Correspondence

Restrictive Cardiomyopathy

N Engl J Med 1997; 336:1917-1918June 26, 1997

Article

To the Editor:

We wish to raise some points of disagreement with the description of cardiac amyloidosis by Kushwaha et al. (Jan. 23 issue)1 in their article on restrictive cardiomyopathy. The internationally accepted classification of the amyloidosis is based on the chemical nature of the deposited protein fibrils.2 Secondary amyloidosis refers exclusively to the reactive form characterized by deposition of a nonimmunoglobulin, amyloid A (AA), in association with chronic infection and inflammation (e.g., rheumatoid arthritis, inflammatory bowel disease, osteomyelitis, tuberculosis, or leprosy). The familial and senile amyloidoses are distinct entities that have never been classified as secondary and that have unique biochemical and clinical features. The majority of patients with primary (now known as AL) amyloidosis do not have multiple myeloma.3 This is important, because the clinician must consider AL amyloidosis if features of a restrictive cardiomyopathy are present, despite the absence of signs of myeloma.

We disagree with several of the authors' clinical statements about cardiac amyloidosis. They state that the ventricular cavities are often moderately dilated, that cardiomegaly is uncommon, and that atrial dilatation is a function of atrioventricular valvular regurgitation. In our own data base of more than 200 patients with cardiac amyloidosis (unpublished data), echocardiographic left ventricular dilatation was seen in only 3 percent of the patients and when present was frequently associated with coexisting coronary artery disease or substantial mitral regurgitation. Although atrial enlargement was common, it was generally unrelated to atrioventricular valvular regurgitation — rather, it was a function of high atrial-filling pressures. In our experience, mild-to-moderate cardiomegaly is frequently apparent on chest films once heart failure occurs. This may reflect either atrial enlargement and ventricular thickening or right ventricular dilatation, since the left ventricular cavity size remains normal.

While left-ventricular-wall thickness is a prognostic determinant in amyloidosis, the paper cited4 does not deal exclusively with cardiac amyloidosis. Indeed, most patients with normal wall thickness (median survival, 2.4 years) had no evidence of cardiomyopathy. Once severe heart failure due to amyloid cardiomyopathy supervenes, the prognosis is very poor regardless of the degree of left ventricular thickening.

Finally, it should be mentioned that dose-intensive melphalan with autologous-blood stem-cell support for the treatment of AL amyloidosis is currently undergoing intensive evaluation.5 Initial data suggest a good response of the plasma-cell dyscrasia, but the tolerability and effectiveness of this treatment in patients with cardiac amyloidosis are still undetermined.

Johann Reisinger, M.D.
Simon W. Dubrey, M.D.
Rodney H. Falk, M.D.
Boston University Medical Center, Boston, MA 02118

5 References

1
Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336:267-276
Full Text | Web of Science | Medline

2
WHO-IUIS Nomenclature Sub-CommitteeNomenclature of amyloid and amyloidosis. Bull World Health Organ 1993;71:105-112
Web of Science | Medline

3
Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45-59
Web of Science | Medline

4
Cueto-Garcia L, Reeder GS, Kyle RA, et al. Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737-743
CrossRef | Web of Science | Medline

5
Comenzo RL, Vosburgh E, Simms RW, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996;88:2801-2806
Web of Science | Medline

To the Editor:

The excellent review of restrictive cardiomyopathy by Kushwaha et al. requires some clarification of the often difficult problem of differentiating restrictive cardiomyopathy from constrictive pericarditis. Apart from the fact that constrictive pericarditis can be associated with an S₄ gallop, the contrast of S₃ in restrictive cardiomyopathy and pericardial knock in constrictive pericarditis is erroneous. The abnormal third heart sound of constrictive pericarditis has the same dynamics as any abnormal third heart sound (perhaps with an added element of diastolic suction). A truly “knocking” third heart sound is extremely uncommon today and characterizes a bygone era when diagnosis was delayed and the chronic constrictive pericarditis developed in the fortunate survivor. Acute and subacute constriction are more common today, mainly because of rapid recognition. Conceptually, the phenomenon is a third heart sound that both in constrictive pericarditis and restrictive cardiomyopathy tends to be earlier than other abnormal third heart sounds. Also, the pericardium itself does not generate the abnormal third heart sound, except to the extent that the constricting pericardium contributes to the degree of myocardial restriction.

David H. Spodick, M.D., D.Sc.
Saint Vincent Hospital, Worcester, MA 01604-4593

Author/Editor Response

The authors reply:

To the Editor: Dr. Reisinger and colleagues correctly point out that the classification of amyloidosis is based on the chemical nature of the amyloid fibrils, and we agree that the majority of patients with primary amyloidosis do not have multiple myeloma. In fact, we stated in the article that primary amyloidosis is often due to multiple myeloma, which does not necessarily suggest that multiple myeloma occurs in the majority of patients who present with primary amyloidosis. The intention of the paper was not to discuss the classification of amyloidosis but to review its relevance to restrictive cardiomyopathy. We acknowledge that familial and senile amyloidoses have unique biochemical and clinical features, which are discussed in the article, and that those diseases are best not classified as secondary forms of amyloidosis.

The unpublished observations of Reisinger and colleagues are interesting, and we agree that gross cardiomegaly is uncommon. In fact, as the review states, the ventricular cavities are often normal in this condition. Atrial enlargement may indeed be secondary to high atrial-filling pressures, but it is our observation that it tends to be more common in the presence of atrioventricular valvular regurgitation, which is also correlated with the development of heart failure. We agree that once cardiac failure due to cardiomyopathy supervenes, the prognosis is poor; however, this tends to be correlated with increased wall thickness — although this may not always be the case.

We thank Reisinger and colleagues for bringing to our attention the therapy with dose-intensive melphalan and autologous-blood stem-cell support, and it will be interesting to see what effect this therapy may have on the treatment of cardiac amyloidosis.

We recognize the expertise of Dr. Spodick on the pericardium and its physiology and would like to thank him for his insightful remarks and clarification regarding the third heart sound and the pericardial knock. We agree that this sound may be uncommon but contend that when it does occur, it is diagnostic. And we acknowledge that an S₄ gallop can also occur in constrictive pericarditis.

Sudhir S. Kushwaha, M.D.
John T. Fallon, M.D., Ph.D.
Valentin Fuster, M.D., Ph.D.
Mount Sinai Medical Center, New York, NY 10029-6574

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