*From the Division of Hematology and Internal Medicine (Drs. Dingli and Gertz) and the Division of Pulmonary and Critical Care Medicine (Dr. Utz), Mayo Clinic and Mayo Foundation, Rochester, MN.
Correspondence to: Morie A. Gertz, MD, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: Gertz.Morie@mayo.edu
Pulmonary hypertension (PH) with right-sided cardiac failure is a rare
complication of amyloidosis, and its natural history is not
well-defined. The aim of our study was to evaluate patients who were
seen at our institution who had PH and amyloidosis and to describe the
natural history of this complication. The study was a retrospective
chart review of patients seen at the Mayo Clinic with both PH and
amyloidosis listed as major diagnoses between January 1, 1980, and
December 31, 1999. Patients with known causes of PH were excluded. Five
patients met our criteria (four women and one man). Four patients had
light-chain amyloidosis and one had amyloid A deposition secondary to
familial Mediterranean fever. All patients had symptoms related to PH
without echocardiographic evidence of left ventricular dysfunction. The
median survival time after the diagnosis of amyloidosis was 2.8 years,
and PH was found a median of 73 days before death. Five patients died
of cardiac complications, including one with sudden cardiac death. PH
is an unusual complication of amyloidosis. Patients develop PH late in
the disease process and do not have a worse prognosis compared to other
patients with cardiac amyloidosis. PH is a marker of advanced
amyloidosis group of disorders is characterized by the deposition of
amorphous extracellular material.1 The nomenclature is
based on the composition of the amyloid subunit protein in these
deposits. Light-chain amyloid (AL) and heavy-chain amyloid
result from Ig light-chain or heavy-chain deposition, respectively.
Chronic inflammatory conditions result in elevated levels of serum
amyloid A (AA) protein, leading to AA amyloidosis. End-stage
renal failure is associated withβ
2-microglobulin deposition, causing the
formation of β2-M amyloid.
Transthyretin deposition leads to ATTR amyloid, which may be present in
familial or senile amyloidosis.,1 All types of
amyloid bind Congo red, produce apple-green birefringence under
polarized light, and have a β-pleated sheet appearance.1
The extracellular deposits interfere with organ function and can lead
to premature death. The most common presentations are unexplained
nephrotic syndrome, cardiomyopathy, hepatomegaly, and peripheral
The most frequent cardiac presentation is that of a restrictive
cardiomyopathy with diastolic dysfunction. The presence of systolic
dysfunction suggests advanced disease. Less commonly, patients present
with conduction system disease or an embolic event.3–
Rarely, patients present with ischemic heart disease from obstructive
intramural amyloid deposits.4Right-sided heart failure
secondary to pulmonary hypertension (PH) from vascular amyloid
deposits is rare.5–8 Herein, we report our
experience with five patients who had PH secondary to pulmonary
vascular amyloidosis in the absence of significant left-sided cardiac
We performed a computerized search of all patient records at the
Mayo Clinic having both PH and amyloidosis listed as major diagnoses.
The study was approved by the institutional review board in accordance
with federal regulations. Our search covered the period from January 1,
1980, to December 31, 1999. Amyloidosis was diagnosed by tissue biopsy.
