Stepwise Approach for the Diagnosis of Amyloid Heart Disease

Transcription

1 Stepwise Approach for the Diagnosis of Amyloid Heart Disease Mat Maurer, MD Columbia University Medical Center Arnold and Arlene Goldstein Professor of Cardiology April 13, 2019

2 Disclosures I am under-funded I have research support from several pharmaceutical companies : NIH/NIA/NHLBI -Akcea Eidos, Inc -Novartis Ionis Pharmaceuticals -Alnylam Pfizer, Inc. -Prothena Will discuss a novel and investigational products for cardiac amyloidosis.

3 Misdiagnosis and Delayed Diagnosis of Cardiac Amyloidosis 75% saw > 3 physicians before diagnosis made 63% > 6 months to diagnosis 44% received an incorrect diagnosis first You ve got to think of amyloidosis 31% required air travel to establish diagnosis Only 18% of these patients with cardiac AL had the correct to diagnose it!!! diagnosis made by a cardiologist Cardiologists are the most common subspecialists to make a misdiagnosis most commonly - hypertrophic cardiomyopathy Lousada et al, European Hematology Association (EHA) 22nd Annual Congress 2017; June 22 25,

4 Systemic Amyloidosis Characterized by extra-cellular deposition of a fibrillar protein Deposits progressively interfere with the structure / function of affected organs throughout the body Two dozen proteins known to form amyloid fibrils in vivo Two predominant types involve the heart: AL typically associated with plasma cell dyscrasia TTR Associated transthyretin (TTR) 3. a. mutation or b. wild type (SCA)

5 Cardiac AL Amyloidosis A Race Against Time Cardiac AL is a medical emergency If cardiac amyloid is suspected -- consider it AL until proven otherwise Once the diagnosis considered, give yourself one week to get the answer; amyloid yes/no Amyloid typing may take a little longer, but by then you should be referring the patient to an amyloid center 5

6 AL Cardiac Amyloidosis: Delayed Diagnosis is Major Factor in Prognosis Patients are dying while cardiologists ponder the diagnosis J Clin Oncol, 2012; 30:

7 Figure 7. Diagnostic algorithm for evaluation of suspected ATTR-CM Diagnostic Algorithm for Cardiac Amyloidosis Heightened Index of Suspicion Increased wall thickness without obvious cause HFpEF with concomitant right heart failure (+JVP, hepatomegaly, edema) Discordance of wall thickness and electrocardiographic voltage History of carpal tunnel syndrome, lumbar spinal stenosis, or spontaneous biceps tendon rupture Low flow, low gradient aortic stenosis Diffuse late gadolinium enhancement or increased extracellular volume of cardiac MRI Apical longitudinal strain preservation Natriuretic peptides elevated out of proportion to clinical syndrome Persistently positive troponin in the absence of acute coronary syndrome Assess for presence of monoclonal protein by: Serum kappa/lambda free light chain ratio (NOT SPEP) AND Immunofixation electrophoresis of serum and urine Obtain biomarkers for staging including NTproBNP, Troponin I/T and egfr. Monoclonal Protein Present Monoclonal Protein Absent Referral to hematology, and Biopsy of clinically involved organ or fat pad (if fat pad negative, biopsy of clinically involved organ should be pursued) Congo red staining, and Identification of precursor protein with mass spectroscopy or IHC + - AL, ATTR or other amyloidosis AL Cardiac Amyloidosis Unlikely Yes Non-invasive Evaluation with PYP, DPD or HMDP + - ATTR Cardiac Amyloidosis TTR Gene Sequencing + - hattr wtattr Cardiac Amyloidosis Unlikely Bone Scintigraphy Available? No Endomyocardial Biopsy with Congo red staining, and Identification of precursor protein with mass spectroscopy or IHC + - ATTR Cardiac Amyloidosis TTR Gene Sequencing + - hattr wtattr Cardiac Amyloidosis Unlikely

8 You ve got the think of it to diagnose it! Heightened Index of Suspicion Increased wall thickness without obvious cause HFpEF with concomitant right heart failure (+JVP, hepatomegaly, edema) Discordance of wall thickness and electrocardiographic voltage History of carpal tunnel syndrome, lumbar spinal stenosis or spontaneous biceps tendon rupture Paradoxical low flow low gradient aortic stenosis Diffuse delay enhancement or increased extracellular volume of cardiac MRI Apical preservation on speckled strain echo Natriuretic peptides elevated out of proportion to clinical syndrome Persistently positive troponin in the absence of acute coronary syndrome.

