Download An Interesting Case of Cardiac Amyloidosis Initially Diagnosed as

Hellenic J Cardiol 2010; 51: 552-557
Case Report
An Interesting Case of Cardiac Amyloidosis
Initially Diagnosed as Hypertrophic
Cardiomyopathy
Amalia Boufidou1, Lilian Mantziari1, Stelios Paraskevaidis1, Haralambos Karvounis1,
Eleni Nenopoulou2, Maria-Eleni Manthou2, Ioannis H. Styliadis1, Georgios Parcharidis1
1
First Cardiology Department, AHEPA University Hospital, 2General Pathology Laboratory, Aristotle University of
Thessaloniki, Greece
Key words: Amyloid,
cardiac involvement,
endomyocardial
biopsy, ECG
findings,
echocardiography.
Cardiac involvement occurs frequently in primary amyloidosis and is associated with heart failure hospitalizations and poor survival. The initial presentation of the disease may be misleading, resulting in under-diagnosis of cardiac amyloidosis and late initiation of treatment. We present a case of cardiac amyloidosis initially misdiagnosed as hypertrophic cardiomyopathy and we discuss the key findings of the disease along with
the latest evidence regarding the management and prognosis of cardiac amyloidosis.
A
Manuscript received:
April 2, 2009;
Accepted:
February 9, 2010.
Address:
Lilian Mantziari
First Cardiology Dept.
AHEPA University
Hospital
1 Kiriakidi St.
Thessaloniki, Greece
e-mail: lmantziari@
yahoo.com
myloidosis refers to a rare group
of disorders caused by the extracellular deposition of insoluble
abnormal fibrils, called amyloid, which are
composed of a variety of serum proteins.
Cardiac involvement may occur, with or
without clinical manifestations, as a part
of systemic amyloidosis or as a localized
phenomenon, and is associated with poor
prognosis.1,2 We present a case of biopsyproven cardiac amyloidosis in a woman
with symptoms of congestive heart failure
who was referred to our hospital with the
diagnosis of hypertrophic cardiomyopathy,
and we discuss the key ECG and echocardiographic findings that a clinician should
evaluate in order to eliminate under-diagnosis of cardiac amyloidosis, along with
the current data concerning prognosis and
treatment.
Case presentation
A 48-year-old woman was admitted to our
clinic with dyspnea on exertion, fatigue,
anorexia and lower limb edema. She al-
552 • HJC (Hellenic Journal of Cardiology)
so mentioned exertional chest pain. The
patient was free of any personal history
until three months before presentation,
when peripheral edema and ascites first
occurred. The diagnosis by her cardiologist was hypertrophic cardiomyopathy,
based on asymmetrical hypertrophy of the
left ventricle on echocardiography. She
had no family history of cardiovascular
disease, sudden cardiac death or syncope.
On physical examination she had blood
pressure 90/70 mmHg, heart rate 66 beats/
min, a second heart sound with an increased intensity of the pulmonic component, a 2/6 apical systolic murmur and
normal lung auscultation. Jugular vein dilatation and a palpable liver with positive
hepatojugular reflux were present, along
with signs of ascites. There was a first degree atrioventricular block on the ECG
and a pseudo-infarct pattern without signs
of left ventricular hypertrophy (Figure 1).
The chest X-ray on admission showed cardiomegaly. Blood count was normal. Serum biochemistry was normal except for
elevated creatine kinase (CPK), 435 U/L,
Interesting Case of Cardiac Amyloidosis
I
V1
II
V2
III
V3
aVR
V4
aVL
V5
aVF
V6
Figure 1. Twelve-lead ECG on admission showed a QS complex in lead V1, Rsr complex in V2, rS in V3, QS in V4, rS complexes in V5 and
V6, and QS waves in leads II, III, aVF, consistent with a pseudo-infarct pattern. A first-degree atrioventricular block is also present, with a
PQ duration of 325 ms.
with the myocardial isoenzyme CK-MB equal to 25
U/L, and elevated lactate dehydrogenase. Serum homocysteine levels were also increased (14.7 μmol/L,
normal range 9-12 μmol/L). Testing for connective
tissue diseases was negative (Ra test, antinuclear and
anti-mitochondrial antibodies).
