Cardiac Amyloidosis Final Presentation.pdf

Cardiac Amyloidosis
Jonathan Strandberg PharmD Candidate 23’
APPE Institutional: South County Hospital
11/22/2022

Objectives
• Work up patient PM that presented to ED
• Review pathology of Transthyretin Cardiac Amyloidosis and treatment
decisions.
• Suggest recommendation based on patients' presentation and potential
underlying cardiac amyloidosis.

Patient PM
• Sex: Male. Age: 71; CrCl: 72 mL/min
• Height: 71in, Weight: 113 kg, BMI:
34.9kg/m^2
• Allergies: codeine; Adverse Reaction:
Unknown
• CC: Shortness of Breath
• HPI: Patient is 71-year-old male who
presented to the ED with increasing
shortness of breath. Patient was 91% on
room air as he left his house and when
he arrived, he was saturating 80% on 10L
via nonrebreather.
• After arrival, patient was intubated
and mechanically ventilated. Chest
x-ray reveals worsening of pulmonary
infiltrates with bilateral pleural
effusions.

Past Medical History
• Mild cognitive impairment
• Paroxysmal atrial fibrillation
• CAD status post non-STEMI
• Diabetes Type II
• COPD
• Hypertension
• Depression
• Diverticulosis
• Moderation pulmonary arterial hypertension
• Morbid obesity
• CHF and pleural effusions
• Family History: Both parents had heart
disease in their 50s
• Social History;
• Patient is a retired machinist
• He does drink alcohol or smoke.
• He is divorced and lives alone
• He has 2 children

Home
Medications
Medication Dose Frequency Indication
Losartan Potassium 100 mg 1 TABLET PO DAILY Hypertension
Furosemide 40 mg ` 1 TABLET PO DAILY CHF
Atenolol 50 mg 1 TABLET PO DAILY Hypertension
Tylenol 500 mg 2 TABLETES PO BID Prn pain
Metformin 1000 mg 1 TABLET PO BID Diabetes
Isosorbide
Mononitrate
60 mg 1 TABLET PO QAM Prevent or treat
angina
Trazadone 50 mg 1 TABLET PO QHS Insomnia
Amlodipine besylate 10 mg 1 TABLET PO DAILY Hypertension
Glipizide ER 5 mg 1 TABLET PO DAILY Diabetes
Atorvastatin 40 mg 1 TABLET PO QPM Hypercholesteremia
Albuterol Sulfate 8.5 Gm Hfa 1 PUFF TID PRN for
SOB/wheezing
Nitroglycerin 0.4 mg SL 1 TABLET SL Q5MIN PRN Chest pain
Bupropion XL 150 mg 2 TABLERS PO DAILY Depression
Apixaban 5 mg 1 TABLET PO BID Anticoagulant
Aspirin 81 mg 1 TABLET PO DAILY CV prevention

Vital Signs / Physical Exam
Temperature:
97.6
Pulse: 119
Respiratory
rate: 44
Blood
pressure:
184/115
Pulse Ox: 80%
on Non-
rebreather
• General: Obese middle-aged man lying
flat, intubated, sedated and unresponsive
• Neck: Difficult to assess for Juglar venous
distention due to his thick neck
• Heart: An irregularly irregular rate and
rhythm
• Extremities: significant edema of the lower
extremities and some chronic venous statis
changes

Initial Lab Results
• WBC: 19.8 K/mm^3 (Normal 4.0-10.8
K/mm^3)
• Hgb: 12.5 g/dL (Normal 13.5-17.5 g/dL)
• Chloride 100 mmol/L (Normal 101-111
mmol/L)
• Glucose 248 mg/dL (Normal 74-106
mg/dL)
• Troponin <0.01 (Normal <0.05)
• CRP 57.4 mg/L (Normal 0.0-10.0 mg/L)
• BNP 767 pg/mL (Normal 0-100 pg/mL)
• Procalcitonin 0.54 ng/mL (Normal <0.1 ng/mL)
• Arterial Blood Gases
• PCO2: 71 mmHg (normal 35-45 mmHg)
• pH 7.34 (Normal 7.35-7.45)
• HCO3 38.3mmol/L (Normal 20-26 mmol/L)