9 Percentage of Subject ATTRwt Cardiac Amyloid: Common in HFpEF Distribution of Ejection Fraction in Subjects Hospitalized with Heart Failure 15% HFrEF HFpEF HFnEF Technetium 99m bone tracers (DPD, PYP, HDP) have ~90% sensitivity/specificity for identifying ATTR cardiac amyloid Negative Uptake Positive Uptake 10% 5% Scan 0% Ejection Fraction (%)? Prevalence of ATTR Cardiac Amyloid Eur Heart J Jul 28 C) Emerging Therapies 13% of HFnEF had ATTR Cardiac Amyloid

10 Discordance Between Wall Thickness and Voltage Males Females

11 Discordance Between Wall Thickness and Voltage Carroll Index Sokolow index (sum of S wave in lead V1 and R wave in lead V5 or V6) divided by the cross-sectional area (CSA) of the LV wall, where CSA = (π()*((lv end-diastolic diameter/20)+mean LV wall thickness/10)^2-π()*(lv enddiastolic diameter/20)^2) / body surface area, (mm/cm2/m2); Total QRS/LVWT Males, cutoff 8.4 Females, cutoff 7.7 Total QRs / LVWT / h 2.7 Males, cutoff 36.4 Female, cutoff 27.3 Am J Cardiol. 1982;49:9 13;

12 You ve Got to Think of IT History/Exam Clues HFPEF without hypertension, particularly in men (for TTR) Evidence of right-sided heart failure (e.g. hepatomegaly, ascites, and lower extremity edema) Intolerance of ACE, Beta-blockers. AL Periorbital purpura TTR Bilateral carpal tunnel syndrome Lumbar Spinal Stenosis Biceps tendon rupture to Diagnose IT!!!

13 Orthopedic Clues to TTR Amyloidosis Ups J Med Sci 2014;119:223-8, Mod Pathol 2015;28:201-7; JAMA Sep 12;318(10): ; Amyloid Dec;24(4):

14 UNVEIL Study Using Nuclear & Echocardiographic Vehicles to Expose Inherent Loads of Amyloid 151 patients with severe AS. 99m Tc-PYP planar imaging. Uptake in 16% (n=24), 22 of which were men. Phenotype of severe concentric LVH and low flow AS Men (92%) Elevated BNP 522 [302-1,023] vs 275 [ ] pg/ml, p=0.041 Increased LV mass (130 vs 98 g/m 2, p=0.002) Low SVI l(30+11 vs ml/m 2, p=0.009) RBBB (38% vs 16%, p=0.023). ATTRwt in Males Undergoing TAVR ATTRwt 22% Non-Amyloid

15 MRI

16 Preserved Apical Strain Cherry on Top

17 Six Routine Tests to Get on Every Patient with Suspected Cardiac Amyloidosis AL Cardiac Amyloidosis ATTRwt Cardiac Amyloidosis ATTR Cardiac Amyloidosis J Clin Oncol 30: ; JACC.2016 ;68(10): ; Eur Heart J. 2018;39(30):

18 Serum Free Light Chain Assay

19 Biopsy Gold Standard & Only Way to Diagnose AL Our general practice: Biopsy of clinically involved organ Testing for amyloid subtype Immunofluorescence or Mass spectrometry Organ Sensitivity Abdominal fat pad 70% (?) Bone marrow 50-56% Rectal 70-85% Clinically involved organ Nearly 100%

20 Monoclonal Protein is Present Presence of monoclonal proteins does not prove AL cardiac amyloidosis as 20-40% of patients with ATTRwt cardiac amyloidosis have MGUS Misclassification by IHC is common rely on mass spectroscopy if in doubt.

