Heart Failure Reviews

, Volume 20, Issue 2, pp 163–178 | Cite as

Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs

  • Adam Castaño
  • Brian M. Drachman
  • Daniel Judge
  • Mathew S. Maurer


Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.


Cardiac amyloidosis Transthyretin Cardiomyopathy Senile systemic amyloidosis Familial amyloid polyneuropathy Diflunisal ALN-TTR02 ALN-TTRSc Tafamidis Doxycycline TUDCA siRNA Oligonucleotides 



We acknowledge the patients with cardiac amyloidosis who continue to participate in clinical trials and wait patiently for the development of effective treatments.

Conflict of interest

Dr. Castaño has no conflicts of interest or financial ties to disclose. Dr. Drachman has received funding as a scientific advisor to ISIS Pharmaceuticals. Dr. Judge has received funding as a scientific advisor to both Pfizer and Alnylam Pharmaceuticals. Dr. Maurer serves on the advisory board of the Transthyretin Amyloid Outcomes Survey (THAOS), which is funded by Pfizer, Inc., and has received unrestricted educational grant support from Alnylam Pharmaceuticals.


  1. 1.
    Dharmarajan K, Maurer MS (2012) Transthyretin cardiac amyloidoses in older North Americans. J Am Geriatr Soc 60(4):765–774CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Rapezzi C et al (2009) Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 120(13):1203–1212CrossRefPubMedGoogle Scholar
  3. 3.
    Connors LH et al (2009) Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 158(4):607–614CrossRefPubMedGoogle Scholar
  4. 4.
    Jacobson DR et al (1996) Revised transthyretin Ile 122 allele frequency in African-Americans. Hum Genet 98(2):236–238CrossRefPubMedGoogle Scholar
  5. 5.
    Hornsten R et al (2010) Heart complications in familial transthyretin amyloidosis: impact of age and gender. Amyloid 17(2):63–68CrossRefPubMedGoogle Scholar
  6. 6.
    Bonaiti B et al (2010) TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance? Eur J Hum Genet 18(8):948–952CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Rapezzi C et al (2008) Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 15(1):40–48CrossRefPubMedGoogle Scholar
  8. 8.
    Suhr OB et al (2006) Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy. Amyloid 13(3):154–159CrossRefPubMedGoogle Scholar
  9. 9.
    Suhr O et al (1994) Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Intern Med 235(5):479–485CrossRefPubMedGoogle Scholar
  10. 10.
    Coelho T, Maurer MS, Suhr OB (2013) THAOS—the transthyretin amyloidosis outcomes survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin 29(1):63–76CrossRefPubMedGoogle Scholar
  11. 11.
    Maurer MS et al (2013) Cardiac biomarkers in patients with transthyretin amyloidosis as documented in THAOS: the transthyretin amyloidosis survey. J Am Coll Cardiol 61(10):E1244–E1244CrossRefGoogle Scholar
  12. 12.
    Givens RC et al (2013) Comparison of cardiac amyloidosis due to wild-type and V122I transthyretin in older adults referred to an academic medical center. Aging Health 9(2):229–235CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Ihse E et al (2008) Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J Pathol 216(2):253–261CrossRefPubMedGoogle Scholar
  14. 14.
    Khella S, Drachman B, Divito P, Polydefkis M, Brannagan T, Judge D, Maurer MS (2013) Neurologic involvement in Val122Ile familial amyloidosis. In: IXth international symposium on familial amyloid polyneuropathy; VIIIth international symposium on liver transplantation in familial amyloid polyneuropathy, Rio de Janeiro, BrazilGoogle Scholar
  15. 15.
    Ng B et al (2005) Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 165(12):1425–1429CrossRefPubMedGoogle Scholar
  16. 16.
    Pinney JH et al (2013) Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2(2):e000098CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Quarta CC et al (2014) Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 129(18):1840–1849CrossRefPubMedGoogle Scholar
  18. 18.
    Liao R et al (2001) Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 104(14):1594–1597PubMedGoogle Scholar
