WHEN IS LVH NOT JUST LVH?PRACTICAL CLINICAL ALGORITHMS WHEN YOU SUSPECT CARDIAC AMYLOID

WHEN IS LVH NOT JUST LVH?PRACTICAL CLINICAL ALGORITHMS WHEN YOU SUSPECT CARDIAC AMYLOID Mazen Hanna, MDCo-Director, Amyloidosis CenterSection of Heart Failure and Cardiac TransplantCleveland Clinic Disclosures•Grants/research support: Term chair for Amyloid Heart Disease, Philanthropic donation•Consulting fees: Pfizer, Alnylam, Akcea, Eidos(served on an advisory board)•Speaker fees: Alnylam, Akcea•Other: •I willnot bediscussingnamesof medicationsfor treatmentduringthislecture.______ HCM HTNheart w/ renal failureLysosomalstorage disease Amyloid Two Main Types of Amyloid That Affect the HeartALLight chain amyloidosisTransthyretin amyloidosisATTR Wild typeHereditary AL Amyloidosis(Light Chain amyloidosis)•Plasma cell disorder•IgGlight chain (κ:λ) •3000-4000 cases annually•Median age 63•Untreated 6 mo survival if CHF Kyle RA & RajkumarV Immunological Reviews 194: 112–139; 2003 ProductionCirculationDeposition ATTR _ TherapyTransthyretin(TTR)“Prealbumin”Transport protein: thyroxineand retinolHomotetramer: 127 amino acids monomers130 mutations described in monomer “Senile systemic amyloidosis” (SSA)Median age at dx 74 yearsCardiomyopathy/ Atrial fibrillation/ Conduction diseaseBilateral carpal tunnel syndrome/ Spinal Stenosis *The most common type of amyloidosis!!Median survival 3-4 years Wild Type TransthretinAmyloidosis (wtATTR) Hereditary TTR amyloidosis (hATTR)> 130 point mutations Autosomal dominant inheritance Familial amyloid polyneuropathy (FAP)Familial amyloid cardiomyopathy (FAC) Phenotype“Neurologic” “Cardiac”V122II68LL111MT60AS77YE89LI107VF64LE89Q T49A V30Mearly onset V30Mlate onset Mixed Phenotype CommonG47A 3.5% African-Americans Irish Descent Pathology: Diffuse involvement •Increase in LV mass w/out dilatation•Atrial infiltration impairing atrial contraction•Conduction system / valves•Microvascular ischemia 11 CONFIDENTIAL Echocardiogram: Prompts Suspicion Normal Amyloid Reference: 1. QuartaCC, et al. 2012;126(12):e178-e182. doi: 10.1161/CIRCULATIONAHA.111.069195. 12 CONFIDENTIAL •Classic Low-Voltage Electrocardiogram inCardiac Amyloidosis1,2 Low voltage: 50% in AL25% in ATTR(10% meet LVH criteria)Pseudoinfarctionpattern:~50% in AL References: 1.Maurer M, et al. Circulation 2017;135:1357-1377. 2. Grogan M, et al. Heart.2017;103:1065-1072. 81 year old white male with biopsy proven ATTR cardiac amyloidosis 13 CONFIDENTIAL 55 year old male with nephroticsyndrome and HF LV &RV Thickening, Atrial Dilation, Thickened Valves, Pericardial Effusion 55 year old male Nephroticsyndrome and heart failure AL Amyloid 1.7 cm 1.6 cm CONFIDENTIAL15 Clinical Presentation •HFpEF(“right sided”)•“Hypertrophic cardiomyopathy”•Low-flow low-gradient AS•Afib/cardioembolic stroke•Pacemaker/Heart Block•Angina with normal course Cardiac1-5 •Orthostasis•Neuropathy•Peripheral•Autonomic•Bilateral CTS (TTR > AL)•Spinal stenosis (TTR) Non-Cardiac6,7 References: 1. DharmarajanK, et al. J Am GeriatrSoc. 2012;60:765-774. 2. MohtyD, et al. Arch Cardiovasc Dis. 2013;106:528-540.3. Ruberg FL, et al. Circulation.2012;126:1286-1300.4. Maurer MS, et al. Circulation. 2017;135(14):1357-1377.5. Falk RH, et al. Prog Cardiovasc Dis.2010;52(4):347-361. 