Echocardiographic study showed asymmetric hypertrophy of the left ventricle, with the posterior wall
V
A
thicker than the septum (20 and 16 mm, respectively) and a granular “sparkling” texture. The left and
right atria were dilated and there was a small pericardial effusion (Figure 2). Transmitral Doppler flow revealed a restrictive filling pattern (Figure 3) with an E
wave equal to 1.3 m/s, an A wave equal to 0.6 m/s, and
an E/A ratio >2; reduced deceleration time ≤150 ms;
and the diastolic wave of pulmonary vein flow higher
V
Β
RV
IVS
LV
RV
LV
LVPW
PE
PE
LA
LA
RA
Figure 2. Parasternal short axis view (A) and apical four-chamber view (B) revealed thickened left ventricular walls with a granular “sparkling” appearance, enlarged atria and a small pericardial effusion. LV – left ventricle; LA – left atrium; RV – right ventricle; RA – right
atrium; IVS – interventricular septum; LVPW – left ventricular posterior wall; PE – pericardial effusion.
(Hellenic Journal of Cardiology) HJC • 553
A. Boufidou et al
Figure 3. Transmitral Doppler flow showed a restrictive filling
pattern with E/A >2, reduced deceleration time and reduced
isovolumic relaxation time. E – early diastolic velocity; A – late
diastolic velocity.
than the systolic. Tissue Doppler imaging revealed reduced systolic and diastolic mitral annular velocities.
There was mild mitral and tricuspid regurgitation and
the estimated right ventricular systolic pressure was
34 mmHg.
The patient was on atenolol 50 mg/day and a hydrochlorothiazide-amiloride combination (25/2.5
mg). Amiodarone 200 mg twice daily was added because of multifocal ventricular premature beats and
an episode of non-sustained ventricular tachycardia
on the 24-hour ECG. On the fifth day of treatment
with amiodarone the patient experienced a presyncopal episode with nausea, dizziness, hypotension
(systolic arterial pressure equal to 65 mmHg) and a
Figure 4. Extended degeneration of the myocardium, vacuolization and disruption of the cardiac myocytes. Focal necrosis and
interstitial fibrosis are also seen.
554 • HJC (Hellenic Journal of Cardiology)
slow junctional rhythm of 38 bpm. A temporary pacemaker was implanted while atenolol and amiodarone
were withdrawn. The pacemaker was removed three
days later when sinus rhythm was restored and amiodarone was started again in a smaller dose of 200 mg
once daily.
Coronary angiography showed normal coronary
arteries. Ventriculography revealed a reduced ejection fraction and mild to moderate mitral regurgitation. Right heart catheterization had the following
findings: mean right atrial pressure 9 mmHg, right
ventricular pressures 35/0-10 mmHg (systolic/diastolic-mean), pulmonary artery pressure 36/12-24, mean
capillary wedge pressure 18 mmHg and increased left
ventricular end-diastolic pressure of 19 mmHg (systolic 105 mmHg). An endomyocardial biopsy was taken, which revealed severe lesions consistent with cardiac amyloidosis with muscle cell necrosis (Figures 4
& 5).
Once the diagnosis of amyloidosis was established
by echocardiographic and biopsy findings, methylprednisolone 16 mg daily was added and we sought to
differentiate between primary amyloidosis (PA) and
secondary amyloidosis (SA). PA is often associated
with multiple myeloma, which was ruled out using appropriate tests. Urine protein immunoblotting indicated a lambda light monoclonal chain, which is diagnostic for PA.
The patient was treated with amiodarone 200 mg
daily, furosemide 40-80 mg, spironolactone 50-100
mg and folic acid. During six months of follow up,
symptoms of right heart failure with ascites and pe-
Figure 5. Amyloid (black arrows) was identified on immunohistochemical testing with the use of monoclonal antibodies.