  19. 19.
    Mishra S et al (2013) Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol 305(1):H95–H103CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Ruberg FL et al (2012) Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the transthyretin amyloidosis cardiac study (TRACS). Am Heart J 164(2):222–228 e1CrossRefPubMedGoogle Scholar
  21. 21.
    Falk RH (2005) Diagnosis and management of the cardiac amyloidoses. Circulation 112(13):2047–2060CrossRefPubMedGoogle Scholar
  22. 22.
    Feng D et al (2007) Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation 116(21):2420–2426CrossRefPubMedGoogle Scholar
  23. 23.
    Berghoff M et al (2003) Endothelial dysfunction precedes C-fiber abnormalities in primary (AL) amyloidosis. Ann Neurol 53(6):725–730CrossRefPubMedGoogle Scholar
  24. 24.
    Yood RA et al (1983) Bleeding manifestations in 100 patients with amyloidosis. JAMA 249(10):1322–1324CrossRefPubMedGoogle Scholar
  25. 25.
    Feng D et al (2009) Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation 119(18):2490–2497CrossRefPubMedGoogle Scholar
  26. 26.
    Dubrey S et al (1995) Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J 74(5):541–544CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Murphy L, Falk RH (2000) Left atrial kinetic energy in AL amyloidosis: can it detect early dysfunction? Am J Cardiol 86(2):244–246CrossRefPubMedGoogle Scholar
  28. 28.
    Lip GY et al (2010) Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest 137(2):263–272CrossRefPubMedGoogle Scholar
  29. 29.
    Klein AL et al (1990) Comprehensive doppler assessment of right ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 15(1):99–108CrossRefPubMedGoogle Scholar
  30. 30.
    Koyama J, Ray-Sequin PA, Falk RH (2003) Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation 107(19):2446–2452CrossRefPubMedGoogle Scholar
  31. 31.
    King DL, El-Khoury Coffin L, Maurer MS (2002) Myocardial contraction fraction: a volumetric index of myocardial shortening by freehand three-dimensional echocardiography. J Am Coll Cardiol 40(2):325–329CrossRefPubMedGoogle Scholar
  32. 32.
    Tendler AHA, Maurer MS (2013) Myocardial contraction fraction is superior to the myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with cardiac amyloidosis. In: IX international symposium on familial amyloidotic polyneuropathy (ISFAP) and the VIII international symposium on liver transplantation in familial amyloidotic polyneuropathy, Rio de Janeiro, BrazilGoogle Scholar
  33. 33.
    Damy T, Plante-Bordeneuve V, Karayal O, Mundayat R, Kristen AV (2013) Clinical and echocardiographic signs associated with increased interventricular thickness (IVST) due to TTR related amyloidosis. In: European Society of Cardiology, Amsterdam, NetherlandsGoogle Scholar
  34. 34.
    Suhr OB et al (2000) Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl 6(3):263–276CrossRefPubMedGoogle Scholar
  35. 35.
    Tsay DM, Maurer MS (2014) Biomarkers in ATTR cardiac amyloidosis (in submission)Google Scholar
  36. 36.
    Bokhari S et al (2013) (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 6(2):195–201CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Cassidy JT (1961) Cardiac amyloidosis. Two cases with digitalis sensitivity. Ann Intern Med 55:989–994CrossRefPubMedGoogle Scholar
  38. 38.
    Pomerance A (1965) Senile cardiac amyloidosis. Br Heart J 27(5):711–718CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Rubinow A, Skinner M, Cohen AS (1981) Digoxin sensitivity in amyloid cardiomyopathy. Circulation 63(6):1285–1288CrossRefPubMedGoogle Scholar
  40. 40.
    Wiklund U et al (2008) Abnormal heart rate variability and subtle atrial arrhythmia in patients with familial amyloidotic polyneuropathy. Ann Noninvasive Electrocardiol 13(3):249–256CrossRefPubMedGoogle Scholar
  41. 41.
    Okamoto S et al (2011) Continuous development of arrhythmia is observed in Swedish transplant patients with familial amyloidotic polyneuropathy (amyloidogenic transthyretin Val30Met variant). Liver Transpl 17(2):122–128CrossRefPubMedGoogle Scholar
  42. 42.
