Cardiac Amyloidosis: Diagnostic & Therapeutic Approaches
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Michel Khouri, MD Duke University
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Cardiac Amyloidosis: Diagnostic & Therapeutic Approaches
- 1. Cardiac Amyloidosis Diagnostic & Therapeutic Approaches Michel Khouri, MD Associate Professor of Medicine Duke University Medical Center May 4, 2024
- 2. Consulting: PRIME Education Advisory Board: Alnylam Pharmaceuticals, Inc.; BridgeBio, Inc. Speakers Bureau: Alnylam Pharmaceuticals, Inc. Research (Institutional): Pfizer, Inc.; Alnylam Pharmaceuticals, Inc.; BridgeBio, Inc.; Ionis-Astra Zeneca, Inc.; Moleculin Biotech Disclosures
- 3. • Overview of Amyloidosis • Screening for Cardiac Amyloidosis • Diagnosing Cardiac Amyloidosis & Subtype • Current Treatments • Future Directions of Therapy Outline
- 4. OVERVIEW
- 5. Amyloid comes in a variety of “flavors” • Amyloidosis is a disorder of protein folding • Misfolded proteins form insoluble fibrillar proteins that deposit in organs • Resulting organ dysfunction • AL & ATTR most common (~95%) cardiac involvement Adapted from Rubin, et al. Annu. Rev. Med. 2020. 71:203–19 • ATTR-CM is hereditary or wild type
- 7. Evolving Epidemiology of Cardiac Amyloidosis • Increased awareness with emergence of therapies • Validated non-invasive diagnostic techniques • Increased access to genetic testing • Recognition of ATTR-CA in at-risk populations • Significant challenges remain: • Delayed diagnoses • Geographic disparities • Access to therapies Adapted from Canepa, et al. Vessel Plus 2022 10-15% prevalence with screening Increased diagnosis
- 8. SCREENING
- 9. When to Suspect Cardiac Amyloidosis Red Flags to prompt Suspicion of ATTR Amyloidosis Heart Failure ≧ 60 yo Voltage on ECG discordant with LVH on imaging Newly unable to tolerate anti-HTN meds Low-Flow, Low-Gradient Aortic Stenosis AV Conduction Disease Bilateral Carpal Tunnel Syndrome / Spinal Stenosis Biceps Tendon rupture Peripheral Neuropathy Autonomic dysfunction LV Wall thickness ≧ 12 mm Clinical Features Suspicious for Amyloidosis Evaluate for Systemic Amyloidosis Multi-disciplinary referral? Evaluate for Cardiac Involvement Non-invasive vs. Invasive diagnosis Adapted from Garcia-Pavia, et al. EHJ 2021
- 10. Pseudoinfarct pattern, Low voltage * ECG for Cardiac Amyloidosis Common Misconception Low voltage ECG = sensitive for cardiac amyloidosis Adapted from Cyrille, et al. Am J Cardiol 2014
- 11. Echo: Restrictive & Strain Features Adapted from Maurer, et al. Circulation 2017 Infiltrative Features Longitudinal Strain ‘Relative’ Apical Sparing Apical --------------- > 1.0 Basal + Mid Adapted from Narotsky, et al. Canadian J Cardiol 2016 and Garcia-Pavia, et al. EHJ 2021
- 12. Japanese Society of Pathology CMR for Cardiac Amyloidosis
- 13. DIAGNOSIS
- 14. Non-invasive Diagnosis: Rule out AL
- 15. Garcia-Pavia, et al. EHJ 2021 Hanna, et al. JACC 2020 Pitfalls: 1. Don’t do SPEP/UPEP, not as sensitive as IFE 2. Tissue required if monoclonal protein present Pearl: 1. Renal adjustment for serum free light chains: Rule out AL: Monoclonal Proteins
- 16. Non-invasive Tc-PYP for ATTR-CA Adapted from Gillmore, et al. Circulation 2016 Hanna, et al. JACC 2020 ASNC Practice Points PYP Imaging
- 17. Invasive Diagnostic Testing for CA Tissue biopsy • Extra-cardiac biopsy – Bone marrow, abdominal fat pad, labial salivary gland – Yield: AL (>70%), ATTRm (50-70%) ATTRwt (20-25%) • Endomyocardial biopsy (EMB) – ~100% sensitive / specific • Congo red stain to identify amyloid – Apple green birefringence (polarized light) • Typing of amyloid – Immunohistochemistry (IHC) • Less accurate; problematic high background – Laser dissection mass spectrometry (mass spec) • Gold standard; Mayo Clinic Lab send out • Genetic test to establish TTR genotype – Blood test - PCR Adapted from Connors LH, et al. Circulation 2016 Typing Amyloid Identifying Amyloid Siddiqi, et al. EHJ 2017
- 18. Diagnosing Cardiac Amyloidosis Conceptual Algorithm Duke Diagnostic Algorithm
- 19. Duke Maestro Order Set for Cardiac Amyloidosis
- 21. A timeline of therapeutics for AL amyloid. Autologous SCT 1998 PIs/ CyBorD 2005 Immunotherapy 2019 Amyloid associated with MM 1867 AL Amyloid Palladini et al. Blood, 2020. AL modifying therapies
- 22. Spectrum of ATTR modifying therapies Maurer, et al. Am J Cardiol 2022
- 23. TTR Silencing & Knockdown Adapted from Aimo, et al. Nat Rev 2022 and Maurer, et al. Am J Cardiol 2022
