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Canadian Journal of Cardiology

Cardiac Amyloidosis: We’ve Come So Far, It’s Only the Beginning

Published:December 12, 2019DOI:https://doi.org/10.1016/j.cjca.2019.12.009
      The care of cardiac amyloidosis patients has evolved dramatically in recent years. This disorder, long considered to be rare, challenging to recognize, and with a dismal prognosis, has now become the focus of significant renewed interest. This is owing in large part to exciting discoveries and advancements in both clinical and basic science research, which have led to improved techniques and strategies for diagnosis, and perhaps most importantly, development of novel disease-modifying treatments. Consider the innovations that have occurred in only the last few years for the 2 systemic amyloidosis subtypes that are primarily responsible for cardiac involvement, light chain (AL) and transthyretin (ATTR). We now have a better understanding of the incidence and prevalence of these subtypes, and perhaps of equal importance, we recognize existing knowledge gaps. Although the annual incidence of AL is ~ 10 per million per year and considered to be stable,
      • Falk R.H.
      • Alexander K.M.
      • Liao R.
      • Dorbala S.
      AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy.
      we now recognize that ATTR is likely underdiagnosed and its true prevalence in Canada is uncertain. Recent screening studies from other regions have demonstrated that ATTR is highly under-recognized within certain subpopulations of patients with different cardiovascular disorders. For example, ATTR was identified in 13% of patients over 60 years of age hospitalized for heart failure with preserved ejection fraction with increased left ventricular wall thickness,
      • Gonzalez-Lopez E.
      • Gallego-Delgado M.
      • Guzzo-Merello G.
      • et al.
      Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.
      16% of patients undergoing transcatheter aortic valve replacement for severe aortic valve stenosis,
      • Castano A.
      • Narotsky D.L.
      • Hamid N.
      • et al.
      Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.
      and 5% of patients with a presumed diagnosis of hypertrophic cardiomyopathy.
      • Damy T.
      • Costes B.
      • Hagege A.A.
      • et al.
      Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness.
      ,
      • Maurer M.S.
      • Bokhari S.
      • Damy T.
      • et al.
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      These statistics suggest a high prevalence within the Canadian population, challenging ATTR’s reputation as a “rare disease.” Furthermore, improved approaches for noninvasive assessment have reduced reliance on myocardial biopsy to confirm the diagnosis, obviating the need for many patients to undergo this invasive procedure. This is especially true for the field of cardiac imaging, which has seen innovations in the use of advanced modalities in echocardiography (such as strain measurement using speckle-tracking echocardiography) and cardiac magnetic resonance imaging (late gadolinium enhancement imaging and T1-mapping techniques). The rise of nuclear scintigraphy using bone-seeking radiotracer to noninvasively confirm the diagnosis of ATTR cardiomyopathy has had a great impact on modern diagnostic algorithms. New disease-modifying treatments have dramatically improved the prognosis for both AL and ATTR. For AL patients, modern chemotherapy regimens and autologous stem cell transplant approaches have simultaneously improved survival and reduced treatment toxicity. For ATTR, exciting new therapeutic classes (ie, transthyretin protein silencers and stabilizers) have demonstrated the ability to effectively stabilize disease progression, as well as to improve symptoms and prolong survival, depending on the specific agent and ATTR subtype (wild-type or hereditary). Other diagnostic techniques and novel therapies are in development, which promise to further change the face of patient management and improve outcomes in years to come.
      These advancements have occurred in the setting of several initiatives and organizations dedicated to increasing and translating knowledge, with the overall goal of improving patient care. Examples include international research initiatives such as the Amyloidosis Research Consortium and national and international societies aimed at providing education and improving awareness such as the International Society of Amyloidosis. Concurrently, patient advocacy groups have played an important role in advancing the needs of patients and their caregivers both in Canada (Canadian Amyloidosis Support Network, Hereditary Amyloidosis Canada) and abroad (Amyloidosis Support Groups).
      Within this rapidly changing landscape, it is imperative that Canadian health care providers remain up to date with new developments to continue to offer our patients the best care possible. Addressing this evolving need created the motivation for this focus issue of the Canadian Journal of Cardiology (CJC) on Emerging Concepts in Cardiac Amyloidosis. An important component of this issue is the Canadian Cardiovascular Society (CCS)–Canadian Heart Failure Society (CHFS) Joint Position Statement on the Diagnosis and Management of Cardiac Amyloidosis.
      • Fine N.M.
      • Davis M.K.
      • Anderson K.
      • et al.
      Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement on the evaluation and management of patients with cardiac amyloidosis.
      This document joins a growing library of published guidelines and expert consensus statements aimed at facilitating delivery of optimal evidence-based patient care. Examples include guidelines describing best practices for diagnosis and staging of AL,
      • Gertz M.A.
      • Comenzo R.
