallythe same as in HD, but since it is a continuous system,
the load on the patient’s cardiovascular system is comparatively lighter. HD is impossible in the presence of alow cardiac output associated with hypotension, as inthis patient. That is the reason why we chose the CHDF
for this patient.
The two merits of CHDF are shown in Table 2. (1)the load on the cardiovascular system is lighter as compared to that during HD and hypotension is less common in CHDF. In the healthy humans, approximately 3

Keio J Med 2002; 51 (3): 165–177
Table 2

Merits and Signiﬁcance of CHDF

1. It imposes only a slight load on the cardiovascular system andscarcely causes a decrease in blood pressure.
HD: 3 L of ﬂuid is forced to be removed (volume normally
removed over 2 days) in 4 hours. Electrolytes, such as Na, K
are rapidly eliminated. Even though the molecular weight ofthese substances is low, a unit of osmotic pressure isdecreased by elimination of one molecule. Consequently,
with the decrease in the osmotic pressure, the bloodpressure may decrease. This potential decline is notcompensated for in HD.
Normal kidneys: A volume of 3 L is removed in 2 days.
CHDF: The volume of 3 L can be removed in 2 days. When one
molecule is eliminated, the a unit of osmotic pressure isdecreased; however, this decrease is compensated for in
CHDF.
2. Substances with molecular weights of 1,000–15,000, which cannot
be eliminated by HD, can be eliminated by CHDF.

Fig. 5 Relationships between the molecular weights of substances
eliminated by HD and CHDF and the elimination rates (clearance).
Substances with molecular weights of 1,000 to 10,000 (e.g., TGFb andIL-8) show a high clearance with CHDF.

L of urine are excreted from the capillaries of the renal
glomeruli in 2 days. The same excretion can be obtained by CHDF. In contrast, in HD, 3 L of water are
removed within 4 hours. (2) CHDF can remove substances with molecular weights between 1,000 and
15,000, which cannot be removed by HD. Cytokines
and some growth factors are involved in the development of heart failure. As shown Fig. 5, the curve running steeply from the upper left side to the lower rightside illustrates how substances are removed during HD,
and the less steep curve alongside it on the right illustrates how substances are removed during CHDF. The
molecular weights of the substances are plotted along
the horizontal axis, and the volume (clearance) of thesubstances removed from the patient’s blood is plottedalong the longitudinal axis. Substances, such as urea, Cr
and uric acid, of which molecular weights are 100 to
1,000, are removed efﬁciently by HD.

173

However, the substances of which molecular weights
are 1,000 to 10,000 or 15,000, such as TGF-b, IL-8, andIL-1, cannot be removed by HD and can be by CHDF.
Since these substances may be involved in the exacerbation of heart failure, removal of these substances by
CHDF is desirable.
On the other hand, CHDF has some demerits; patients are connected to devices with tubes all day long,
because it is a continuous process. This is a big disadvantage for patients. Usually, the procedure is performed over 24 hours a day for about 3 days, and whena signiﬁcant improvement is observed, it is discontinued
for the subsequent 2 days. CHDF can also be switchedto the conventional HD (conducted for 4–5 hours every
other day or every day). In the present patient, however, CHDF was successful; since the cardiac index
increased slightly, and the pulmonary arterial wedge
pressure decreased. The physician-in-charge wanted for
CHDF to be continued. Throughout the treatment, thehighly intelligent patient was conscious and alert. He
and his wife hoped that the CHDF be continued for
longer. Under these circumstances, CHDF was continued for subsequent 20 days, with only a few interruptions, although such long-term continuation of thisprocedure is quite exceptional.
Since the patient is connected to tubes and devices
and the anticoagulant (heparin) is used during CHDF,
the risk of hemorrhage should be always borne in mind.
Therefore, the patient’s condition has to be closely
monitored. It is usually difﬁcult to continue CHDF for along term, but it was continued in this patient because
he was extremely cooperative.
Dr. Ogawa: Heart failure is always associated withvarious degrees of renal dysfunction. While this newtreatment was temporarily efﬁcient, it could not inﬂuence the deterioration in cardiac function or improve
the low cardiac output.
Dr. Sato, could you please comment on assisted circulation as a possible method of treatment, and also
other novel methods of treatment for heart failure?
Dr. Satoh (Internal Medicine): We had administeredalmost all the drugs available for the treatment of heart
failure, including CHDF. We had planned to make thepatient register for a heart transplantation and wait for
donors when his condition had improved a little more.
Dr. Ogawa: As for registration for heart transplantation, would this patient have met the criteria for suchregistration? What are the current criteria for registration?
Dr. Yoshikawa: There are various criteria: e.g., it isrecommended that the patient be younger than 60 years
old, that the patient be on a b-blocker, that the pulmonary vascular resistance be less than 6 wood unit, andthat there be no serious infectious diseases, such as human immunodeﬁciency virus infection.

