Author + information
- Marc J. Semigran, MD∗ ()
- Cardiology Division and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Marc J. Semigran, Cardiology Division, Department Of Medicine, Massachusetts General Hospital, Bigelow 800, Fruit Street, Boston, Massachusetts 02114.
One of the most devastating diagnoses a cardiologist may give a patient is that their heart failure (HF) is due to light-chain (AL) amyloidosis, because their median survival is <1 year. The report from Sperry et al. (1) in this issue of the Journal marks the beginning of a change in that dire prognosis.
AL amyloidosis, previously referred to as primary amyloidosis, is the most common form of systemic amyloidosis and results from a plasma cell dyscrasia that causes the uncontrolled production of a monoclonal immunoglobulin light chain. This excess of light chains polymerizes into an insoluble fibril, with subsequent deposition into the extracellular space of various tissues such as the kidney, heart, gut, peripheral nerves, and skin, with associated organ dysfunction. Approximately 90% of patients with AL amyloidosis present with cardiac involvement, which can range from the appearance of abnormalities on echocardiography or cardiac magnetic resonance imaging consistent with an infiltrative cardiomyopathy to the clinical manifestations of HF. Symptomatic HF is present in 50% of patients with AL amyloidosis on presentation, and its presence is the major factor impacting survival. Amyloid deposition within the myocardium results in thickening of ventricular and atrial walls, leading to restrictive cardiomyopathy and, initially, diastolic dysfunction. Left ventricular (LV) systolic dysfunction subsequently occurs and may be related to a direct toxic effect of light-chain fibrils on myocardial contractility (2). Infiltration of the cardiac muscle may also induce conduction disorders and ventricular or supraventricular arrhythmias. Amyloid deposits sometimes affect coronary arteries, and may manifest with symptoms of coronary heart disease or even myocardial infarction.
It is estimated that the incidence of AL amyloidosis in the United States is 2,500 to 3,000 cases/year, with a median age of presentation of 55 to 60 years (3). Thus, the diagnosis of AL cardiac amyloidosis necessitates that the clinician be aware of the possibility that HF due to an infiltrative cardiomyopathy is leading to symptoms of dyspnea, fatigue, and edema in a middle-aged patient without a history of coronary disease or its risk factors. The presence of discordance between electrocardiogram QRS voltage and echocardiographic ventricular wall thickness (>14 mm) should raise the possibility of AL amyloidosis in a HF patient. Left atrial enlargement is usually also present. The observation of global transmural or subendocardial late gadolinium enhancement on cardiac magnetic resonance imaging of a patient can be very sensitive, though with a specificity of only ∼50% (4). Noninvasive imaging findings combined with hematologic observations of an abnormal serum-free light-chain kappa/lambda ratio, can be sufficient to make the diagnosis of AL cardiac amyloidosis (5). Endomyocardial biopsy, combined with immunofluorescence or laser dissection/mass spectrometry, can be used to definitively confirm the diagnosis, particularly when knowledge of the amyloid subtype will guide advanced therapies such as organ transplantation.
Investigators at the Mayo Clinic have developed a classification scheme incorporating cardiac biomarkers and level of amyloidogenic light-chain synthesis to determine prognosis based on a group of AL amyloidosis patients undergoing stem cell transplant, immunomodulatory therapy, or cytotoxic chemotherapy. A troponin T level ≥0.025 ng/ml, N-terminal-pro B-type natriuretic peptide (NT-proBNP) ≥1,800 pg/ml, or serum-free light-chain difference ≥18 mg/dl were each identified as indicative of a poor prognosis. Patients with all 3 variables greater than these thresholds had a median survival of 5.8 months (6).
There are 2 broad targets for the treatment of AL cardiac amyloidosis, addressing the underlying HF due to systolic and diastolic function, and addressing the production of light chains and their binding to the myocardium and alteration of its function. Unfortunately, many of the pharmacological and device-based treatments successful for HF due to LV systolic dysfunction are not useful in the treatment of AL amyloidosis. The use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or neprilysin inhibitors/angiotensin receptor blockers, is difficult in AL patients due to the development of hypotension with even small doses. Underlying conduction system abnormalities are often present in AL amyloidosis patients, further limiting the use of beta-adrenergic antagonists. Diuretics are the mainstay of the management of volume overload, and they are often required in high doses. Spironolactone can be used to augment diuresis and treat hypokalemia; it's independent benefit as a neurohormonal antagonist remains to be assessed in this population. Although pacemakers will treat symptomatic bradyarrhythmias, the benefit of implantable cardioverters on survival is debatable. Cardiac transplantation alone does not achieve long-term benefit (7), but when combined with autologous stem cell transplantation (8) or other definitive treatment, it can be successful in a select group of patients without significant extracardiac amyloid organ involvement.