The diagnosis of PH was based on either transthoracic echocardiography
(TTE) data and/or measurements during right-sided heart catheterization
or pulmonary angiography procedures. We considered patients to have PH
either if their estimated right ventricular systolic pressure (RVsys)
was > 35 mm Hg as measured by TTE or if their mean pulmonary artery
pressure (PAP) was > 25 mm Hg during right-sided heart
catheterization or pulmonary angiography procedures.9–10
Patients were excluded from further analysis if one of the following
known causes of PH was evident: left-sided heart failure; congenital
heart disease; PE (documented or suspected); moderate-to-severe COPD
(ie, FEV1 < 40% of predicted
maximum); moderate-to-severe restrictive lung disease (total lung
capacity, < 70% of predicted maximum); connective tissue disorder
with pulmonary involvement; thoracic wall deformities; carcinoid
syndrome; chronic liver disease; sleep apnea syndromes; HIV infection
or use of anorectic medication.,9 The echocardiographic
features of cardiac amyloidosis have been well-described and were used
to exclude patients with significant cardiac
involvement.11–12 Particular attention was paid to Doppler
ultrasound parameters that were indicative of subtle cardiac
involvement as well as the comments made by the consultant
cardiologists reporting on these patients.13–15
Our search generated a list of 18 patients with both PH and
amyloidosis. Of these, 13 patients were excluded. Eleven patients had
echocardiographic evidence of severe cardiac amyloidosis, 1 patient had
severe valvular heart disease (ie, aortic stenosis and grade
4 mitral regurgitation), and another patient had solitary bronchial
amyloidosis. The characteristics of our remaining five patients are
summarized in Table 1
. One patient already has been reported.16 Testing to rule
out pulmonary embolism (PE) was performed in three patients. One
patient underwent a pulmonary angiogram, one patient underwent a
ventilation-perfusion lung scan, and another patient underwent an
ultra-fast CT scan of the chest. The results of all these tests were
negative for PE.
Four patients were women, and one patient was a man. The median age at
diagnosis of amyloidosis was 61 years (age range, 48 to 82 years),
while the median age at the diagnosis of PH was 64 years (age range, 48
to 82 years). All patients had symptoms related to PH. The most common
presenting symptom was dyspnea (5 of 5 patients), and one patient had
exertional chest pain. No patient had syncope or presyncope. All five
patients had elevated jugular venous pressure and lower limb edema, and
three patients had hepatomegaly with ascites at presentation. Two
patients had a palpable right ventricular lift and an audible
Amyloidosis was diagnosed histologically in all patients. Four patients
had AL present, and two of these patients had multiple myeloma. Three
patients had amyloid in the bone marrow, and one patient had amyloid in
the lungs. One patient had AA amyloid present in a liver biopsy
specimen, a condition that was secondary to familial Mediterranean
TTE data were available for four patients. None had echocardiographic
evidence of cardiac amyloid (Table 2
). The median ejection fraction was 66% (range, 50 to 73%). The
median RVsys was 54 mm Hg (range, 51 to 91mm Hg). All patients had
right ventricular dilatation with depressed function. Three patients
(patients 1, 4, and 5) had invasive measurements of PAP, and the mean
PAP measurements were 58, 48, and 62 mm Hg, respectively.
Data from pulmonary function tests were available for one
patient.3 He had a decrease in diffusing capacity that was
suggestive of advanced pulmonary amyloidosis.17 The
results of the rest of the pulmonary function studies were normal.
Chest radiograph findings were abnormal in three patients (patients 2,
3, and 5) who had interstitial infiltrates. The presence of pulmonary
parenchymal amyloid was confirmed at autopsy in two patients
(patients 4 and 5) and was suspected in patient 1. Four patients
underwent CT scans of the chest, and the findings were abnormal in
three patients who showed interstitial reticulonodular infiltrates.
These features of pulmonary amyloidosis have been described
All patients were treated for their PH (Table 3
). Four patients were prescribed diuretics, three patients were
prescribed calcium channel blockers, one patient was prescribed
aspirin, and one patient was prescribed digoxin. The two patients with
multiple myeloma were given combination chemotherapy, while the patient
with familial Mediterranean fever was treated with colchicine.
We have follow-up data on all patients. All patients died from
cardiac causes. Four patients had severe right-sided heart failure, and
one patient (patient 4) died suddenly while being evaluated for her
symptoms at our institution. Two patients (patients 4 and 5) had
postmortem examinations. Both patients had multiorgan amyloid
deposition. In the lungs, there was widespread vascular obstruction
secondary to amyloid deposition (Fig 1
). The median time to death after the diagnosis of PH was 73 days
(range, 19 to 1,036 days).
Amyloid deposition can be a systemic or focal process. The
deposition of fibrils in the extracellular matrix leads to organ
dysfunction, though the exact mechanisms for this are not understood.