174

Anyway, our patient had severe heart failure, with aserum BNP level of 5,000 pg/mL, and he would havebeen a good candidate for heart transplantation fromthe point of view of his age as well. We were discussing
whether or not to apply for cardiac transplantation,
but it turned out to be too late. If such a patient had
been admitted to the institute where transplantation is
actively carried out, he might have had a left ventricularassist device (LVAD) implanted and been ranked as
status I in the transplantation registry, which means anurgent condition.
As a matter of fact, heart transplantation has been
performed so far in 10 cases in Japan. Approximately
168 patients in total have applied to the Japanese Circulation Society transplantation sub committee, as ofMarch 2001. Approximately 30 patients have diedduring the waiting period for elective transplantation.
Eighty percent of these had DCM. Such patients canthus die without LVAD even while waiting for transplantation. In all, about 50% die in a year, and approximately 80% survive even in the presence of
LVAD.
Anyway, the most serious problem is that there arevery few organ donors available. Only a limited patients
who undergo transplantation ﬁnd themselves in the
media spotlight. In reality, most patients die while
waiting for transplantation.
Dr. Ogawa: As just mentioned, there are many patients with severe refractory heart failure, who die while
waiting for cardiac transplantation. Our present patient
might also have been a candidate for another form of
non-drug therapy, i.e., biventricular pacing. In thisrecently introduced treatment for heart failure, improvement of the cardiac function is sought by narrowing the QRS interval by pacing from both the right andleft ventricles with a pacemaker, particularly in patientswith a very wide QRS interval seen on ECG. What doyou feel, Dr. Mitamura?
Dr. Mitamura: The method that Dr. Ogawa justreferred to is called re-synchronization therapy; a lagof synchronism between the left and right ventricles
induces abnormal motion of the interventricular septum; when the left ventricle contracts, for example, theinterventricular septum protrudes into the right ventricle. To avoid this, innovations, such as simultaneous
excitation and contraction of the right and left ventricles with a pacemaker have been introduced.
However, the present patient had a right bundle
branch block, so his right ventricle in any event probably contracted later than his left ventricle. So, while
there is the possibility that he would have felt slight relief with pacing of the right ventricle, the probability of
improvement of his cardiac status is indeed rather limited, even if left ventricular pacing had been performed
with a pacemaker introduced into the coronary sinus.

Ogawa S, et al: A case of DCM treated by prolonged CHDF
Table 3Autopsy Finding

1. Dilated cardiomyopathy
A. Dilatation of the bilateral ventricles, severe
Endocardial ﬁbroelastosis
Diffuse ﬁbrosis in the left ventricle
B. Fibrinous ﬁbroelastosis
C. Congestion of the lung
D. Congestion of the liver
E. Pleural effusion (left, 850 ml)þ Ascites (290 ml)
2. Rectal cancer
A. Moderately differentiated adenocarcinoma,
mp, ly0, v1, INFg
B. No invasion or metastasis
3. Acute pancreatitis, severe