Electrocardiogram Analysis
• Ventricles: There is probable concentric left ventricular (LV) hypertrophy with
upper septal thickening. There is normal LV systolic function. EF 60% to 65%.
Cannot exclude basal inferior hypokinesis. The right ventricle is not well
visualized, but systolic function appears normal
• Valves: The aortic valve is minimally sclerotic. The mitral valve has some very
mild annular calcification. There is trace mitral and tricuspid insufficiency. The
pulmonic valve is not visualized.
• Other: Moderate pulmonary hypertension and biatrial dilation with estimated
pulmonary artery systolic pressure of 63 mmHg. The rhythm during the study
was atrial fibrillation.

Assessment &
Plan
Acute hypoxemic respiratory failure-
suspected due to CHF
• Mechanical ventilation intubation in ICU
Acute on chronic HFpEF, diastolic heart
failure. EF: 60-65%.
• IV furosemide 40 mg twice daily
• Monitor strict ins and outs
Probable bilateral lower lobe pneumonia:
Aspiration
• Empiric therapy due to high white count
• Broad spectrum antibiotics including doxycycline and
PIP/tazobactam to cover aspiration pneumonia.

Cardiac Amyloidosis
• Disorder caused by amyloid fibril deposition in the extracellular space of the
heart.
• It can present with cardiac signs or symptoms or may be diagnosed as the
result of screening patients who manifest extracardiac signs of amyloidosis
• Two types of cardiac amyloidosis
• Transthyretin amyloidosis (ATTR amyloidosis)
• Wild-type amyloidosis
• Hereditary amyloidosis
• Light chain amyloidosis (AL amyloidosis)
Fontana, F. (2022). Amyloid Cardiomyopathy: Treatment and Prognosis Uptodate. Retrieved November 22, 2022, from: thttps://www-uptodate-com.uri.idm.oclc.org/contents/cardiac-amyloidosis-
epidemiology-clinical-manifestations-and-diagnosis?search=cardiac%20amyloidosis&source=search_result&selectedTitle=1~89&usage_type=default&display_rank=1#H2649780190

Transthyretin Cardiac Amyloidosis (ATTR-CA)
• ATTR-CA demonstrates infiltrative cardiomyopathy caused by extracellular
deposition of insoluble transthyretin (TTR)amyloid fibrils in the myocardium
• Wild Type amyloidosis: Caused by the deposition of misfolded wild-type
transthyretin. The mechanism by which normal transthyretin causes
pathogenic deposits is unclear.
• Hereditary amyloidosis: Caused by gene mutation in the TTR gene that
predispose the tetrameric structure of transthyretin to instability, misfolding and
deposition.
Fontana, F. (2022). Amyloid Cardiomyopathy: Treatment and Prognosis Uptodate. Retrieved November 22, 2022, from: thttps://www-uptodate-com.uri.idm.oclc.org/contents/cardiac-
amyloidosis-epidemiology-clinical-manifestations-and-diagnosis?search=cardiac%20amyloidosis&source=search_result&selectedTitle=1~89&usage_type=default&display_rank=1#H2649780190

Clinical Presentation
• The clinical manifestations of amyloidosis are diverse, depending on the
pattern of organ involvement. The variable clinical phenotype and generally
nonspecific clinical features make diagnosis difficult
• Patients with ATTR amyloidosis typically present as males, age >60 and with
HFpEF.
• Patients present with signs and symptoms such as dyspnea, lower extremity
edema, elevated jugular venous pressure, hepatic congestion and ascites.
• Anginal chest pain caused by microvascular amyloid infiltration in patients
without epicardial coronary stenosis can also occur.
Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC Heart Fail. 2019
Dec;6(6):1128-1139. doi: 10.1002/ehf2.12518. Epub 2019 Sep 25. PMID: 31553132; PMCID: PMC6989279.