Interesting Case of Cardiac Amyloidosis
ripheral edema were prominent and resulted in repeated hospitalizations. Chemotherapy cycles with
melphalan hydrochloride 14 mg and methylprednisolone 16 mg three times daily were added without any
improvement. One month after diagnosis, the patient’s condition was complicated by thrombosis of
the celiac aortic bifurcation and the right deep femoral artery (Figure 6). Thrombectomy with a Fogarty
catheter was performed and dicoumarol was added.
Repeated hospitalizations due to congestive heart
failure continued until nine months after diagnosis when the patient died suddenly while asleep. A
24-hour ECG fifteen days before death was negative
for malignant arrhythmia.
Discussion
Our patient presented with symptoms of right heart
failure and echocardiographic findings of asymmetric
hypertrophy of the left ventricle. The initial diagnosis by the referring cardiologist was hypertrophic cardiomyopathy. A closer observation, however, of the
echocardiographic and ECG findings was sufficient to
call into question the diagnosis of hypertrophic cardiomyopathy. Moreover, it is interesting that our patient had a typical disease course, which was complicated by both arrhythmias and thrombosis, and typically died suddenly while asleep, nine months after
cardiac involvement occurred.
The ECG in hypertrophic cardiomyopathy shows
signs of left ventricular hypertrophy, while our patient presented low voltage R waves. A normal ECG
may be present in 15% of hypertrophic cardiomyopathy patients, usually those with localized hypertrophy. Low voltage waves in the limb and the precordial
leads are the most common ECG finding in cardiac
amyloidosis and are present in over 50% of patients
with PA.3,4 The largest series of ECG findings, in 127
patients with PA and biopsy-proven cardiac involvement, comes from the Mayo Clinic. 4 The two main
ECG abnormalities were the presence of low voltages
and a pseudo-infarct pattern in 46% and 47% of patients, respectively. Both ECG findings were present
in 25% of patients. Our patient had low voltages and
poor R-wave progression in the precordial leads, as
well as abnormal Q waves in the limb and the precordial leads.
Thickening of the left ventricular wall due to amyloid infiltration can be misdiagnosed as true left ventricular hypertrophy. The increased left ventricular
wall thickness in cardiac amyloidosis, however, is as-
Figure 6. Angiography showing thrombosis of the celiac aortic
bifurcation.
sociated with low voltages on the ECG and this feature is a specific finding for infiltrative diseases, of
which amyloidosis is the most common.4-6 Rahman et
al showed that a septal thickness >1.98 cm combined
with low voltages on ECG has a sensitivity of 72%
and a specificity of 91% for the diagnosis of cardiac
amyloidosis.6
The granular “sparkling” appearance of the myocardium in echocardiography is characteristic, but not
specific to amyloidosis. In one series this finding was
present in 26% of patients. 7 This echocardiographic criterion has a sensitivity of 87% and a specificity
of 81% for the diagnosis of cardiac amyloidosis, but
when atrial enlargement is also present it can reach a
sensitivity of 100%.
