Abstract
Aims
Light chain amyloidosis (AL) patients with heart failure (HF) are usually with revised Mayo (rMayo) stage III/IV disease and have a poor prognosis. We sought to investigate whether and what echocardiographic phenotype provides value for further risk stratification and guiding optimal risk-adapted treatment in this subgroup of AL patients.
Methods and Results
95 AL patients who presented with HF and were on rMayo stage III/IV were retrospectively included. Of them, 51 patients (53.7%) were with stage III, 44 (46.3%) were with stage IV, and 44 (46.3%) underwent chemotherapy. Laboratory and echocardiographic measurements were acquired before the initiation of chemotherapy. The relevance of different variables with survival was assessed in the entire cohort, chemotherapy, and non-chemotherapy group. By Multivariate Cox regression analysis, right ventricular wall thickness (RVT) [HR 1.145, 95% confidence interval (CI) 1.026–1.279, P = 0.016], relative wall thickness (RWT) (HR 6.709, 95% CI 1.101–40.877, P = 0.039), and left ventricular ejection fraction (LVEF) < 50% (HR 1.939, 95% CI 1.048–3.590, P = 0.035) were found to be independently associated with survival in the entire cohort, RWT (HR 15.488, 95% CI 2.045–117.292, P = 0.008) in the non-chemotherapy group, and RVT (HR 1.331, 95% CI 1.054–1.681, P = 0.016) in the chemotherapy group, respectively. Kaplan–Meier survival analysis revealed that survival was significantly reduced in the presence of RVT ≥ 6.5 mm or LVEF < 50% in the entire cohort, and the significance of RVT ≥ 6.5 mm was irrespective of rMayo stages. In the chemotherapy group, survival was decreased if RVT ≥ 6.5 mm alone or together with RWT ≥ 0.67 were present, particularly in patients on rMayo stage IV.
Conclusions
Echocardiographic phenotype provides incremental value beyond rMayo staging for predicting survival and could further guide treatment in advanced AL with HF. Those with high-risk echocardiographic phenotypes as higher RVT and RWT and lower LVEF had a worse prognosis.
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The data underlying this article cannot be shared publicly for the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.
References
Abdallah N et al (2021) Prognostic restaging after treatment initiation in patients with AL amyloidosis. Blood Adv 5:1029–1036. https://doi.org/10.1182/bloodadvances.2020003782
Badano LP et al (2018) Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging 19:591–600. https://doi.org/10.1093/ehjci/jey042
Barros-Gomes S et al (2017) Prognosis of light chain amyloidosis with preserved LVEF: added value of 2D speckle-tracking echocardiography to the current prognostic staging system. JACC Cardiovasc Imaging 10:398–407. https://doi.org/10.1016/j.jcmg.2016.04.008
Basset M et al (2022) Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival. Blood. https://doi.org/10.1182/blood.2022016348
Bhole MV, Sadler R, Ramasamy K (2014) Serum-free light-chain assay: clinical utility and limitations. Ann Clin Biochem 51:528–542. https://doi.org/10.1177/0004563213518758
Cappelli F et al (2012) Right ventricular function in AL amyloidosis: characteristics and prognostic implication. Eur Heart J Cardiovasc Imaging 13:416–422. https://doi.org/10.1093/ejechocard/jer289
Cohen OC et al (2022) Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis. Eur Heart J 43:333–341. https://doi.org/10.1093/eurheartj/ehab507
Comenzo RL et al (1996) Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 88:2801–2806
DePace NL, Colby J, Hakki AH, Manno B, Horowitz LN, Iskandrian AS (1983) Poor R wave progression in the precordial leads: clinical implications for the diagnosis of myocardial infarction. J Am Coll Cardiol 2:1073–1079. https://doi.org/10.1016/s0735-1097(83)80332-5
Dispenzieri A et al (2004) Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 22:3751–3757. https://doi.org/10.1200/jco.2004.03.029
Falk RH, Skinner M (2000) The systemic amyloidoses: an overview. Adv Intern Med 45:107–137
Falk RH, Alexander KM, Liao R, Dorbala S (2016) AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol 68:1323–1341. https://doi.org/10.1016/j.jacc.2016.06.053
Gertz MA et al (2013) Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant 48:557–561. https://doi.org/10.1038/bmt.2012.170
Gertz MA (2022) Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol 97:818–829. https://doi.org/10.1002/ajh.26569
Gottdiener JS et al (2004) American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 17:1086–1119. https://doi.org/10.1016/j.echo.2004.07.013
Hwang IC et al (2021) Time trajectory of cardiac function and its relation with survival in patients with light-chain cardiac amyloidosis. Eur Heart J Cardiovasc Imaging 22:459–469. https://doi.org/10.1093/ehjci/jeaa146
Jaccard A et al (2014) Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica 99:1479–1485. https://doi.org/10.3324/haematol.2014.104109
Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M (2017) Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood 130:900–902. https://doi.org/10.1182/blood-2017-01-763599
Knight DS et al (2019) Cardiac structural and functional consequences of amyloid deposition by cardiac magnetic resonance and echocardiography and their prognostic roles. JACC Cardiovasc Imaging 12:823–833. https://doi.org/10.1016/j.jcmg.2018.02.016
Kristensen SL et al (2017) Prognostic value of N-terminal Pro-B-type natriuretic peptide levels in heart failure patients with and without atrial fibrillation. Circ Heart Fail. https://doi.org/10.1161/circheartfailure.117.004409
Kumar S et al (2012) Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 30:989–995. https://doi.org/10.1200/jco.2011.38.5724
Kyle RA, Gertz MA (1995) Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 32:45–59