    Algalarrondo V et al (2012) Prophylactic pacemaker implantation in familial amyloid polyneuropathy. Heart Rhythm 9(7):1069–1075CrossRefPubMedGoogle Scholar
  43. 43.
    Epstein AE et al (2008) ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary. Heart Rhythm 5(6):934–955CrossRefPubMedGoogle Scholar
  44. 44.
    Zhao Y et al (2012) Left ventricular dyssynchrony is associated with reduced heart rate variability in familial amyloidotic polyneuropathy. Int J Cardiol 155(2):273–278CrossRefPubMedGoogle Scholar
  45. 45.
    Dubrey SW et al (1998) The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 91(2):141–157CrossRefPubMedGoogle Scholar
  46. 46.
    Falk RH, Rubinow A, Cohen AS (1984) Cardiac arrhythmias in systemic amyloidosis: correlation with echocardiographic abnormalities. J Am Coll Cardiol 3(1):107–113CrossRefPubMedGoogle Scholar
  47. 47.
    Kristen AV et al (2008) Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm 5(2):235–240CrossRefPubMedGoogle Scholar
  48. 48.
    Dhoble A et al (2009) Cardiac amyloidosis treated with an implantable cardioverter defibrillator and subcutaneous array lead system: report of a case and literature review. Clin Cardiol 32(8):E63–E65CrossRefPubMedGoogle Scholar
  49. 49.
    Lin G, Dispenzieri A, Brady PA (2010) Successful termination of a ventricular arrhythmia by implantable cardioverter defibrillator therapy in a patient with cardiac amyloidosis: insight into mechanisms of sudden death. Eur Heart J 31(12):1538CrossRefPubMedGoogle Scholar
  50. 50.
    Lin G et al (2013) Implantable cardioverter defibrillators in patients with cardiac amyloidosis. J Cardiovasc Electrophysiol 24(7):793–798CrossRefPubMedGoogle Scholar
  51. 51.
    Garan AR, Kolluri S, Lombardo I, Maurer MS (2012) The prevalence of Holter abnormalities in ATTR cardiac amyloidosis. In: XIII international symposium on amyloidosis, Groningen, NetherlandsGoogle Scholar
  52. 52.
    Varr BC et al (2014) Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis. Heart Rhythm 11(1):158–162CrossRefPubMedGoogle Scholar
  53. 53.
    Holmgren G et al (1991) Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40(3):242–246CrossRefPubMedGoogle Scholar
  54. 54.
    Holmgren G et al (1993) Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341(8853):1113–1116CrossRefPubMedGoogle Scholar
  55. 55.
    Jonsen E et al (2001) Early liver transplantation is essential for familial amyloidotic polyneuropathy patients’ quality of life. Amyloid 8(1):52–57CrossRefPubMedGoogle Scholar
  56. 56.
    Sandgren O et al (1991) Vitreous involvement in familial amyloidotic neuropathy: a genealogical and genetic study. Clin Genet 40(6):452–460CrossRefPubMedGoogle Scholar
  57. 57.
    Olofsson BO (1983) Cardiac involvement in familial amyloidosis with polyneuropathy. Int J Cardiol 4(3):379–382CrossRefPubMedGoogle Scholar
  58. 58.
    Steen LE, Ek BO (1984) Familial amyloidosis with polyneuropathy. Aspects of the relationship between gastrointestinal symptoms, EMG findings, and malabsorption studies. Scand J Gastroenterol 19(4):480–486PubMedGoogle Scholar
  59. 59.
    Bispo M et al (2009) High incidence of thrombotic complications early after liver transplantation for familial amyloidotic polyneuropathy. Transpl Int 22(2):165–171CrossRefPubMedGoogle Scholar
  60. 60.
    Sharma P et al (2003) Outcome of liver transplantation for familial amyloidotic polyneuropathy. Liver Transpl 9(12):1273–1280CrossRefPubMedGoogle Scholar
  61. 61.
    Liepnieks JJ, Benson MD (2007) Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid 14(4):277–282CrossRefPubMedGoogle Scholar
  62. 62.
    Liepnieks JJ, Zhang LQ, Benson MD (2010) Progression of transthyretin amyloid neuropathy after liver transplantation. Neurology 75(4):324–327CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Gustafsson S et al (2012) Amyloid fibril composition as a predictor of development of cardiomyopathy after liver transplantation for hereditary transthyretin amyloidosis. Transplantation 93(10):1017–1023CrossRefPubMedGoogle Scholar
  64. 64.
    Furtado A et al (1997) Sequential liver transplantation. Transplant Proc 29(1–2):467–468CrossRefPubMedGoogle Scholar