6. Ando Y, et al. OrphanetJ Rare Dis. 2013;8:31.7. WestermarkP, et al. Ups J Med Sci2014;119(3):223-228. Physical Exam Findings Specific to AL AmyloidosisMacroglossiaPeriorbitalPurpura 18 CONFIDENTIAL •Diagnosing Cardiac Amyloid: •Endomyocardialbiopsy used to be the first option MUST SUBTYPE THE AMYLOIDDetermines further testingPrognosisTreatment ImmunohistochemistryMass Spectrometry Diagnostic ApproachClinical + Echo + ECG ĸ or תּlight chains Heme/OncConsult Transthyretin Genetic testing Mutant TTRWild Type Cardiac MRIEcho w/ Strain IMAGING Tc PYP ScanBIOPSY Serum free light chains Serum immunofixation Urine immunofixation Labs NTproBNPTroponin T Laboratory Testing for work up of AL •SPEP and UPEP•Serum free light chain assay (Kappa/Lambda)•Serum immunofixation•Urine immunofixation Diagnosis Cardiac Amyloid by MRI 80 % sensitivity90% specificity85% negative predictive value Vogelsburget al. JACC 2008;51:1022-30 Apical Sparing Pattern on Echo 24 CONFIDENTIAL Apical Sparing Pattern: Longitudinal Strain 99mTechnetium pyrophosphate (PYP) or dipyrophosphate(DPD) Scintigrahpy: TcPYPscan Rapezzi EurJ NucMed MolImag2011, JACC Img2011: Banypersad, JAHA 2012 Diagnostic of ATTR Cardiac Amyloidosis1)Grade 2 or 3 scan2)Negative monoclonal lab testing3)91% sensitivity and 100% specificity for ATTR amyloidosis 26 CONFIDENTIAL AL TTR ECHOECG (CARDIAC MRI) HEART BIOPSY Starts With Clinical Suspicion Serum free light chainsSerum immunofixationUrine immunofixationTechnetium pyrophosphate scan Bone marrow biopsyFat pad aspirateBiopsy affected organGenetic testingWild type Hereditary Grade 2/3 uptake (-) monoclonal 78 yo AA female h/o HTN & EF 45% Referred for shortness of breath Echocardiogram AL TTR Serum free light chainsSerum immunofixationUrine immunofixationTechnetium pyrophosphate scan ECHO (with strain)ECG NORMAL fLCNo M proteinATTR-CMGenetic testing + V122I mutationHereditary transthyretincardiac amyloidosis (ATTRv) 61 yowhite female •SOB and edema X 1 year•Urine with 9 grams proteinuria ECG: 1stdegree AV block, LAFB Global LGS –10.5 % AL TTR Serum free light chainsSerum immunofixationUrine immunofixationTcPYPscan ECHO (with strain) ECG Kappa light chain AL Amyloid Kidney Biopsy + Kappa light chain amyloidSerum and urine immunofixation: No M Protein Bone Marrow biopsy only 1% plasma cells, Congo red negative 81 yrold white male •Bilateral carpal tunnel syndrome, Spinal stenosis, Biceps tendon rupture•Diagnosed with diastolic heart failure, atrial fibrillation•Myledyplasticsyndrome with platelets in 60’s•Metop25 bid, Warfarin•BP 128/65 mm Hg AL TTR Serum free light chainsSerum immunofixationUrine immunofixationTechnetium pyrophosphate scan ECHO (with strain)ECG Wild type transthyretincardiac amyloid Serum immunofixationNo M protein TTR cardiac amyloidGenetic testingNo mutation HEART BIOPSY Teaching points•Look at ECG and wall thickness on ECHO•Diagnostic work up•DO NOT ORDER SPEP AND UPEP!!!!!!!!•Rather order serum free light chains & immunofixationserum +/-urine•Technetium pyrophosphate scan specific for TTR •Red flags •Older white male w previous carpal tunnel and diastolic HF or “HOCM”•Older African American with “diastolic heart failure”•As about both carpal tunnel and spinal stenosis in history taking