Heart Fail Rev DOI 10.1007/s10741-014-9464-5
Natural history and therapy of AL cardiac amyloidosis Martha Grogan • Angela Dispenzieri
Ó Springer Science+Business Media New York 2014
Abstract The natural history of immunoglobulin light chain associated amyloidosis (AL) is determined by the extent of cardiac involvement. Patients with cardiac AL and symptomatic heart failure have a median survival of approximately six months without successful treatment of the underlying plasma cell disorder The outcome in cardiac AL is determined by both the severity of cardiac involvement and the response to treatment. Staging systems using cardiac biomarkers, including NT- proBNP and troponin, have been found to be powerful predictors of prognosis and are used to guide treatment. Arrhythmias are common in cardiac AL and may lead to acute hemodynamic compromise. Sudden cardiac death, often due to pulseless electrical activity, is an important cause of early mortality. Supportive therapy for heart failure is usually limited to diuretics. Beta-blockers, ACE-inhibitors, and angiotensin receptor blockers are poorly tolerated in cardiac AL and should be avoided. Cardiac transplantation is controversial and reserved for highly selected patients with limited extracardiac involvement. The primary target of treatment in cardiac AL is obliteration of the plasma cell clone, using chemotherapy alone or combined with autologous stem cell transplantation. Despite the risk of early mortality, overall survival has improved with advances in disease modifying therapy. Earlier diagnosis and treatment of cardiac AL is crucial to improving survival.
M. Grogan (&) Division of Cardiology, Department of Medicine, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] A. Dispenzieri Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
Keywords Cardiac amyloidosis Heart failure Sudden cardiac death
Introduction Amyloidosis (AL) cardiac amyloid is a plasma cell proliferative disorder in which misfolded immunoglobulin light chains form amyloid fibrils and deposit in the heart. Cardiac dysfunction in AL amyloid occurs both due to extracellular infiltration of the myocardium and due to direct toxic effects of circulating light chains. The extent of cardiac dysfunction is the major determinant of morbidity and mortality in AL amyloid. In this review, we will review the natural history, staging system, predictors of outcome and mortality, and current state-of-the-art treatment of AL cardiac amyloid.
Natural history of AL cardiac amyloidosis The presence and degree of cardiac involvement in AL is the major determinant of survival. Patients with AL cardiac amyloid who present with symptomatic heart failure have a median survival of 6 months without successful therapy [1]. The second most important prognostic factor is how effectively chemotherapy kills the underlying plasma cell clone [2]. Despite advances in treatment and improvement in overall survival over time, the 1-year mortality remains unchanged at approximately 45 % [3]. Heart failure in cardiac AL is generally rapidly progressive and difficult to treat, unless disease-specific treatment is effective. However, regression of cardiac amyloid deposits is slow, and patients may die of progressive heart failure or sudden death despite a successful hematologic response.