21 Endomyocardial Biopsy: Not Routinely Necessary

22 Noninvasive Diagnosis of TTR Cardiac Amyloidosis Using 99mTc-DPD Scintigraphy J Am Coll Cardiol 2005;46:

23 Differences in Cardiac Retention with Tc-99 in Controls, AL and ATTR Amyloid Circ Cardiovasc Imaging. 2013;6(2):

24 Bone Scintigraphy for TTR Cardiac Amyloidosis Consensus that ATTR cardiac amyloidosis can be reliably diagnosed in the absence of histology provided that all of the following criteria are met; Heart failure with an echocardiogram or CMR that is consistent with or suggestive of amyloidosis Grade 2 or 3 cardiac uptake on a bone scan, using either DPD, PYP or HMDP Absence of a detectable monoclonal protein despite serum and urine IFE, and serum free light chains Circulation. 2016;133(24):

25 Nuclear Bone Scintigraphy for ATTR Cardiac Amyloidosis Circulation. 2016;133:

26 TTR Amyloid Cascade

27 TTR (Prealbumin) Transthyretin - TTR Tetramer of subunits of 127 amino acids each; TTR is a plasma transport protein for thyroxine - T4 - and for retinol. Mutation Val30Met Transthyretin Amyloidoses Predominant Features PN, AN Val122Ile Thr60Ala Heart Heart, Carpal Tunnel Syndrome

28 Age Dependent Penetrance Using THAOS Transthyretin Amyloid Outcomes Survey ( 111 persons meeting inclusion criteria were identified. 4 genotypes were represented: Wild-type (59%), Val122Ile (23%), Thr60Ala (9%), Leu111Met (9%).

29 The Amino Acid Sequence of Human TTR Kanda, Y.; Goodman, D. S.; Canfield, R. E.; Morgan, F. J. J. Biol. Chem. 1974, 249,

30 Transthyretin V122I allele frequencies in Africa Gambia (100) Senegal (66) Mali (62) Nigeria 0.00 (70) Guinea (28) Cameroon 0.009(110) Sierra Leone (502) Ivory Coast (44) Ghana NB: (948) Adult: 0.02 (300) Tanzania.013(117) Malawi (84) South Africa (91) Courtesy of Joel Buxbaum, Scripps Clinic

31 TTR Gene Sequencing Genetests.gov Clinically available in several labs: Athena Diagnostics, Inc Genedx, Inc Harvard Correlegan Ambry Genetics Costs $250 -$800

32 Figure 7. Diagnostic algorithm for evaluation of suspected ATTR-CM Diagnostic Algorithm for Cardiac Amyloidosis Heightened Index of Suspicion Increased wall thickness without obvious cause HFpEF with concomitant right heart failure (+JVP, hepatomegaly, edema) Discordance of wall thickness and electrocardiographic voltage History of carpal tunnel syndrome, lumbar spinal stenosis, or spontaneous biceps tendon rupture Low flow, low gradient aortic stenosis Diffuse late gadolinium enhancement or increased extracellular volume of cardiac MRI Apical longitudinal strain preservation Natriuretic peptides elevated out of proportion to clinical syndrome Persistently positive troponin in the absence of acute coronary syndrome Assess for presence of monoclonal protein by: Serum kappa/lambda free light chain ratio (NOT SPEP) AND Immunofixation electrophoresis of serum and urine Obtain biomarkers for staging including NTproBNP, Troponin I/T and egfr. Monoclonal Protein Present Monoclonal Protein Absent Referral to hematology, and Biopsy of clinically involved organ or fat pad (if fat pad negative, biopsy of clinically involved organ should be pursued) Congo red staining, and Identification of precursor protein with mass spectroscopy or IHC + - AL, ATTR or other amyloidosis AL Cardiac Amyloidosis Unlikely Yes Non-invasive Evaluation with PYP, DPD or HMDP + - ATTR Cardiac Amyloidosis TTR Gene Sequencing + - hattr wtattr Cardiac Amyloidosis Unlikely Bone Scintigraphy Available? No Endomyocardial Biopsy with Congo red staining, and Identification of precursor protein with mass spectroscopy or IHC + - ATTR Cardiac Amyloidosis TTR Gene Sequencing + - hattr wtattr Cardiac Amyloidosis Unlikely

33 ATTR Cardiac Amyloidosis Transition from a rare, underdiagnosed and untreatable condition to increasingly and easily recognized and treatable

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