Dr. Ogawa: In regard to the differential diagnosis,
the pathological study would ultimately determine
whether the DCM in this patient was primary or secondary. However, the possibility of primary hereditary
cardiomyopathy was clinically considered to be high.
Dr. Umezawa, could you please describe the ﬁndings inthis patient at autopsy.
Dr. Umezawa (Pathology): I shall now describe thebiopsy and autopsy ﬁndings in this patient (Table 3).
This is a heart biopsy slide prepared in April 1993
(Fig. 6). The myocardium is slightly hypertrophic andcharacterized by the presence of abundant collagenﬁbrils in the intermyocardial interstitial tissue. Thus,
there was myocardial hypertrophy with interstitial ﬁbrosis.
The heart weighed 450 g, which represented an increase over the normal heart weight of 300 g. Marked
dilatation of both the ventricles was observed (Fig. 7).
The left ventricular wall was 0.9 cm thick (normal at
autopsy, 1.5 cm). Thus, there was considerable thinningof the ventricular wall. The right ventricular wall was
0.3 cm thick (normal, 0.3–0.4 cm at autopsy). Therefore, the right ventricle showed slight thinning. There
was also ﬁbrinous pericarditis and endocardial ﬁbroelastosis.
Histologically, (1) there were no inﬂammatorychanges, (2) there was no evidence of any granuloma
suggestive of cardiac sarcoidosis, and (3) diffuse myocardial ﬁbrosis was present (Fig. 8A, B).
Mallory’s staining was conducted to show the proportions of the myocardial ﬁbers and collagen ﬁbrils(Fig. 8C, D). The myocardial ﬁbers were stained red
and the collagen ﬁbrils blue by the stain. The myocardial ﬁbers were very coarse, and the collagen ﬁbrils
ﬁlled the spaces between the myocardial ﬁbers. Poor
contractility of the wall observed by echocardiography
was supported by the histological ﬁndings – myocardialﬁbers which are essential for contraction of the muscle
were replaced by collagen ﬁbrils, which explained the
hypokinesia of the myocardial wall observed clinically.

Keio J Med 2002; 51 (3): 165–177

175

Fig. 7

Fig. 6 Histological ﬁndings of the heart biopsy specimen. H.E.
staining. Original magniﬁcation, A. 40. B. 200.

Vacuolar degeneration around the nuclei and thedisappearance of the violet color reﬂecting myocardial
degeneration and deﬁcit are shown by PTAH staining(Fig. 8E). The myocardial ﬁbers disappeared singly,
and not in bundles, while ﬁbers replaced by collagenﬁbrils showed hyperplasia. There was no complicatedarrangement. The deﬁcit and hypertrophy of the myocardial ﬁbers were marked. Based on these ﬁndings, thepatient’s condition was diagnosed as DCM.
In addition, the lungs were edematous and severe
hepatic congestion was observed; 850 ml of pleural ﬂuid
was found on the left side and 0 ml on the right side. In
the right lung, complete adhesion of the parietal pleuraand visceral pleura, which was probably consequent to
the trafﬁc accident, was observed.
A second remarkable ﬁnding was the presence ofadvanced cancer of the rectum. Since this was detected at autopsy, it was a latent carcinoma. It was amoderately differentiated adenocarcinoma, which had
inﬁltrated up to the tunica muscularis propria. Slight

Severe dilation of the right ventricle.

venous invasion was observed. There was no inﬁltration to the bladder or other organs and no metastasis
to other organs. Therefore, there was presumably no
causal relationship between the rectal cancer and thepatient’s fatal course.
Dr. Yoshikawa: I got the impression that the histologically observed ﬁbrosis was prominent, consideringthat this was a case of DCM. The tissue sample may
have been collected from the site of ﬁbrosis around theinterventricular septum, which showed poor contraction
echocardiographically. Administration of a b-blocker
was attempted in this patient, but the heart failure
deteriorated. Such patients often show severe interstitial ﬁbrosis on histological examination. It is therefore
noteworthy that DCM patients who have not respondsatisfactorily to a b-blocker have also showed severeinterstitial ﬁbrosis on histology.
A b-blocker along with an ACE inhibitor is recommended prior to considering cardiac transplantation.
Efforts were made with this patient, but introduction of
the drug in this case was not successful. It is important
to note that patients who do not tolerate b-blockers
have a very poor prognosis.
Dr. Ogawa: This patient had mainly left heart failure,of course, but right heart failure was also a prominent
clinical feature. In many cases with general DCM, theleft cardiac system is mainly affected, and secondary
pulmonary hypertension causes right heart failure. In
this patient, however, the biopsy and autopsy ﬁndings
revealed that the changes in the right ventricle were
almost as marked as those in the left ventricle.
Dr. Umezawa: In this patient, ﬁbrosis of the rightventricular wall was diffuse and severe. The dilatationof the right ventricle was slightly greater than that of
the left ventricle.
Dr. Ogawa: This patient’s condition was familial. Dr.
Yoshikawa, could you please explain the characteristicsof hereditary cardiomyopathy? One more thing I want

