Managing complications in ATTR-CM

Take-home messages:

  • HF, AF, thromboembolism and aortic stenosis are among a number of complications caused by ATTR-CM
  • The ESC recommends deprescribing beta-blockers and avoiding ACEi/ ARB for patients with ATTR-CM and HF
  • Atrial myopathy is common in patients with ATTR-CM and can lead to AF and thrombosis
  • A complex relationship exists between aortic stenosis and ATTR-CM

"A challenging, fascinating disease. It is indeed a source of complications." This is how Professor Claudio Rapezzi, University of Ferrara, described transthyretin-mediated amyloidosis with cardiac myopathy (ATTR-CM) to delegates at this year's ESC Heart Failure & World Congress on Acute Heart Failure, and, with the recent publication of eight sets of guidelines/ position statements covering ATTR-CM, it is clearly a hot topic.

Professor Rapezzi highlighted some of the complications caused by this "challenging" disease and delved deeper into the treatment of them against a background of ATTR-CM, focusing on heart failure (HF), atrial fibrillation (AF), thromboembolism and aortic stenosis.

HF

Professor Rapezzi began with HF and, specifically, the lack of consensus across guidelines on the use of beta-blockers, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB).

Summary of recommendations for treating HF with beta-blockers
and ACEi/ ARB in patients with cardiac amyloidosis

  ESC WG on Myocardial and Pericardial Diseases1 DGK2 AHA3 CCS/ CHFS4 JCS5
Beta-blockers Recommended to deprescribe Can lead to symptomatic hypotension even at low doses and often poorly tolerated No data for clinical benefit Frequently poorly tolerated and should be used with considerable caution Tolerated dosing might be considered
ACEi/ ARB Recommended to avoid Can lead to symptomatic hypotension even at low doses and often poorly tolerated No data for clinical benefit Frequently poorly tolerated and should be used with considerable caution Tolerated dosing might be considered

AHA: American Heart Association; CCS/ CHFS: Canadian Cardiovascular Society/ Canadian Heart Failure Society; DGK: German Cardiac Society; ESC: European Society of Cardiology; JCS: Japanese Circulation Society; WG: Working Group

Despite some discrepancies between guidelines, Professor Rapezzi believes that the recommendation to consider deprescribing beta-blockers is the most relevant of the ESC recommendations, especially for patients with overt restriction. As ATTR-CM progresses, patients develop severely depressed systolic left ventricular function and overt restriction. Professor Rapezzi explained, "If you put together reduced ejection fraction and overt restrictive disease, this means that stroke volume is the main modulator of life and death of your patients. […] When stroke volume is fixed […] heart rate is the main determinant of cardiac output and so you must be very cautious in using beta-blockers."

Professor Rapezzi next discussed the potential of a new class of drugs, SGLT2 inhibitors, for HF in ATTR-CM. Dapagliflozin and empagliflozin have shown good results in HF with preserved ejection fraction however, efficacy in patients with ATTR-CM is unknown due to the exclusion of patients with ATTR-CM from HF studies. Professor Rapezzi posits that this is due to unknown problems that these conditions may cause, rather than a precise pathological consideration. He concluded "Personally, I would strongly consider the hypothesis of testing this new class of drugs in amyloidosis."

AF and thromboembolism

Professor Rapezzi next discussed thromboembolism and AF, sharing a summary of the ESC recommendations for treatment of thromboembolism or AF in the presence of ATTR-CM:

  • Thromboembolism is common in patients with ATTR-CM
  • Guidelines recommend anticoagulation if AF is present, or in selected cases with sinus rhythm, independent of CHADS-VASc score
  • The preferred treatment for AF is amiodarone, and digoxin should be used cautiously
  • Electrical cardioversion has significant risk of complications and AF recurrence is frequent
  • Thrombi should be excluded before electrical cardioversion
  • AF ablation data is scarce and controversial

Finding new targets to treat and new trials for thromboembolism or AF with ATTR-CM is problematic, according to Professor Rapezzi, since amyloidosis affects the whole heart not just the ventricles. In some cases, atrial myopathy actually precedes overt development of ventricular cardiomyopathy.

