Recognizing and Treating Amyloidosis in Heart Failure Patients. Denise Barnard, M.D., F.A.C.C. 18 th Annual HF Symposium

Transcription

1 Recognizing and Treating Amyloidosis in Heart Failure Patients Denise Barnard, M.D., F.A.C.C. 18 th Annual HF Symposium

2 Disclosures: None

3 Lecture Outline What is Amyloidosis? What forms of amyloid affect the heart? Major types of Cardiac Amyloid Natural History, prognosis Diagnostic tests and suggested workup algorithm Standard and Future Therapies

4 What is Amyloidosis? Amyloidosis is generic term for a localized or systemic deposition disease Proteins with unstable tertiary structures misfold, aggregate and form amyloid fibrils Fibril deposits accumulate in tissues as filaments organized as rigid cross B-pleated sheets The fibrils are insoluble, resistant to proteolysis, disrupt normal tissue architecture & fxn The heart, kidneys, liver, lungs, GI tract, skin, blood vessels, central and peripheral nervous systems and soft tissues can be affected depending on the type of amyloid, The reason for organ tropism is not known. More than 30 proteins can form amyloid fibrils, 5 of which frequently infiltrate the heart. Immunoglobulin light chain (AL), Ig heavy chain, Transthyretin (TTR), serum amyloid A and Apoliprotein A1.

5 What is Cardiac Amyloidosis? Cardiac amyloid infiltration results in a restrictive cardiomyopathy, early diastolic heart failure, arrhythmias and late systolic heart failure. Cardiomyocyte distortion, myocyte separation, tissue stiffening, and organ dysfunction. Angina common In general, prognosis after onset severe heart failure is poor, but is dependent upon the type of amyloid and timing of diagnosis. Cardiac amyloid remains underdiagnosed mostly due to lack of suspicion, often diagnosed only in advanced stages-- when treatment options are limited Early recognition of cardiac amyloidosis has the potential to halt the disease process before irreversible changes occur. Cardiac amyloidosis should be in the differential diagnosis of patients presenting with heart failure and preserved ejection fraction.

6 What is Amyloidosis? Plasma Proteins form, fold & unfold, can combine Feng, ISBN

7 Courtesy of Robert Padera, MD, Brigham and Women s Hospital, Boston, Massachusetts.

8 Most Common Types of Cardiac Amyloidosis Circulation 2016;133:

9 Systemic Amyloidosis AL Amyloidosis Hematologic Malignancy: Incidence similar to Hodgkin s, 8-12 per million population 3000 new cases per yr in US; 30-50% have cardiac involvement Age at onset late 40 s-80 s, median yrs and >60% cases are in men Amyloid protein = monoclonal immunoglobulin light chain + proteoglycans + SAP (serum amyloid P, nonfibrillar plasma glycoprotein). Source: plasma cell >> B-cell dyscrasias, multiple myeloma 10-15%. Prognosis affected by AL subtype (kappa vs lambda) Early HF-pEF, atrial/ventricular arrhythmias or heart block, later pseudo-lvh, HF-rEF Mortality very high in setting of severe HF, often co-morbid renal disease Survival = 26.4, 10.5 and 3.5 months for mild, moderate, severe cardiac disease Extracardiac manifestations: CKD, Nephrotic syndrome, hepatomegaly, macroglossia, capillary fragility, peripheral polyneuropathy Haematologica 2014;99: Circulation 2017; 135:

10 Systemic Amyloidosis (AL) Blood :

11 AL Amyloidosis Natural History Survey of 500 pts, average time from initial symptoms to Dx was 2 yrs. Nearly 1/3 pts saw at least 5 MD s prior to Dx, despite 40% with cardiac involvement. Symptoms may be absent, anginal with or without heart failure, arrhythmias Independent predictors of poor clinical outcomes in AL cardiac amyloidosis Age > 67 years NYHA class III or IV symptoms Pleural effusion NT-proBNP, BNP Troponin T, hs-ctnt Uric acid Free light-chain burden B-2 Microglobulin Ejection time Peak longitudinal systolic basal anteroseptal strain Curr Probl Cardiol 2013;38: Circulation 2017; 135:

12 AL Amyloidosis Natural History Two subsets described: Distinguishes predominant toxic vs infiltrative components Mild to Modest LVH but cardiac dysfunction very disproportionate to LV mass These pts may be more chemo responsive if identified early, otherwise tend to progress very quickly, i.e., more malignant clone with greater direct myocardial toxicity Heart failure diagnosed first, often mild/moderate. May be confused w HCM, often have had symptoms for over a year. LVH nearly 2 cm on average before presentation. Progresses to significant restrictive physiology, dilated atria and atrial fibrillation. Felt to represent slower deposition rates, better prognosis until severe HF develops. Cardiac biopsy may be needed in a select cohort of patients with isolated cardiac amyloidosis and MGUS to differentiate AL amyloidosis from ATTR Haematologica 2014;99:

13 AL Amyloidosis Treatment Treatment: Source of amyloid: bone marrow = chemotherapy Ongoing Antibody High-dose trial therapy melphalan of doxycycline to specifically with autologous in conjunction target stem misfolded with cell transplantation standard light chain chemotherapy, aggregates. in Depletion Bortezomib vitro evidence of (proteasome circulating suggests SAP inhib) that with doxycycline +dexamethasone-cyclophosphamide CPHPC, followed may prevent by an the immunoglobulin-1 formation of fibrils Lenalidomide, anti-sap from light an monoclonal chains immunomodulatory and antibody disrupt fibrils to agent target that the have SAP already on the formed amyloid fibrils so normal phagocytic processes resorb the SAP-depleted fibrils Heart Failure: Mainstay = loop diuretics (torsemide, bumetanide), spironolactone ACE/ARB = freq intolerant, profound hypotension BB = freq intolerant, hypotension, low cardiac output, heart block, brady Digoxin = high frequency of toxicity (altered binding) CCB s = worsening heart failure AAD s = often intolerant, amiodarone best, dofetilide also used ICD s = no data to support efficacy, but often done when EF reduced LVAD = Not feasible, small LV chamber, freq RV dysfunction TP = highly selected candidates JACC 2016; 68 (12) 1232-

14 Transthyretin Amyloidosis ATTR Amyloidosis wild type or mutant Amyloid protein = transthyretin, serum protein transport of thyroxine (T4) & retinol

15 ATTR Amyloidosis wild type or mutant Incidence less well defined than AL Genetic/Hereditary forms are seen in particular geographic regions Val122Ile point mutation, autosomal dominant but incomplete penetrance African and Afro-Carribean descent 3-4% Ile68Leu and Leu 111Met almost exclusively Italy & Denmark, respectively More severe CMY at early age In US most common form is is wt, then Val122Ile, and Thr60Ala Val122Ile seems to have more averse prognosis ATTR-wt is also termed senile amyloidosis Autopsy data show TTR deposits in myocardium in 25% adults >80 yrs Autopsy data of HF-pEF pts show myocardial TTR deposits in 32 % >75 yrs, 8% <75 yrs Underdiagnosis due to lack of clinical suspicion JACC HF 2014; 2: 113 Circulation 2017; 135:

16 Circulation 2017; 135:

17 ATTR Amyloidosis wild type or mutant THAOS (Transthyretin Amyloid Outcome Survey) Registry Circulation 2017; 135:

18 ATTR-wt Natural History Onset typically in older adults in US, but can be seen as early as the 50 s Outcome dependent on timing of diagnosis, average survival 3.5 yrs. Atrial arrhythmias are frequent, progressive effort intolerance related to reduced LV capacitance, contractility and cardiac output. Clues to suspect ATTR: (some can be seen in AL also) History of bilateral carpal tunnel syndrome Found in 50% of pts on average 5-8 yrs before cardiac manifestations Intolerance of standard medical therapy for HF (hypotension, orthostasis) Low grade Troponinemia HF-pEF without hypertension LVH without longstanding HTN or Low voltage to mass ratio on EKG vs Echo Family history may be helpful, but may not J Cardiac Fail 2015; 12 Circulation 2017; 135:

19 Prognosis of ATTR wt amyloidosis Biomarker cutoffs NT-proBNP >3,000 Troponin T > 0.05 Grogan JACC 2016

20 How do you make the Diagnosis? Have a healthy level of suspicion! EKG Echocardiography w Doppler (pulsed, tissue, strain) Laboratory testing SPEP normal in 50% of AL pts, Immunofixation serum/urine? Monoclonal or polyclonal Quant Free light chains & ratio-- abnl kappa/lamda ratio? MRI Bone-tracer scintigraphy (Pyrophosphate scan/spect) Genetic analysis if ATTR proven Tissue Biopsy (heart, marrow, or extracardiac) Biomarkers (Troponin, BNPP, GFR) aid in prognosis and assessing response to Rx Consider diagnosis in every patient with HF-pEF, particularly if other causes are mild or absent!! Circulation 2017; 135:

21 EKG in Amyloid CMY Classic changes Limb leads predominant Low Voltage 25% ATTR Low voltage 50% AL Pseudoinfarct 50% AL J A C C 2016; 68, 2013

22 A Which Patient Has Cardiac Amyloid? B C ALL of them!! D

23 Congo red Current Oncology Reports 2017, 19:46

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26 Diagnosis --echocardiography Typical echocardiographic features of cardiac amyloidosis. Concentric left ventricular hypertrophy and left atrial dilatation Bright myocardium, thickened valves or thickened intra-atrial septum Pulsed-wave Doppler of mitral inflow w increased E/A ratio, normal E wave deceleration time, but a marked reduction in transmitral A-wave velocity. Pulsed-wave Doppler of pulmonary vein inflow w marked diastolic prominence, increased duration and peak velocity of atrial reversal Pulsed-tissue Doppler of the lateral mitral annulus w marked reduction in apical systolic and diastolic velocities Apical sparing of longitudinal strain by speckle tracking Pericardial effusion common (small) more often in AL) Earlier findings = impaired relaxation Circulation. 2017;135:

27 Diagnosis Cardiac MRI Requires gadolinium to assess tissue composition (gadolinium does not enter cardiac myocytes = extracellular agent) Classic finding is global subendocardial late gadolinium enhancement NOT in a classic coronary vascular distribution, and with dark blood pool Enhancement can be diffuse, transmural or localized & patchy Artifacts common if imaging protocol not devised/conducted correctly Site expertise in Cardiac MR imaging and interpretation is important Circulation. 2017;135:

28 Diagnosis Cardiac MRI JACC Imaging 2010 V3(2)

29 Diagnosis Bone Scintigraphy Perugini Visual Score Range 0-3 A score of 2 or 3 is very strongly corellative with ATTR Normal AL ATTR ATTR Circulation. 2017;135:

30 Diagnosis Bone Scintigraphy Quantitative Ratio Measure counts per pixel in Heart vs Contralateral (CL) chest

31 Diagnosis Bone Scintigraphy Sensitivity for ATTR Score Grade 1,2,3 : 99% ATTR Score Grade 2 or 3: 87% Specificity for: ATTR Score Grade 1,2,3 : 74% ATTR Score Grade 2 or 3: 92% ATTR AL Circulation. 2017;135:

32 Tissue Biopsy Definitive diagnosis of cardiac AL amyloidosis in patients with evidence of a monoclonal gammopathy remains a tissue biopsy showing amyloid deposits, whether of abdominal fat, another involved organ, or the heart. We favor endomyocardial biopsy for symptomatic patients because it allows for cardiac hemodynamic measurement at the same time, which can be helpful in management. Abdominal fat pad biopsy by needle aspiration has approximately a 70% to 80% sensitivity for identifying amyloid deposition, but these figures come from centers skilled in appropriate staining of the small amount of tissue often obtained by this technique. Both false negatives and false positives (from overstaining) may occur in less experienced centers The gold standard is proteomic evaluation of amyloid deposits by mass spectrometry and immunochemical staining. Yields highly sensitive and specific results. It is limited to a few centers, but specimens can be sent there for evaluation, even if already fixed in a paraffin block.

33 Endomyocardial biopsy (A) Extracellular pink amyloid material is apparent on hematoxylin-eosin stain. (B) Blue amorphous amyloid material is highlighted by sulfated alcian blue stain. (C) Congo red stain. (D) Apple-green birefringence with polarized light. Curr Probl Cardiol 2013;38:53-96.)

34 Fat aspirate with congo red stain and polarized light apple green birefringence. Curr Probl Cardiol 2013;38:53-96.)

35 Tissue Biopsy There can be false positives in ATTR-m pts Fat pad aspirates are no longer included in diagnostic algorithms for cardiac amyloid Eur Heart J. 2017;38(24):

36 Diagnosis Suggested Algorithm 1

37 Diagnosis Suggested Algorithm 2 Maurer et al. Circulation. 2017;135:

38 ATTR Amyloidosis Treatment Treatment: Source of amyloid: Liver = Disease modulating therapy, depends on WT vs Mutant Liver transplant for selected ATTR-m candidates (or multiorgan) ATTR-wt: Diflusinal mg bid; often not tolerated (NSAID) Tafamadis (designer) Approved in Europe, not US Heart Failure: Mainstay = loop diuretics (torsemide, bumetanide), spironolactone ACE/ARB = freq intolerant, profound hypotension BB = freq intolerant, hypotension, low cardiac output, heart block, brady Digoxin = increased risk of toxicity (less than AL) CCB s = worsening heart failure risk AAD s = often intolerant, amiodarone best, dofetilide also used ICD s = no data to support implant, but often done LVAD = Not feasible if small LV chamber, RV dysfunction may limit use also TP = Selected candidates JACC 2016; 68 (12) 1232-

39 ATTR Amyloidosis Treatments Maurer et al. Circulation. 2017;135:

40 Is Cardiac Transplantation an option? AL Amyloid Yes, but for highly selected candidates Dependent upon extent of other organ involvement and eligibility for subsequent autologous stem cell transplantation Survival rates are higher when chemotherapy done prior to OHT w very good or complete hematologic response ATTR Amyloid Yes, but for highly selected candidates, age alone can be an issue Dependent upon extent of other organ dysfunction, esp CKD UNOS reported 1-yr survival post OHT from as 81.6%, mostly ATTR JACC 2016; 68 (12) 1232-

41 Summary Cardiac amyloidosis has been increasingly recognized, apparent incidence increasing in part due to level of suspicion and improved diagnostic techniques The most common types of amyloid affecting the heart are AL, ATTR-wt and ATTR-m Clinical clues may allow earlier detection of ATTR (i.e., bilateral carpal tunnel, atypical CP and atrial arrhythmias, disproportionate echo LVH to clinical hx) Early recognition of cardiac amyloidosis has the potential to halt the disease process before irreversible changes occur and improve prognosis as treatments are effective for AL, and promising for ATTR. THINK about cardiac amyloid in any patient with HF-pEF!