- 24. TTR Stabilizing Therapies Adapted from Maurer, et al. Am J Cardiol 2022 and Chandrashekar, et al. HF Rev 2022 TTR Stabilizers prevent destabilizing & misfolding Strengthen / occupy ligand binding sites (thyroxine, RBP) on native TTR protein
- 25. Anti-Amyloid Therapies Adapted from Maurer, et al. Am J Cardiol 2022 and Chandrashekar, et al. HF Rev 2022 Adapted from Fontana, et al. NEJM 2023
- 26. Maurer, et al. NEJM 2018 • NNT to prevent 1 death at 30 months: 7.5 • NNT to prevent 1 CV admission at 30 months: 4.5 RRR = 30%
- 27. ATTR Clinical Development Pipeline Adapted from Gonzalez-Duarte, et al. Rev Invest Clin 2021 Adapted from Tschope, et al. J Clin Med 2022 Vutisiran* Eplontersen* (Helios-B, Phase III) (CardioTTRansform, Phase III) (ATTRibute-CM, Phase III) (APOLLO-B (2022), Phase III for ATTR-CM) (NNC6019-001) NTLA-2001 (MAGNITUDE, Phase III) Adapted from Tomasoni, et al. Front CV Med 2023
- 28. = Duke Clinical Trial Site * = Approved for hereditary ATTR-PN Adapted from Tschope, et al. J Clin Med 2022 ATTR-CA Clinical Trials at Duke
- 29. Non-disease modifying therapies for CA Yes Sometimes No Diuretics Aldosterone antagonists Renin-angiotensin system inhibitors --- Beta blockers --- Alpha-1-adrenoreceptor agonists --- Digoxin --- Calcium channel blockers X Oral anticoagulants SGLT2 inhibitors Amiodarone Pacemaker (symptomatic bradycardia) AICD (secondary prevention)
- 31. Griffin, et al. JACC Cardio Onc 2021 Therapy for Primary Prevention? ACT-Early (Acoramidis)
- 32. • If you look for cardiac amyloidosis, you will find it! • ECG and Echo, used in combination, are best for screening cardiac amyloidosis • CMR is useful for diagnosing cardiac amyloidosis but cannot subtype AL-CA vs. ATTR-CA • For non-invasive diagnosis of ATTR-CA, avoid SPEP, order FLC/IFE, watch out for lambda and remember kappa can be in slight excess in CKD • AL-CA always requires histopathology • ATTR-CA can be diagnosed non-invasively by TcPYP w/SPECT or invasively by endomyocardial biopsy • Pursue biopsy when imaging does not satisfy clinical suspicion • Current treatments stabilize or slow progression of disease • Emerging therapies may increasingly attenuate disease progression and have potential for reverse remodeling Conclusions
- 33. Thanks!
Editor's Notes
- Characteristic biventricular thickening as well as biatrial dilation and thickening of both atrioventricular valves. In AL, the pattern of amyloid deposition is usually subendocardial and diffuse Stiff, poorly compliant vent = diastolic dysfxn; systolic in severe and advanced disease High rates of Afib and conduction blocks Dissociation between short and long axis systolic function. Typically, there is much greater restriction of movement at the base compared to the apex. = cherry on top spot on echo
- Across prespecified subgroups, based on TTR status, NYHA class and tafamidis dose, the difference in all cause mortality and frequency of CV-related hospitalization favored tafamidis over placebo, except in patients with NYHA III at baseline, among whom rates of hospitalization were higher than among patients receiving tafamidis than among patients receiving pacebo Using Poisson-regression analysis, there was an interaction between treatment and NYHA class, but not for TTR status Prespecified sensitivity analysis of all cause mortality that did not treat heart transplant or LVAD as death yielded a HR 0.67 (95% CI: 0.49-0.94)
- Under physiologic conditions, dissociation of the TTR tetramer into monomers occurs extremely slowly, por- tending great stability to this protein, particularly when ligands are bound to the binding sites If the TTR tetramer does become unstable and undergo dissociation, the resulting monomers are prone to misfolding and even- tual aggregation into beta pleated sheets of insoluble TTR amyloid fibrils. The TTR tetramer becomes more prone to dissociation by two broad mechanisms. Autosomal dominant inherited vari- ants in the TTR gene induce amino acid substitutions that can destabilize the TTR tetramer by lowering the thermo- dynamic or kinetic barrier for dissociation [6]. Amyloidosis due to one of these > 120 known pathological variants is known as variant ATTR amyloidosis (vATTR). In contrast, when there are no identified pathological TTR variants, aging TTR proteins can become oxidized and/or the pro- tein repair systems can fail, thereby destabilizing the TTR tetramer