      • Falk R.H.
      • et al.
      Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
      diagnosis and management of ATTR familial polyneuropathy,
      • Adams D.
      • Suhr O.B.
      • Hund E.
      • et al.
      First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy.
      clinical evaluation and diagnosis of ATTR cardiomyopathy,
      • Maurer M.S.
      • Bokhari S.
      • Damy T.
      • et al.
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      genetic screening and clinical surveillance of ATTR gene mutation carriers,
      • Conceicao I.
      • Damy T.
      • Romero M.
      • et al.
      Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations.
      and optimal use of cardiac imaging modalities.
      • Dorbala S.
      • Ando Y.
      • Bokhari S.
      • et al.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging.
      ,
      • Dorbala S.
      • Ando Y.
      • Bokhari S.
      • et al.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2—diagnostic criteria and appropriate utilization.
      Within this group of documents, the CCS-CHFS Joint Position Statement is unique in that it provides detailed recommendations to assist cardiovascular health care providers along the spectrum of the patient journey, including clinical presentation and recognition of signs and symptoms, diagnostic investigations, management of cardiovascular manifestations (such as heart failure and arrhythmia), the use of novel disease-modifying therapies for ATTR, and optimal care settings and considerations for follow-up and prognostic assessment. These latter topics, particularly those describing management approaches, had not been covered by previous guideline documents, and hopefully will provide health professionals with a valuable resource to guide patient care.
      In addition to the CCS-CHFS Joint Position Statement, this focus issue of CJC offers a number of other articles that provide contemporary review of important topics related to patient care. Di Giovanni et al. explore the changing face of cardiac amyloidosis by reviewing its epidemiology and the growing incidence resulting from improved awareness and diagnostic approaches.
      • Di Giovanni B.
      • Gustafson D.
      • Adamson M.B.
      • Delgado D.H.
      Hiding in plain sight: cardiac amyloidosis, an emerging epidemic.
      Alexander et al. describe important “dos and don’ts” in the clinical management of cardiac amyloidosis patients,
      • Alexander K.M.
      • Witteles R.M.
      Management of cardiac amyloidosis: do’s and don’ts.
      and Fine describes challenges and optimal strategies for diagnostic work-up.
      • Fine N.M.
      Challenges and strategies in the diagnosis of cardiac amyloidosis.
      Cuddy et al. provide clinical insights into the disease within the context of its being a systemic disorder with important noncardiovascular manifestations.
      • Cuddy S.A.M.
      • Falk R.H.
      Amyloidosis as a systemic disease in context.
      Cheung et al. provide a review of the management of arrhythmic complications, a particularly challenging aspect for many patients,
      • Cheung C.C.
      • Roston T.M.
      • Andrade J.G.
      • Bennett M.T.
      • Davis M.K.
      Arrhythmias in cardiac amyloidosis: challenges in risk stratification and treatment.
      and John and Stern explore the use of implantable electronic devices.
      • John R.M.
      • Stern D.L.
      Use of implantable electronic devices in patients with cardiac amyloidosis.
      Muchtar et al. discuss the important topic of cardiovascular considerations for patients with AL amyloidosis undergoing chemotherapy and autologous stem cell transplantation, which is particularly valuable because this topic was beyond the scope of the CCS-CHFS Joint Position Statement.
      • Muchtar E.
      • Lin G.
      • Grogan M.
      The challenges in chemotherapy and stem cell transplantation for light-chain amyloidosis.
      Finally, Davis and Fine discuss the urgent need for real-world data in an era of new disease-modifying therapies both in Canada and globally, and the importance of patient registries to meet this rising need.
      • Davis M.K.
      • Fine N.M.
      An urgent need for data to drive decision making: rationale for the Canadian Registry for Amyloidosis Research.
      These articles provide the reader with a thorough and modern overview of cardiac amyloidosis.
      As dramatic as the growth in knowledge and improved patient care delivery has been, it is anticipated that the field will continue to evolve and change significantly for years to come. Multiple clinical trials are currently active or in development for new therapeutic agents for both AL and ATTR. Emerging frontiers of research now include earlier recognition of disease, development of improved biomarkers for predicting and measuring treatment response, optimal timing for initiation of ATTR disease-modifying therapy, the value of combining different disease-modifying agents for AL and ATTR (and for which patients), and monitoring of asymptomatic gene mutation carriers with the goal of initiating therapy before the development of irreversible organ damage. These questions are among many other important topics that will need to be addressed as cardiac amyloidosis care continues to change. Indeed, as far as we have come in improving the care for patients with cardiac amyloidosis, this is only the beginning.

      Funding Sources

      There are no funding sources to declare.

      Disclosures

      N.M.F. and M.K.D. have received consulting fees and research support from Alnylam, Pfizer, and Akcea. R.H.F has received consulting fees from Ionis, Alnylam, and Caelum and research support from GlaxoSmithKline and Akcea.

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