Professor Rapezzi described the results of ECHO speckle tracking in 906 patients with ATTR-CM,6 where patients showed patterns of atrial stiffness and impairment of conduit, contractile function and reservoir. The study found that it was possible to subdivide patients into three subgroups: non-sinus rhythm, sinus rhythm with left atrial mechanical contraction (LAMC) and sinus rhythm without LAMC. This final subgroup of patients, sinus rhythm without LAMC, were defined as having ‘atrial electromechanical dissociation’, and showed decreased survival compared with the other groups. Professor Rapezzi explained that atria in patients with ATTR-CM are enlarged, infiltrated by amyloid and mechanically dysfunctional, with electrical dispersion and endocardial damage. Put together, these can lead to AF and thrombosis independently of each other or in turn.

Aortic stenosis

In the last part of his talk, Professor Rapezzi discussed the complexity of the relationship between aortic stenosis and ATTR-CM, with some experts believing the high intramyocardial mechanical stress caused by aortic stenosis accelerates amyloid infiltration, and others believing that amyloid infiltration of aortic valve itself, could be a cause of aortic stenosis.

ATTR-CM has been detected in around 8%-10% of patients with aortic stenosis. The good news for patients with ATTR-CM, according to Professor Rapezzi, is that the in-hospital mortality after transcatheter aortic valve replacement is not significantly different in patients with or without ATTR-CM. The bad news, however, is that rehospitalisation rates are doubled in those patients with ATTR-CM versus those without; Professor Rapezzi suggests that further trials may be helpful in finding treatments for this group of patients.

The problem of cardiac valves and amyloidosis, in Professor Rapezzi’s opinion, is an interesting one. Studies have detected amyloid in the cusps of aortic valves in explanted hearts, but the quality of results vary and studies need to be replicated:

  • A study of 150 surgically removed heart valves found high prevalence of amyloid, but was unable to identify the most common amyloid proteins7
  • A study of an elderly Indian population with severe aortic stenosis found evidence of myocardial ATTR-CM in only 9.4% (3/32) of patients who underwent pyrophosphate scanning, while evidence of valvular ATTR-CM was found in 41% (19/46) of patients by histopathological examination8

Professor Rapezzi concluded that "the concept of amyloidosis as a cause of valve disease, and not only myocardial disease, is challenging."


SGLT2: sodium-glucose cotransporter 2

Based on: Rapezzi, C. How to treat complications. Presented at Heart Failure & World Congress on Acute Heart Failure, 21-24 May 2022, Madrid, Spain; oral presentation

Top image: Design Cells
The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

References

  1. Garcia-Pavia P, Rapezzi C et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2021;42(16):1554-1568
  2. Yilmaz A, Bauersachs J et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 2021;110(4):479-506
  3. Kittleson M M, Maurer M S et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 2020;142(1):e7-e22
  4. Fine N M, Davis M K et al. Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement on the evaluation and management of patients with cardiac amyloidosis. Can J Cardiol 2020;36(3):322-334
  5. Kitaoka H, Izumi C et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J 2020;84(9):1610-1671
  6. Bandera F, Martone R et al. Clinical importance of left atrial infiltration in cardiac transthyretin amyloidosis. JACC Cardiovasc Imaging 2022;15(1):17-29
  7. Kristen A V, Schnabel P A et al. High prevalence of amyloid in 150 surgically removed heart valves--a comparison of histological and clinical data reveals a correlation to atheroinflammatory conditions. Cardiovasc Pathol 2010;19(4):228-235
  8. Singal A K, Bansal R et al. Concomitant transthyretin amyloidosis and severe aortic stenosis in elderly indian population: a pilot study. JACC Cardio Oncol 2021;3(4):565-576