  65. 65.
    Furtado L et al (1999) Maximum sharing of cadaver liver grafts composite split and domino liver transplants. Liver Transpl Surg 5(2):157–158CrossRefPubMedGoogle Scholar
  66. 66.
    Tome L et al (2001) Sequential liver transplantation: 27 cases in 25 patients. Transplant Proc 33(1–2):1430–1432CrossRefPubMedGoogle Scholar
  67. 67.
    Bolte FJ et al (2013) Evaluation of domino liver transplantations in Germany. Transpl Int 26(7):715–723CrossRefPubMedGoogle Scholar
  68. 68.
    Abdelfatah MM, Hayman SR, Gertz MA (2014) Domino liver transplantation as a cause of acquired familial amyloid polyneuropathy. Amyloid 21(2):136–137CrossRefPubMedGoogle Scholar
  69. 69.
    Conner R et al (1988) Heart transplantation for cardiac amyloidosis: successful one-year outcome despite recurrence of the disease. J Heart Transplant 7(2):165–167PubMedGoogle Scholar
  70. 70.
    Kpodonu J et al (2005) Outcome of heart transplantation in patients with amyloid cardiomyopathy. J Heart Lung Transplant 24(11):1763–1765CrossRefPubMedGoogle Scholar
  71. 71.
    Rapezzi C et al (2010) Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 7(7):398–408CrossRefPubMedGoogle Scholar
  72. 72.
    Sekijima Y, Dendle MA, Kelly JW (2006) Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13(4):236–249CrossRefPubMedGoogle Scholar
  73. 73.
    Tojo K et al (2006) Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci Res 56(4):441–449CrossRefPubMedGoogle Scholar
  74. 74.
    Johnson SM et al (2012) The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol 421(2–3):185–203CrossRefPubMedCentralPubMedGoogle Scholar
  75. 75.
    Miller SR, Sekijima Y, Kelly JW (2004) Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab Invest 84(5):545–552CrossRefPubMedGoogle Scholar
  76. 76.
    Adamski-Werner SL et al (2004) Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem 47(2):355–374CrossRefPubMedGoogle Scholar
  77. 77.
    Kearney PM et al (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332(7553):1302–1308CrossRefPubMedCentralPubMedGoogle Scholar
  78. 78.
    Epstein M (2002) Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J Hypertens Suppl 20(6):S17–S23PubMedGoogle Scholar
  79. 79.
    Marnett LJ, Kalgutkar AS (1999) Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci 20(11):465–469CrossRefPubMedGoogle Scholar
  80. 80.
    Wallace JL (2001) Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract Res Clin Gastroenterol 15(5):691–703CrossRefPubMedGoogle Scholar
  81. 81.
    Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286(8):954–959CrossRefPubMedGoogle Scholar
  82. 82.
    Page J, Henry D (2000) Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 160(6):777–784CrossRefPubMedGoogle Scholar
  83. 83.
    Castano A et al (2012) Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail 18(6):315–319CrossRefPubMedCentralPubMedGoogle Scholar
  84. 84.
    Berk JL et al (2013) Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310(24):2658–2667PubMedCentralPubMedGoogle Scholar
  85. 85.
    Quarta CCF, Solomon RH, Suhr SD, Obici OB, Perlini L, Lindqvist S, Koyama P, Sekijima J, Zeldenrust Y, Yamashita SR, Horibata T, Miller Y, Gorevic F, Merlini P, Ando G, Ikeda Y, Ruberg S, Berk F (2014) The prevalence of cardiac amyloidosis in familial amyloidotic polyneuropathy with predominant neuropathy: the diflunisal trial. In: International symposium on amyloidosis, Indianapolis, USA, pp 88–89Google Scholar
  86. 86.
    Bulawa CE et al (2012) Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A 109(24):9629–9634CrossRefPubMedCentralPubMedGoogle Scholar
  87. 87.
    Hammarstrom P et al (2002) Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci USA 99(Suppl 4):16427–16432CrossRefPubMedCentralPubMedGoogle Scholar
  88. 88.
    Coelho T et al (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79(8):785–792CrossRefPubMedCentralPubMedGoogle Scholar
  89. 89.
    Merlini G et al (2013) Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res 6(6):1011–1020CrossRefPubMedCentralPubMedGoogle Scholar
  90. 90.