Doppler transmitral flow measurements showed
a restrictive filling pattern with an E/A ratio >2. Restrictive physiology in cardiac amyloidosis is attributed to amyloid infiltration, which results in a stiff
myocardium. Systolic function impairment is a late
phenomenon. Tissue Doppler imaging in cardiac amyloidosis has been shown to detect early diastolic dysfunction, even with minimal wall thickening. Moreover, a tissue Doppler mitral annular early diastolic
velocity (E΄) < 8 cm/s can discriminate between restrictive cardiomyopathy and constrictive pericartidis.8
Differential diagnosis between PA and SA is important in order to specify further management and
prognosis.1,2 Cardiac involvement occurs in 50% of
patients with PA and has been associated with severe
(Hellenic Journal of Cardiology) HJC • 555
A. Boufidou et al
cardiac impairment and a worse prognosis than cardiac involvement due to SA; the median survival is 1.08
years and is shorter in the presence of heart failure.9
PA involves extracellular tissue and cardiac deposition of fibrils, called amyloid, that are composed
of light chain immunoglobulin (AL) produced by
monoclonal plasma cells. 10 Multiple myeloma and
Waldestrom macroglobulinemia are the two main diseases associated with PA.1 Multiple myeloma and amyloidosis may coexist, or the diagnosis of multiple myeloma may come before or after the presentation of
amyloidosis or cardiac amyloidosis. Amyloid deposition in the heart may involve the myocardium and the
conductive system. Other sites where amyloid can be
found are the intima, media and adventitial layers of
the epicardial11 and endomyocardial coronary arteries, the cardiac valves and the pericardium. Extensive
amyloid deposition in coronary arteries may result in
typical anginal symptoms with normal coronary angiography.12
Amyloid deposition in the conductive tissue may
cause atrioventricular conduction abnormalities, mainly second- and third-degree atrioventricular block. Patients with cardiac amyloidosis are sensitive to digitalis, nifedipine and verapamil. It is possible that this increased sensitivity to antiarrhythmics was the substrate
for the manifestation of junctional rhythm in our patient, as a response to treatment with the combination
of atenolol and amiodarone, while a reduced dosage of
amiodarone alone was well tolerated.
Our case was complicated by thrombosis of the
celiac aortic bifurcation and the right deep femoral
artery. Even though amyloidosis may be associated
with hemorrhagic diathesis, the occurrence of thromboembolic episodes is common even in sinus rhythm.
In one series of patients with PA, 9 out of 15 patients
who were not receiving anticoagulation therapy had
arterial thromboembolic events involving ischemic
stroke, multiple peripheral emboli and mesenteric
ischemia. All 9 patients were in sinus rhythm and only
one had a visible thrombus on echocardiography.13 It
is generally believed that amyloid deposition in atrial
walls results in a mechanic atrial standstill, which favors thrombus formation. This is the rationale behind
the recommendation of dicoumarol prescription in
patients with severe cardiac amyloidosis and abnormal atrial function.
The prognosis of PA is poor, with a mean survival
of 13 months without treatment, which may be prolonged to 17 months after cyclic melphalan and methylprednisolone treatment.14 Cardiac involvement is as556 • HJC (Hellenic Journal of Cardiology)
sociated with an even worse prognosis. Mean survival
from onset of heart failure symptoms is no more than
6 months and predisposes to sudden death.15
Heart transplantation remains controversial because of the potential for amyloid deposition in the
graft, or for multiple myeloma occurrence during follow up. There are a few patients who have received a
cardiac transplant and shown variable survival. Early
postoperative results do not differ from other heart
transplantation patients, but survival rates drop 30
months after transplantation in amyloidosis patients.1
The survival of 7 patients with PA treated with heart
transplantation and chemotherapy in the United Kingdom was 71% at 1 and 2 years, but 36% at 5 years.16
High-dose intravenous melphalan in combination
with stem cell autologous transplantation is currently
used for systemic PA, but its efficacy has not yet been
proved. The overall survival of 92 patients who received this treatment in the United Kingdom was 5.3
years and survival among those who survived beyond
day 100 was 8.5 years.17 Alternatively, a more aggressive treatment with sequential heart and stem cell
transplantation has been applied in selected patients;
after a median of 95 months follow up, 3 out of 5 patients were asymptomatic, without evidence of cardiac or extra-cardiac amyloid accumulation.18 Recently, new chemotherapy regimens have been developed
and various specific anti-amyloid drugs have shown
very promising results.19
In conclusion, cardiac amyloidosis is a severe disease with a poor prognosis. The clinical cardiologist should suspect cardiac amyloidosis in a patient
with right heart failure symptoms and thickened left
ventricular walls, with a restrictive filling pattern of
the left ventricle combined with low voltages on the
ECG. In addition, anticoagulation treatment with
dicoumarol is recommended in patients with severe
cardiac amyloidosis, even those in sinus rhythm, in order to avoid thromboembolic events.
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