Diagnosis
• When to suspect cardiac amyloidosis
• ATTR-CA should be highly suspected if left ventricle (LV)
wall thickening is observed in combination with one or
more red flags (shown right)
• Newly diagnosed HFpEF patients with LVH over 60
years old
• Atrial fibrillation and symptomatic atrioventricular block
requiring pacemaker are common in ATTRwt-CA.
• Blood pressure often falls as the disease progresses,
symptomatic hypotension or resolution of hypertension
in previously hypertensive patients
Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC Heart Fail. 2019
Dec;6(6):1128-1139. doi: 10.1002/ehf2.12518. Epub 2019 Sep 25. PMID: 31553132; PMCID: PMC6989279.

Diagnostic Test
• Electrocardiography: Unexplained LVH, characterized by low QRS voltage can provide clues
for CA
• Echocardiography: Can recognize diastolic dysfunction at early stages and systolic
dysfunction at later stages. Can detect presence of LV wall thickness, small LV chamber size
with systolic impairment, atrial enlargement, and signs of elevated filling pressures caused by
restrictive diastolic filling
• Cardiac magnetic resonance: Can provide unique information on myocardial tissue
properties. CMR shows various characteristic patterns of late gadolinium enhancement
(LGE). CMR with LGE are sensitive (80%)and specific (94%) for diagnosing CA.
• Radionuclide bone scintigraphy: Nuclear imaging technique, reliable diagnostic method for
ATTR-CA, which is distinguished from AL-CA or other wall thickening disease.
Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk
Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016 Sep 6;68(10):1014-20. doi: 10.1016/j.jacc.2016.06.033. Erratum in: J Am Coll Cardiol. 2017 Jun 13;69(23):2882. PMID: 27585505.

ATTR Amyloidosis Staging/Prognosis
• The first published staging system of ATTRwt is based on serum levels of NT-pro BNP and
cardiac troponin T. Threshold of troponin T (0.05 ng/mL) and NT-pro BNP (3000 pg/mL)
were used. The respective four-year overall survival estimates were 57, 42, and 18
percent for stage I (both values below cutoff), stage II (one above), and stage III (both
above)
• The second staging system, validated in both ATTRwt and ATTRm, is based on serum
levels of NT-pro BNP and eGFR. Stage I is defined as NT-pro BNP <3000 ng/L and eGFR
>45 mL/min, Stage III is NT-pro BNP >3000 ng/L and eGFR <45 mL/min and the remainder
were stage II Median survival among stage I patients was 69.2 months, stage II patients
46.7 months, and Stage III patients 24.1 months.
Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk
Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016 Sep 6;68(10):1014-20. doi: 10.1016/j.jacc.2016.06.033. Erratum in: J Am Coll Cardiol. 2017 Jun 13;69(23):2882. PMID: 27585505.

Treatment: Approach to Heart Failure
• Loop diuretics are a mainstay of the management of HF and cardiac amyloidosis. If
edema is severe, IV diuretics are strongly considered. Combination of loop diuretics and
aldosterone antagonist is most effective.
• Although beta blockers reduce morbidity and mortality in patients with systolic HF
generally, they have no proven benefit in patients with HF due to cardiac amyloidosis
• The safety and efficacy of ACEi and ARBs in patients with cardiac amyloidosis is
uncertain
• They do appear to be better tolerated in patients with ATTRwt amyloidosis
• Patients with ATTRm or ATTRwt generally respond better to HF therapy than patients with
AL amyloidosis
Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR Amyloidosis: Current and Emerging Management Strategies: JACC: CardioOncology State-of-the-Art Review. JACC
CardioOncol. 2021 Oct 19;3(4):488-505. doi: 10.1016/j.jaccao.2021.06.006. PMID: 34729521; PMCID: PMC8543085.