AL and AA tend to be the results of systemic processes with deposition
of fibrils in the kidney, heart, liver, GI tract, nervous system and
respiratory tract. This explains why amyloidosis can present as
different “organ syndromes” requiring a high index of
An increase in pulmonary vascular resistance (PVR) requires a higher
PAP to maintain a given right ventricular output. The estimation of PVR
requires invasive measurements of left ventricular end-diastolic
pressure. Transthoracic echocardiography and Doppler analysis allow the
noninvasive estimation of RVsys. If the pulmonary valve is normal, then
RVsys is similar to PAP as measured during right-sided heart
catheterization or pulmonary angiography. Therefore, PAP is used as a
surrogate for PVR, assuming that left ventricular end-diastolic
pressure is normal. However, subtle left ventricular dysfunction may
undermine this assumption. Cardiac amyloidosis manifests itself
as a restrictive process that may be difficult to detect.
Doppler evaluation of ventricular function is essential to rule out
early cardiac amyloidosis.13,15 Very rarely,
extensive echocardiographic evaluation can still miss significant
In all reported cases, vascular obstruction due to the amyloid deposits
is considered to be the cause of increased PVR. Vascular smooth muscle
tone is under the opposing influences of vasodilator substances
(eg, nitric oxide and prostacyclin) and vasoconstrictor
substances (eg, endothelin 1).19In primary PH,
the underlying mechanism is thought to be a dysfunctional
endothelium.20The abnormal endothelial cells express
lower levels of nitric oxide synthase and cyclooxygenase with increased
levels of endothelin 1 promoting vasoconstriction and smooth muscle
proliferation. Coronary arteries with amyloid deposits have an
attenuated vasodilator response to acetylcholine (ie, an
endothelium-dependent factor).21 In addition, β-amyloid
enhances the vasoconstriction induced on aortic rings by phenylephrine
and endothelin.22 Therefore, amyloid deposits in blood
vessel walls can result in endothelial dysfunction. It is possible that
similar mechanisms operate in the pulmonary circulation leading to
vasoconstriction and PH in the absence of severe intravascular amyloid
Treating PH in patients with amyloidosis can be a challenge. The
mainstay of therapy is the administration of vasodilators with calcium
channel blockers, often in high doses. However, patients with
amyloidosis often have orthostatic hypotension and cannot tolerate the
high doses that are required for treatment. In addition, calcium
channel blockers have been shown to increase the incidence of heart
failure in patients with cardiac amyloid
deposits.23 It is not known whether there is any
improvement in PH with treatment of the underlying process that is
driving the amyloid deposition. Patients with systemic amyloidosis
respond slowly to chemotherapy. Often, the disease is far advanced, and
they do not survive long enough to achieve a response.
In published case reports,6,8–9 the prognosis of patients
with PH and amyloidosis has been poor (median survival time, 2 days;
range, 1 to 41 days). The median survival time in our series was 73
days. However, there is no difference in survival time once amyloidosis
is found. The median survival time in our patients was 2.8 years
compared to a median survival time of 2 years for all patients with
amyloidosis at our institution (p = 0.11). Therefore, it seems that
the development of PH is a sign of advanced amyloidosis.
In conclusion, patients with amyloidosis may develop PH. If present, PH
is a sign of advanced disease, and the survival rate after diagnosis is
low. A diagnosis of PH should be considered in patients with
amyloidosis and unexplained dyspnea or fluid overload and normal left
Abbreviations: AA =
amyloid A; AL = light-chain amyloid; PAP = pulmonary artery
pressure; PE = pulmonary embolism; PH = pulmonary hypertension;
PVR = pulmonary vascular resistance; RVsys = right ventricular
systolic pressure; TTE = transthoracic echocardiography
BM = bone marrow; CHF = congestive heart
failure; F = female; M = male.
After diagnosis of PH.
RV = right ventricle.
+ = medical treatment administered; – =
medical treatment not administered; CCB = calcium channel blocker; A =
doxorubicin; B = BCNU; C = cyclophosphamide; D = dexamethasone; M =
melphalan; P = prednisone; V = vincristine.
We thank William D. Edwards, MD, Division of
Anatomic Pathology, Mayo Clinic Rochester, for the photomicrograph.
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