Author + information
- Merrill D. Benson, MD∗ ( and )
- Noel R. Dasgupta, MD
- Department of Pathology and Laboratory Medicine, and Department of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana
- ↵∗Reprint requests and correspondence:
Dr. Merrill D. Benson, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MS-128, Indianapolis, Indiana 46202-5126.
The retrospective study by Kristen et al. (1) in this issue of the Journal brings attention to cardiac amyloidosis as an often under-recognized cause of restrictive cardiomyopathy and highlights the differences between immunoglobulin light-chain (LC) and transthyretin (TTR) amyloidosis. There are, however, a number of different types of amyloidosis that can affect the heart, and with present and newly emerging forms of therapy, a definitive diagnosis is required (2). Immunoglobulin LC amyloidosis and TTR amyloidosis are the most common types of amyloidosis that cause cardiomyopathy, but apolipoprotein AI, apolipoprotein AII, and even secondary amyloidosis (amyloid A) have been reported to give clinically significant cardiac involvement.
The diagnosis of amyloidosis is often delayed until patients develop end-stage organ involvement, and treatment options are limited. Classically described features, such as low voltage on the electrocardiogram despite evidence of left ventricular hypertrophy on echocardiography, are supportive of an infiltrative myopathy but are not sufficient to make a specific diagnosis. Other tests including serum and urine electrophoresis with immunofixation, serum free light-chain concentrations, echocardiography with strain, cardiac magnetic resonance, and radionuclide imaging are useful, but tissue biopsy remains the gold standard to diagnose cardiac amyloidosis when diagnostic uncertainty exists (3–6).
Even though the diagnosis of amyloidosis is confirmed by Congo red-stained deposits on biopsy, it is necessary to determine the specific type of amyloidosis to plan therapy and venture a prognosis. The pattern of amyloid deposition in a cardiac biopsy may be suggestive of 1 type of amyloidosis, but characterization of the amyloid subunit protein by immunohistochemistry or mass spectroscopy plus clinical correlation are recommended to make a definitive diagnosis (7–9) (Figures 1, 2, 3, and 4).
To judge the importance of the amount of amyloid in a cardiac biopsy requires attention to certain aspects of both transthyretin (ATTR) and AL amyloidosis. Restrictive cardiomyopathy is a feature of ATTR caused by many of the TTR mutations. Although there is considerable variation in the degree of cardiac involvement and the rate of progression of amyloid deposition in the heart, the amount of amyloid found in a random endocardial biopsy would not be expected to be of much prognostic value, because clinically significant cardiac dysfunction that would lead to a heart biopsy for diagnosis is far past the time frame of early diagnosis. With hereditary TTR cardiomyopathy and wild-type TTR cardiomyopathy, which may differ with respect to rate of progression, prognostication is best left to serial measures of cardiac parameters on echocardiography and magnetic resonance imaging (3,10). This is of particular importance for wild-type TTR cardiomyopathy, which is being seen with increasing frequency by practicing cardiologists.
Immunoglobulin AL amyloidosis presents even more vagaries that need to be kept in mind. Every case of immunoglobulin AL amyloidosis is unique. The primary cause of AL is a plasma cell dyscrasia, which generates light-chain protein capable of forming amyloid fibrils (11). Thus, it depends on which plasma cell clone is selected, for whatever reasons, to expand and produce a monoclonal protein. We know that certain subtypes of light-chain proteins are more amyloidogenic than others. In particular, there are more lambda light-chain amyloids than there are kappa, although in the human antibody repertoire kappa light-chains predominate. We also know that certain light-chain proteins are more prone to amyloid deposition. For example, lambda II subgroup is more prevalent than expected, and lambda VI monoclonal proteins are always associated with amyloidosis. Tissue tropism may also be a factor in organ involvement. Massive hepatic amyloid is more likely associated with kappa than lambda proteins, and pulmonary amyloid has an increased association with lambda III proteins.
AL amyloidosis prognostication related to the amount of amyloid deposition on endocardial biopsy should be approached with caution. Clinical experience suggests that amyloid patients with cardiomyopathy might be assigned to 2 groups with varying degrees of overlap (12). One group has rapid-onset and progression of disease. Left ventricular walls are usually modestly thickened and cardiac dysfunction is way out of proportion to left ventricular mass, unlike what is usually observed with ATTR. These are patients who might be expected to respond to chemotherapy or they would have suffered an early death before coming to a definitive diagnosis. A second group of AL patients with cardiomyopathy come to endocardial biopsy long after the onset of their disease and may have had medical care without a specific diagnosis for ≥1 year. They may have had slowly progressive deposition of amyloid and present with left ventricular walls approaching 2 cm before they develop clinically significant restrictive phenomena with dilated atria and atrial fibrillation. Some of the patients in this group may have had arrhythmias as a principal manifestation of their disease, which fortunately is not always fatal. Whether the patients in this clinical grouping have passed through a “toxic period of amyloid deposition” is certainly open to speculation. This does not mean that these patients would not benefit from specific therapy to alter production of the amyloidogenic light-chain and perhaps slow progression of disease. Patients in this group may be in the age range of 60 to 65 years, and although amyloid deposition may be relatively slow, most people would elect to live another 10 years rather than 5 years.
Myocardial biopsy is the most expedient way to make a definitive diagnosis of cardiac amyloidosis, but if you do not think to do it, it tends to be of little value.
↵∗ Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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