Graham Lohrmann1, Alexandra Pipilas1, Roberta Mussinelli2, Deepa M Gopal3, John L Berk4, Lawreen H Connors4, Nirupama Vellanki1, Jennifer Hellawell5, Omar K Siddiqi3, Jonathan Fox5, Mathew S Maurer6, Frederick L Ruberg7. 1. Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. 2. Clinica Medica 2, Department of Internal Medicine and Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. 3. Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts; Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. 4. Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. 5. Eidos Therapeutics, San Francisco, California. 6. Division of Cardiology, Department of Medicine, Center for Advanced Cardiac Care, Columbia University Medical Center, New York, New York. 7. Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts; Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. Electronic address: frruberg@bu.edu.
Abstract
BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. METHODS AND RESULTS: ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m2, P = .002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups. CONCLUSIONS: In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.
BACKGROUND:Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. METHODS AND RESULTS:ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m2, P = .002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups. CONCLUSIONS: In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.
Authors: Martha Grogan; Christopher G Scott; Robert A Kyle; Steven R Zeldenrust; Morie A Gertz; Grace Lin; Kyle W Klarich; Wayne L Miller; Joseph J Maleszewski; Angela Dispenzieri Journal: J Am Coll Cardiol Date: 2016-09-06 Impact factor: 24.094
Authors: Scott D Solomon; David Adams; Arnt Kristen; Martha Grogan; Alejandra González-Duarte; Mathew S Maurer; Giampaolo Merlini; Thibaud Damy; Michel S Slama; Thomas H Brannagan; Angela Dispenzieri; John L Berk; Amil M Shah; Pushkal Garg; Akshay Vaishnaw; Verena Karsten; Jihong Chen; Jared Gollob; John Vest; Ole Suhr Journal: Circulation Date: 2019-01-22 Impact factor: 29.690
Authors: Jacquelyn L S Hanson; Marios Arvanitis; Clarissa M Koch; John L Berk; Frederick L Ruberg; Tatiana Prokaeva; Lawreen H Connors Journal: Circ Heart Fail Date: 2018-02 Impact factor: 8.790
Authors: David Adams; Alejandra Gonzalez-Duarte; William D O'Riordan; Chih-Chao Yang; Mitsuharu Ueda; Arnt V Kristen; Ivailo Tournev; Hartmut H Schmidt; Teresa Coelho; John L Berk; Kon-Ping Lin; Giuseppe Vita; Shahram Attarian; Violaine Planté-Bordeneuve; Michelle M Mezei; Josep M Campistol; Juan Buades; Thomas H Brannagan; Byoung J Kim; Jeeyoung Oh; Yesim Parman; Yoshiki Sekijima; Philip N Hawkins; Scott D Solomon; Michael Polydefkis; Peter J Dyck; Pritesh J Gandhi; Sunita Goyal; Jihong Chen; Andrew L Strahs; Saraswathy V Nochur; Marianne T Sweetser; Pushkal P Garg; Akshay K Vaishnaw; Jared A Gollob; Ole B Suhr Journal: N Engl J Med Date: 2018-07-05 Impact factor: 91.245
Authors: Merrill D Benson; Márcia Waddington-Cruz; John L Berk; Michael Polydefkis; Peter J Dyck; Annabel K Wang; Violaine Planté-Bordeneuve; Fabio A Barroso; Giampaolo Merlini; Laura Obici; Morton Scheinberg; Thomas H Brannagan; William J Litchy; Carol Whelan; Brian M Drachman; David Adams; Stephen B Heitner; Isabel Conceição; Hartmut H Schmidt; Giuseppe Vita; Josep M Campistol; Josep Gamez; Peter D Gorevic; Edward Gane; Amil M Shah; Scott D Solomon; Brett P Monia; Steven G Hughes; T Jesse Kwoh; Bradley W McEvoy; Shiangtung W Jung; Brenda F Baker; Elizabeth J Ackermann; Morie A Gertz; Teresa Coelho Journal: N Engl J Med Date: 2018-07-05 Impact factor: 91.245
Authors: Mathew S Maurer; Jeffrey H Schwartz; Balarama Gundapaneni; Perry M Elliott; Giampaolo Merlini; Marcia Waddington-Cruz; Arnt V Kristen; Martha Grogan; Ronald Witteles; Thibaud Damy; Brian M Drachman; Sanjiv J Shah; Mazen Hanna; Daniel P Judge; Alexandra I Barsdorf; Peter Huber; Terrell A Patterson; Steven Riley; Jennifer Schumacher; Michelle Stewart; Marla B Sultan; Claudio Rapezzi Journal: N Engl J Med Date: 2018-08-27 Impact factor: 91.245
Authors: Omar K Siddiqi; Yuliya Y Mints; John L Berk; Lawreen Connors; Gheorghe Doros; Deepa M Gopal; Shivangi Kataria; Graham Lohrmann; Alexandra R Pipilas; Frederick L Ruberg Journal: Amyloid Date: 2022-01-27 Impact factor: 6.571