176

Ogawa S, et al: A case of DCM treated by prolonged CHDF

Fig. 8 Histological ﬁndings of the heart at autopsy. A and B: H.E.
staining. C and D: Mallory staining. E: PTAH staining. Original magniﬁcation. A: 40; B: 100; C: 100; D: 100; E: 400.

to ask is whether there is any basis for considering
DCM as an autoimmune disease. It is possible thatboth the right and left ventricles are affected when
autoantibodies directed against the myocardium arepresent.
Dr. Yoshikawa: No speciﬁc description has been
made in terms of the clinical features of hereditary

DCM. Many cases of hereditary hypertrophic cardiomyopathy have been reported, with a variety of genemutations. As for the genetic mechanism responsible
for the development of DCM, however, only a limited
number of cases have been reported. Several proteins
which support the contractile elements, including titin,are responsible for the development of DCM.

Keio J Med 2002; 51 (3): 165–177

Basically, autoimmune cardiomyopathy in animal
experiments shows the following pattern: the rightventricle is dilated and cardiomyopathy mimicking
arrhythmogenic right ventricular cardiomyopathy(ARVC) develops. It remains unknown whether or not
autoimmunity was involved in the present patient, but itwould have been of interest to study this aspect.
Dr. Umezawa: There was no morphological evidenceof viral infection. I wonder whether viruses are related
to autoimmunity.
Dr. Yoshikawa: It has generally been considered thatviral infection causes acute myocarditis, in which cellular immune mechanisms are activated. When the cellular membrane becomes disrupted, various proteins are
exposed. If some proteins are presented persistently on
antigen presenting cells, some antibodies will be produced, causing chronic and persistent damage to the
myocardium.
Dr. Ogawa: Could you please give your concludingcomments on the case, Dr. Mitamura?
Dr. Mitamura: Of the many patients who die of heart
failure, about half die a sudden death, and the remaining die of progressive heart failure. The present patient
followed a fairly atypical course; the heart function wasconsiderably poor; even as far back as in 1997, the patient had already reached the level where patients are
generally expected to survive for only 1 or 2 years. Of
the various treatment methods introduced recently, theuse of a b-blocker was initiated in this patient, but
unfortunately, it proved to be ineffective. However,pimobendan, a PDE inhibitor, also known as a calcium
sensitizer, exerted some beneﬁcial effect, and the patient himself felt signiﬁcant improvement in his condition. The heart function was very poor, but it remained

177

stable for some time. Death in cases of heart failure isfrequently associated with infection, but we often encounter patients, like the present patient, in whom
death occurs as a consequence of rapid deterioration ofrenal function.
One remarkable characteristic in this patient wasthat the changes in the right ventricle were also
marked. The arrhythmia recorded in his case could
easily explained by this ﬁnding. The serum BNP level
was also markedly increased. These ﬁndings suggest
widespread lesions in the myocardium. The elevation of
the BUN level was believed to be inﬂuenced by the useof a diuretic, and it is known to be very difﬁcult to use
diuretics in the presence of right heart failure. Thesepatients easily slip into dehydration. This also seems tohave made the treatment of this patient more difﬁcult.
In conclusion, heart transplantation could have been
considered, but my impression is that transplantation
would have been a difﬁcult proposition in this case, because his pulmonary function was also compromised asa result of his trafﬁc accident.
Dr. Ogawa: Thank you very much for your comments.
The patient discussed in today’s CPC had refractory
heart failure. According to the text book, 50% of heart
failure patients die within 5 years of the diagnosis.
Thus, it is a very serious disease; patients usually die
within 2 to 3 years, on average, after the onset of heart
failure. Despite this bleak prognosis, owing to the currently available methods of treatment, our patient lived
for 8 years after the diagnosis of heart failure. If hearttransplantation were introduced more aggressively inclinical cases, it could be lifesaving.