Liu D et al (2013) Effect of combined systolic and diastolic functional parameter assessment for differentiation of cardiac amyloidosis from other causes of concentric left ventricular hypertrophy. Circ Cardiovasc Imaging 6:1066–1072. https://doi.org/10.1161/circimaging.113.000683
McDonagh TA et al (2021) Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 42:4901. https://doi.org/10.1093/eurheartj/ehab670
Mikhael JR et al (2012) Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 119:4391–4394. https://doi.org/10.1182/blood-2011-11-390930
Monda E, Palmiero G, Lioncino M, Rubino M, Caiazza M, Dongiglio F, Limongelli G (2021) External validation of the increased wall thickness score for the diagnosis of cardiac amyloidosis. Int J Cardiol 339:99–101. https://doi.org/10.1016/j.ijcard.2021.07.035
Muchtar E et al (2021) Treatment of AL amyloidosis: Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus statement 2020 update. Mayo Clin Proc 96:1546–1577. https://doi.org/10.1016/j.mayocp.2021.03.012
Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M (2005) Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 95:535–537. https://doi.org/10.1016/j.amjcard.2004.10.028
Mussinelli R et al (2013) Diagnostic and prognostic value of low QRS voltages in cardiac AL amyloidosis. Ann Noninvasive Electrocardiol 18:271–280. https://doi.org/10.1111/anec.12036
Nagano N et al (2020) Assessment of prognosis in immunoglobulin light chain amyloidosis patients with severe heart failure: a predictive value of right ventricular function. Heart Vessels 35:521–530. https://doi.org/10.1007/s00380-019-01513-y
Nagueh SF et al (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 17:1321–1360. https://doi.org/10.1093/ehjci/jew082
Nordlinger M, Magnani B, Skinner M, Falk RH (2005) Is elevated plasma B-natriuretic peptide in amyloidosis simply a function of the presence of heart failure? Am J Cardiol 96:982–984. https://doi.org/10.1016/j.amjcard.2005.05.057
Pagourelias ED et al (2017) Echo parameters for differential diagnosis in cardiac amyloidosis: a head-to-head comparison of deformation and nondeformation parameters. Circ Cardiovasc Imaging 10:e005588. https://doi.org/10.1161/circimaging.116.005588
Potter JM, Simpson AJ, Kerrigan J, Southcott E, Salib MM, Koerbin G, Hickman PE (2017) The relationship of plasma creatinine (as eGFR) and high-sensitivity cardiac troponin and NT-proBNP concentrations in a hospital and community outpatient population. Clin Biochem 50:813–815. https://doi.org/10.1016/j.clinbiochem.2017.04.003
Pun SC et al (2018) Prognostic and added value of two-dimensional global longitudinal strain for prediction of survival in patients with light chain amyloidosis undergoing autologous hematopoietic cell transplantation. J Am Soc Echocardiogr 31:64–70. https://doi.org/10.1016/j.echo.2017.08.017
Salinaro F et al (2017) Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis. Eur Heart J Cardiovasc Imaging 18:1057–1064. https://doi.org/10.1093/ehjci/jew298
Sanchorawala V et al (2017) A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood 130:597–605. https://doi.org/10.1182/blood-2017-03-771220
Sanchorawala V et al (2022) Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines. Amyloid 29:1–7. https://doi.org/10.1080/13506129.2021.2002841
Semigran MJ (2016) Chemotherapy to treat heart failure: appropriate for light-chain amyloidosis? J Am Coll Cardiol 67:2949–2951. https://doi.org/10.1016/j.jacc.2016.05.003
Sperry BW, Ikram A, Hachamovitch R, Valent J, Vranian MN, Phelan D, Hanna M (2016) Efficacy of chemotherapy for light-chain amyloidosis in patients presenting with symptomatic heart failure. J Am Coll Cardiol 67:2941–2948. https://doi.org/10.1016/j.jacc.2016.03.593
Tahir UA, Doros G, Kim JS, Connors LH, Seldin DC, Sam F (2019) Predictors of mortality in light chain cardiac amyloidosis with heart failure. Sci Rep 9:8552. https://doi.org/10.1038/s41598-019-44912-x
Tendler A, Helmke S, Teruya S, Alvarez J, Maurer MS (2015) The myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with AL cardiac amyloidosis. Amyloid 22:61–66. https://doi.org/10.3109/13506129.2014.994202
Tsai WC, Liu YW, Huang YY, Lin CC, Lee CH, Tsai LM (2010) Diagnostic value of segmental longitudinal strain by automated function imaging in coronary artery disease without left ventricular dysfunction. J Am Soc Echocardiogr 23:1183–1189. https://doi.org/10.1016/j.echo.2010.08.011
Wechalekar AD et al (2013) A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 121:3420–3427. https://doi.org/10.1182/blood-2012-12-473066
Zuo H et al (2015) Diagnostic power of longitudinal strain at rest for the detection of obstructive coronary artery disease in patients with type 2 diabetes mellitus. Ultrasound Med Biol 41:89–98. https://doi.org/10.1016/j.ultrasmedbio.2014.08.011
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HW, DWW and HSZ contributed to the conception of the article and revision of the article critically for important intellectual content. HY and RL drafted the manuscript, were responsible for analysis and interpretation of the data. YJL and QY acquire the data, searched the literature, and revised the figures. FM and XWH drew the figures. All authors made a substantial contribution to the manuscript preparation. All authors read and approved the final manuscript.
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Yang, H., Li, R., Ma, F. et al. Echocardiographic phenotype for refined risk stratification and treatment selection in light chain amyloidosis with heart failure. J Cancer Res Clin Oncol 149, 8415–8427 (2023). https://doi.org/10.1007/s00432-023-04783-2
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DOI: https://doi.org/10.1007/s00432-023-04783-2