123
Heart Fail Rev
Staging of cardiac AL Soluble cardiac biomarkers, such as troponin and NT-proBNP, have been found to be powerful markers of prognosis in AL amyloid and led to the development of the Mayo 2004 and 2012 staging systems [4–6]. The presence of zero, one, or two biomarkers above the designated cutoff threshold defines stage I, II, and III, respectively. The threshold values used in the 2004 staging system were an NT-proBNP \332 ng/L, cTnT \0.035 lg/L, and cTnI \0.1 lg/L. Patients with stage III disease had a median survival of only 3.5–4.1 months. The 2012 modified staging system incorporates serum free light chains and assigns one point for each of the following: NT-proBNP C1,800 pg/mL, troponin T C0.025 ng/mL, and a difference in serum free light chains (dFLC) C18 mg/dL defining four groups with increasing risk of mortality [6]. Survival according to the revised staging system is outlined in Fig. 1. Modifications of the staging systems using 100
Overall survival (proportion)
80 60 40
Stage 1 2 3 4
20 0 0
12
24
36
48
60
168
101
F-U from diagnosis (mo) No. at Risk 758
456
332
234
Shaded areas indicate 95% CI estimates
Fig. 1 Kaplan–Meier curves for overall survival (OS) from diagnosis among 758 patients based on the Mayo 2012 staging system; shaded areas indicate the 95 % CI estimates. From Kumar et al. [6]. Reprinted with permission
Survival (proportion)
1.0
different biomarker thresholds and additional variables have also been proposed [7–10]. For those with stage III disease, a threshold value of NT-proBNP [8,500 pg/mL combined with a systolic blood pressure \100 mmHg was found to be the best predictor of survival (Fig. 2). Some reports have included high-sensitivity troponin T and highsensitivity troponin I into prognostic models [9, 10]. Although the Mayo 2004 and 2012 staging systems are accepted as standards in the international amyloidosis community and are accepted as gold standard for stratifying patients in prospective clinical trials, the availability of multiple biomarker reagents at different institutions may challenge the average practitioner. Obvious examples are the large market share of BNP and cTnI in the USA, and the growing market share of hs-cTnT use in many European practices. The novel biomarker soluble ST2 (sST2) has been demonstrated to be a marker of cardiac remodeling and fibrosis and has been reported to predict survival in patients with coronary artery disease [11], myocardial infarction [12–14], and heart failure [15–17]. Galectin-3 is a betagalactoside lectin, which causes myofibroblast activation, and has been associated with the development of myocardial fibrosis and remodeling [18]. These novel biomarkers represent different pathophysiological pathways from those of NT-proBNP and troponin and may further improve prognostication in patients with AL amyloidosis. We recently studied sST2 and Galectin-3 to determine whether these novel biomarkers added further prognostic value in AL. Both sST2 and Galectin-3 were predictive of survival on univariate analysis. However, using a multivariate model, only sST2 was independent of troponin, NT-proBNP, serum immunoglobulin free light chain, and blood pressure in prediction of survival in AL [19]. The addition of sST2 to staging systems of AL may provide further insight into those patients with potential for recovery of cardiac function and may play a role in selection of therapy, including cardiac transplantation.
NT-proBNP >8500 ng/L Systolic BP
Natural history and therapy of AL cardiac amyloidosis Martha Grogan • Angela Dispenzieri
Ó Springer Science+Business Media New York 2014
Abstract The natural history of immunoglobulin light chain associated amyloidosis (AL) is determined by the extent of cardiac involvement. Patients with cardiac AL and symptomatic heart failure have a median survival of approximately six months without successful treatment of the underlying plasma cell disorder The outcome in cardiac AL is determined by both the severity of cardiac involvement and the response to treatment. Staging systems using cardiac biomarkers, including NT- proBNP and troponin, have been found to be powerful predictors of prognosis and are used to guide treatment. Arrhythmias are common in cardiac AL and may lead to acute hemodynamic compromise. Sudden cardiac death, often due to pulseless electrical activity, is an important cause of early mortality. Supportive therapy for heart failure is usually limited to diuretics. Beta-blockers, ACE-inhibitors, and angiotensin receptor blockers are poorly tolerated in cardiac AL and should be avoided. Cardiac transplantation is controversial and reserved for highly selected patients with limited extracardiac involvement. The primary target of treatment in cardiac AL is obliteration of the plasma cell clone, using chemotherapy alone or combined with autologous stem cell transplantation. Despite the risk of early mortality, overall survival has improved with advances in disease modifying therapy. Earlier diagnosis and treatment of cardiac AL is crucial to improving survival.
M. Grogan (&) Division of Cardiology, Department of Medicine, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] A. Dispenzieri Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
Keywords Cardiac amyloidosis Heart failure Sudden cardiac death
Introduction Amyloidosis (AL) cardiac amyloid is a plasma cell proliferative disorder in which misfolded immunoglobulin light chains form amyloid fibrils and deposit in the heart. Cardiac dysfunction in AL amyloid occurs both due to extracellular infiltration of the myocardium and due to direct toxic effects of circulating light chains. The extent of cardiac dysfunction is the major determinant of morbidity and mortality in AL amyloid. In this review, we will review the natural history, staging system, predictors of outcome and mortality, and current state-of-the-art treatment of AL cardiac amyloid.
