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(Chest. 2001;120:1735-1739.)
© 2001 American College of Chest Physicians

Pulmonary Hypertension in Patients With Amyloidosis*

David Dingli, MD; James P. Utz, MD, FCCP and Morie A. Gertz, MD

* 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{at}mayo.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.

Key Words: amyloidosis • pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The 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 with ß2-microglobulin deposition, causing the formation of ß2-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 ß-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 neuropathy.1 2

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.4 Right-sided heart failure secondary to pulmonary hypertension (PH) from vascular amyloid deposits is rare.5 6 7 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 involvement.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
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 14 15


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
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.


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  		Table 1.. Features of Patients With PH and Amyloidosis*

 
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 S3.

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 fever.

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.


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  		Table 2.. Echocardiographic Features in Four Patients With PH and Amyloidosis*

 
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 elsewhere.17

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.


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  		Table 3.. Therapy in Five Patients With PH and Amyloidosis*

 
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).



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  		Figure 1.. Photomicrograph of the lungs of a 54-year-old woman, demonstrating extensive amyloid deposition in arteries with secondary thrombus formation (sulfated alcian blue stain, original x10).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
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 suspicion.1

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 amyloid deposition.18

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).19 In primary PH, the underlying mechanism is thought to be a dysfunctional endothelium.20 The 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, ß-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 deposits.

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 ventricular function.


   Acknowledgements
 
We thank William D. Edwards, MD, Division of Anatomic Pathology, Mayo Clinic Rochester, for the photomicrograph.


   Footnotes
 
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

Received for publication December 4, 2000. Accepted for publication May 22, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gertz, MA, Lacy, MQ, Dispenzieri, A (1999) Amyloidosis. Hematol Oncol Clin North Am 13,1211-1233[CrossRef][ISI][Medline]
  2. Gertz, MA, Lacy, MQ, Dispenzieri, A (1999) Amyloidosis: recognition, confirmation, prognosis and therapy. Mayo Clin Proc 74,490-494[ISI][Medline]
  3. Kyle, RA, Gertz, MA (1990) Cardiac amyloidosis. Int J Cardiol 28,139-141[CrossRef][ISI][Medline]
  4. Mueller, PS, Edwards, WD, Gertz, MA (2000) Symptomatic ischemic heart disease resulting from obstructive intramural coronary amyloidosis. Am J Med 109,181-188[CrossRef][ISI][Medline]
  5. Schiue, ST, McNally, DP (1988) Pulmonary hypertension from prominent vascular involvement in diffuse amyloidosis. Arch Intern Med 148,687-689[Abstract]
  6. Johnson, WJ, Lie, JT (1991) Pulmonary hypertension and familial Mediterranean fever: a previously unrecognized association. Mayo Clin Proc 66,919-925[ISI][Medline]
  7. Lutz, AE, Schneider, U, Ehlerding, G, et al (1995) Right ventricular cardiac failure and pulmonary hypertension in a long-term dialysis patient: unusual presentation of visceral ß2-microglobulin amyloidosis. Nephrol Dial Transplant 10,555-558[Free Full Text]
  8. Chapman, AD, Brown, PA, Kerr, KM (1999) Right heart failure as the dominant clinical picture in a case of primary amyloidosis affecting the pulmonary vasculature. Scott Med J 44,116-117[ISI][Medline]
  9. Krowka, MJ (2000) Pulmonary hypertension: diagnostics and therapeutics. Mayo Clin Proc 75,625-629[ISI][Medline]
  10. Rubin, LJ (1997) Primary pulmonary hypertension. N Engl J Med 336,111-117[Free Full Text]
  11. Kyle, RA, Spittell, PC, Gertz, MA, et al (1996) The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 171,395-400
  12. Cueto-Garcia, L, Reeder, GS, Kyle, RA, et al (1985) Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 6,737-743[Abstract]
  13. Klein, AL, Hatle, LK, Burstow, DJ, et al (1989) Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 13,1017-1026[Abstract]
  14. Klein, AL, Hatle, LK, Burstow, DJ, et al (1990) Comprehensive Doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 15,99-108[Abstract]
  15. Abdalla, H, Murray, RD, Lee, JC, et al (1998) Duration of pulmonary venous atrial reversal flow velocity and mitral inflow A wave: new measure of severity of cardiac amyloidosis. J Am Soc Echocardiogr 11,1125-1133[CrossRef][ISI][Medline]
  16. Veinot, JP, Edwards, WD, Kyle, RA (1993) Pulmonary vascular amyloid causing pulmonary hypertension: report of a case and review of literature. Cardiovasc Pathol 2,231-235
  17. Utz, JP, Swensen, SJ, Gertz, MA (1996) Pulmonary amyloidosis: the Mayo Clinic experience from 1980 to 1993. Ann Intern Med 124,407-413[Abstract/Free Full Text]
  18. Gertz, MA, Grogan, M, Kyle, RA, et al (1997) Endomyocardial biopsy proven light chain amyloidosis (AL) without echocardiographic features of infiltrative cardiomyopathy. Am J Cardiol 80,93-95[CrossRef][ISI][Medline]
  19. Fishman, AP (1998) Etiology and pathogenesis of primary pulmonary hypertension: a perspective. Chest 114,242S-247S[ISI][Medline]
  20. Farber, H, Loscalzo, J (1999) Prothrombotic mechanisms in primary pulmonary hypertension. J Lab Clin Med 134,561-566[CrossRef][ISI][Medline]
  21. Al Suwaidi, J, Velianou, JL, Gertz, MA, et al (1999) Systemic amyloidosis presenting with angina pectoris. Ann Intern Med 131,838-841[Abstract/Free Full Text]
  22. Crawford, F, Suo, Z, Fang, C, et al (1998) Characteristics of the in vitro vasoactivity of beta-amyloid peptides. Exp Neurol 150,159-168[CrossRef][ISI][Medline]
  23. Gertz, MA, Falk, RH, Skinner, M, et al (1985) Worsening of congestive heart failure in amyloid heart disease treated with calcium channel-blocking agents. Am J Cardiol 55,1645[CrossRef][ISI][Medline]



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