    Maurer MS, JDP, Rosas GR, Mandel FS, Aarts J (2014) Interim analysis of long-term, open-label tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment. In: International symposium on amyloidosis, Indianapolis, USAGoogle Scholar
  91. 91.
    Pfizer (2014) Safety and efficacy of tafamidis in patients with transthyretin cardiomyopathy (ATTR-ACT). Available from: http://www.clinicaltrials.gov/show/NCT01994889
  92. 92.
    Alhamadsheh MM et al (2011) Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity. Sci Transl Med 3(97):97ra81CrossRefPubMedCentralPubMedGoogle Scholar
  93. 93.
    Penchala SC et al (2013) AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci USA 110(24):9992–9997CrossRefPubMedCentralPubMedGoogle Scholar
  94. 94.
    Fire A et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811CrossRefPubMedGoogle Scholar
  95. 95.
    Elbashir SM et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411(6836):494–498CrossRefPubMedGoogle Scholar
  96. 96.
  97. 97.
    Kanasty R et al (2013) Delivery materials for siRNA therapeutics. Nat Mater 12(11):967–977CrossRefPubMedGoogle Scholar
  98. 98.
    Coelho T et al (2013) Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 369(9):819–829CrossRefPubMedGoogle Scholar
  99. 99.
    van Bennekum AM et al (2001) Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. J Biol Chem 276(2):1107–1113CrossRefPubMedGoogle Scholar
  100. 100.
    Pharmaceuticals A (2014) Phase 2 study to evaluate ALN-TTRSC in patients with transthyretin (TTR) cardiac amyloidosisGoogle Scholar
  101. 101.
    Benson MD et al (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33(5):609–618CrossRefPubMedGoogle Scholar
  102. 102.
    Benson MD et al (2011) Antisense oligonucleotide therapy for TTR amyloidosis. Amyloid 18(Suppl 1):60CrossRefPubMedGoogle Scholar
  103. 103.
    Ackermann EJ et al (2012) Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid 19(Suppl 1):43–44CrossRefPubMedGoogle Scholar
  104. 104.
    Pharmaceuticals, I (2013) Efficacy and safety of ISIS-TTRRx in familial amyloid polyneuropathy. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01737398?term=ISIS+amyloid&rank=1
  105. 105.
    Cardoso I, Saraiva MJ (2006) Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J 20(2):234–239CrossRefPubMedGoogle Scholar
  106. 106.
    Cardoso I et al (2010) Synergy of combined doxycycline/TUDCA treatment in lowering transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med 8:74CrossRefPubMedCentralPubMedGoogle Scholar
  107. 107.
    Obici L et al (2012) Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 19(Suppl 1):34–36CrossRefPubMedGoogle Scholar
  108. 108.
    Matteo IPS (2011) Safety, efficacy and pharmacokinetics of doxycycline plus tauroursodeoxycholic acid in transthyretin amyloidosis. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01171859?term=%EF%82%A7%09NCT01171859&rank=1
  109. 109.
    Hospital, B.a.W.s. (2013) Tolerability and efficacy of a combination of doxycycline and TUDCA in patients with transthyretin amyloid cardiomyopathy. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01855360?term=NCT01855360&rank=1
  110. 110.
    Pepys MB, Dash AC (1977) Isolation of amyloid P component (protein AP) from normal serum as a calcium-dependent binding protein. Lancet 1(8020):1029–1031CrossRefPubMedGoogle Scholar
  111. 111.
    Bodin K et al (2010) Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 468(7320):93–97CrossRefPubMedCentralPubMedGoogle Scholar
  112. 112.
    Pepys MB et al (2002) Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417(6886):254–259CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Adam Castaño
    • 1
    • 4
  • Brian M. Drachman
    • 2
  • Daniel Judge
    • 3
  • Mathew S. Maurer
    • 1
  1. 1.Center for Advanced Cardiac CareColumbia College of Physicians and SurgeonsNew York CityUSA
  2. 2.Division of CardiologyUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Division of CardiologyJohns Hopkins UniversityBaltimoreUSA
  4. 4.Division of CardiologyColumbia University Medical CenterNew YorkUSA

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