Natural history of AL cardiac amyloidosis The presence and degree of cardiac involvement in AL is the major determinant of survival. Patients with AL cardiac amyloid who present with symptomatic heart failure have a median survival of 6 months without successful therapy [1]. The second most important prognostic factor is how effectively chemotherapy kills the underlying plasma cell clone [2]. Despite advances in treatment and improvement in overall survival over time, the 1-year mortality remains unchanged at approximately 45 % [3]. Heart failure in cardiac AL is generally rapidly progressive and difficult to treat, unless disease-specific treatment is effective. However, regression of cardiac amyloid deposits is slow, and patients may die of progressive heart failure or sudden death despite a successful hematologic response.
123
Heart Fail Rev
Staging of cardiac AL Soluble cardiac biomarkers, such as troponin and NT-proBNP, have been found to be powerful markers of prognosis in AL amyloid and led to the development of the Mayo 2004 and 2012 staging systems [4–6]. The presence of zero, one, or two biomarkers above the designated cutoff threshold defines stage I, II, and III, respectively. The threshold values used in the 2004 staging system were an NT-proBNP \332 ng/L, cTnT \0.035 lg/L, and cTnI \0.1 lg/L. Patients with stage III disease had a median survival of only 3.5–4.1 months. The 2012 modified staging system incorporates serum free light chains and assigns one point for each of the following: NT-proBNP C1,800 pg/mL, troponin T C0.025 ng/mL, and a difference in serum free light chains (dFLC) C18 mg/dL defining four groups with increasing risk of mortality [6]. Survival according to the revised staging system is outlined in Fig. 1. Modifications of the staging systems using 100
Overall survival (proportion)
80 60 40
Stage 1 2 3 4
20 0 0
12
24
36
48
60
168
101
F-U from diagnosis (mo) No. at Risk 758
456
332
234
Shaded areas indicate 95% CI estimates
Fig. 1 Kaplan–Meier curves for overall survival (OS) from diagnosis among 758 patients based on the Mayo 2012 staging system; shaded areas indicate the 95 % CI estimates. From Kumar et al. [6]. Reprinted with permission
Survival (proportion)
1.0
different biomarker thresholds and additional variables have also been proposed [7–10]. For those with stage III disease, a threshold value of NT-proBNP [8,500 pg/mL combined with a systolic blood pressure \100 mmHg was found to be the best predictor of survival (Fig. 2). Some reports have included high-sensitivity troponin T and highsensitivity troponin I into prognostic models [9, 10]. Although the Mayo 2004 and 2012 staging systems are accepted as standards in the international amyloidosis community and are accepted as gold standard for stratifying patients in prospective clinical trials, the availability of multiple biomarker reagents at different institutions may challenge the average practitioner. Obvious examples are the large market share of BNP and cTnI in the USA, and the growing market share of hs-cTnT use in many European practices. The novel biomarker soluble ST2 (sST2) has been demonstrated to be a marker of cardiac remodeling and fibrosis and has been reported to predict survival in patients with coronary artery disease [11], myocardial infarction [12–14], and heart failure [15–17]. Galectin-3 is a betagalactoside lectin, which causes myofibroblast activation, and has been associated with the development of myocardial fibrosis and remodeling [18]. These novel biomarkers represent different pathophysiological pathways from those of NT-proBNP and troponin and may further improve prognostication in patients with AL amyloidosis. We recently studied sST2 and Galectin-3 to determine whether these novel biomarkers added further prognostic value in AL. Both sST2 and Galectin-3 were predictive of survival on univariate analysis. However, using a multivariate model, only sST2 was independent of troponin, NT-proBNP, serum immunoglobulin free light chain, and blood pressure in prediction of survival in AL [19]. The addition of sST2 to staging systems of AL may provide further insight into those patients with potential for recovery of cardiac function and may play a role in selection of therapy, including cardiac transplantation.
NT-proBNP >8500 ng/L Systolic BP