The limitation of HF therapies in AL amyloidosis patients has necessitated consideration of the potential benefits of therapies targeting light-chain production. The first of these to be developed for AL amyloidosis was high-dose melphalan followed by autologous hematopoietic stem cell transplantation, based on favorable experience with selected patients with multiple myeloma. Favorable hematologic responses in selected patients as many as 60% of patients have been observed (9). However, survival with high-dose melphalan and autologous stem cell transplantation in patients with significant cardiac involvement is poor (10), related to both treatment-related toxicities and lack of improvement in the underlying HF.
The development of the proteosome inhibitor bortezomib has raised the possibility that chemotherapeutic regimens that include this agent may play a role in the treatment of AL cardiac amyloid patients. Bortezomib inhibits the cellular metabolism of proapoptotic factors in plasma cells, and is effective in the treatment of multiple myeloma. When combined with alkylating agents, such as cyclophosphamide, and steroids, this regimen achieved hematologic response rates >80% in nonrandomized trials, including a hematologic response in patients with advanced cardiac disease (11). A subsequent retrospective analysis of patients with Mayo stage III disease treated with bortezomib, cyclophosphamide, and steroids showed a 1-year survival of 57% with modest reductions in BNP levels, but no reversal of either increased ventricular wall thickness or reduction in LV ejection fraction (12).
In this issue of the Journal, Sperry et al. (1) present a retrospective assessment of the efficacy of several chemotherapy regimens, including bortezomib, alkylating agents, and steroids (BDEX+AA) in AL amyloidosis patients with symptomatic HF. In this group of patients, 37% of patients received BDEX+AA, with the remainder receiving steroids, and most, another chemotherapeutic agent. Due to the potential variance in risk factors for adverse outcomes that may have affected treatment decisions in this retrospective analysis, propensity scores including these factors were utilized in the survival analysis. Indeed, a higher propensity for receiving BDEX+AA was associated with a trend towards lower mortality. The Central Illustration (1) demonstrates, nonetheless, an association between the treatment received and survival, with median survival of 674 days in the BDEX+AA group, 237 days in the patients receiving other treatments, and 87 days in the untreated patients. The association of decreased mortality with BDEX+AA treatment remained after adjustment for the components of the Mayo classification (plasma troponin T, NT-proBNP, and free light-chain difference).
The authors are to be congratulated for their analysis of treatment effectiveness in >100 patients with a relatively rare disease. Furthermore, they showed a benefit of therapy targeting light-chain production in a severely ill population, including biomarkers of elevated NT-proBNP and troponin that place them in more severe Mayo classifications. The performance of this analysis on patients cared for at a single center suggests the likely consistency of the assessment of factors adjusted for in the propensity analysis. On the other hand, it is possible that some variables, particularly related to the extracardiac amyloid burden that can lead to morbidity and mortality, were not accounted for. This includes gastrointestinal amyloidosis, which can lead to malnourishment and luminal bleeding, and autonomic dysfunction, which can lead to life-threatening hypotension and orthostasis. It must be noted that the clinicians who selected patients for BDEX+AA and treated them are at a highly specialized amyloid center with a wealth of expertise in assessing and treating patients with this disease.
In order to ascertain the greater applicability of BDEX+AA, a prospective multicenter study in patients with a spectrum of severity of cardiac involvement, including those being “bridged” to stem cell or cardiac transplant, will be essential to understand the efficacy and ideal patient characteristics for this therapy. Such a study is necessary, because the Mayo classification system (6) did not include patients receiving bortezomib therapy. Because bortezomib administration can have transient myocardial and renal depressant effects, the effect of LV ejection fraction as a predictor of successful BDEX+AA needs to be assessed. Until a comparative effectiveness study is initiated, the ideal patient to be considered for chemotherapy would be one whose extracardiac amyloid burden is relatively small, has a good functional capacity, and whose cardiac dysfunction can be medically managed. Finally, it has been our center’s experience that the severity of gastrointestinal amyloid is often underappreciated, leading to severe dysmotility and malnutrition with subsequent morbidity and mortality. Such a patient is likely to have significant adverse effects from the immunosuppression associated with BDEX+AA.
In conclusion, the work of Sperry et al. (1) raises the hope that chemotherapy targeting plasma cells offers the possibility of mitigating the cardiac morbidity of unchecked light-chain production. It prompts the need for further investigation of this therapy.
↵∗ Editorials published in the 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.
Dr. Semigran has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Sperry B.W.,
- Ikram A.,
- Hachamovitch R.,
- et al.
- Shi J.,
- Guan J.,
- Jiang B.,
- et al.
- Syed I.S.,
- Glockner J.F.,
- Feng D.,
- et al.
- Kumar S.,
- Dispenzieri A.,
- Lacy M.Q.,
- et al.
- Cibeira M.T.,
- Sanchorawala V.,
- Seldin D.C.,
- et al.
- Venner C.P.,
- Lane T.,
- Foard D.,
- et al.
- Jaccard A.,
- Comenzo R.L.,
- Hari P.,
- et al.