Heart Transplantation and Ventricular Assist
Devices
• Patients with ATTRwt amyloidosis generally have the disease clinically isolated
to the heart and as such would appear to be more suitable candidates
• However, since most patients are diagnosed in their 70s or 80s, they are excluded
based on their age.
• Patients with ATTRm cardiac amyloidosis are often diagnosed younger than
ATTRwt, making them more suitable candidates.
• Ventricular assist devices have been used very infrequently in cardiac
amyloidosis, owing to technical difficulties when used in a restrictive
cardiomyopathy as well as the presence of coexisting noncardiac
amyloidosis.

Treatment of Atrial Fibrillation
• If atrial fibrillation with rapid ventricular response develops in patients with AL or ATTR
amyloidosis, low-dose beta blocker or digoxin use may help with rate control.
• CCBs such as diltiazem or verapamil have not been proven in cardiac amyloidosis:
avoid use due to hypotension and syncope.
• Experience with catheter ablation for atrial arrhythmias in patients with cardiac
amyloidosis is limited
• Anticoagulation is indicated if a patient with amyloid develops atrial fibrillation since risk
of intracardiac thrombus is very high.
• The efficacy of implantable cardioverter-defibrillator (ICD) therapy or pacemaker in
patients with cardiac amyloidosis is uncertain.

Specific therapy for ATTR amyloidosis
Treatment of Underlying Protein Misfolding Disorder
• For patients with ATTR cardiomyopathy with NYHA functional class I-III,
recommended treatment with tafamidis
• In addition, patients diagnosed with ATTRm cardiomyopathy should
undergo evaluation for liver transplantation, as this can be curative in
selected patients with ATTRm but not ATTRwt

Tafamidis Treatment for Patients with ATTR
Cardiomyopathy
• ATTR-ACT was a phase 3, multicenter, international, parallel-design, placebo controlled, double-blind
randomized trial.
• Patients between 18-90 years of age were eligible to participate if they had ATTRwt or ATTRm confirmed by
presence of amyloid deposits on analysis of biopsy specimens obtained from cardiac and noncardiac sites
• Cardiac involvement was confirmed by means of ECG
• Included septal wall thickening exceeding 12 mm, hx of HF, elevated intracardiac pressures, pro BNP >600
pg/mL and 6-minute walk test distance exceeding 100m
• Patients were randomly assigned to receive 80 mg of tafamidis, 20 mg tafamidis, or placebo in the ratio of
2:1:2 for 30 months.
• Tafamidis is an orally administered small molecule, binds to transthyretin and stabilizes its native structure,
thereby preventing its dissociation into monomers, the rate-limiting step of transthyretin amyloid formation.
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P,
Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med.
2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27. PMID: 30145929.

Tafamidis Treatment for Patients
with ATTR Cardiomyopathy
Results
• In 441 patients with ATTR (variant or WT) amyloid
cardiomyopathy, tafamidis reduced mortality
compared with placebo (29.5 vs 42.9%; hazard
ratio 0.60, 95% CI 0.51-0.96) and reduced
cardiovascular related hospitalizations (0.48 vs 0.70
per year; RR 0.68, 95% CI 0.56-0.81)
• Across prespecified subgroups (TTR status, NYHA
stage, and tafamidis dose) the difference in all-cause
mortality favored tafamidis over placebo except in
patients with NYHA class III disease at baseline.
• In key secondary endpoints, tafamidis reduced the
decline in the distance walked during the 6-minute
test. Tafamidis also reduced the decline in the
KCCQ-OS score as compared with placebo.
Kaplan–Meier survival curves showed that tafamidis resulted in a reduction in all-
cause mortality, with the curves diverging after approximately 18 months of
treatment
Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P,
Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med.
2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27. PMID: 30145929.

Liver Transplantation
• In ATTR amyloidosis, the source of the amyloidogenic protein is the liver.
Transplantation of the liver removes the mutant amyloidogenic TTR in ATTRm
• Once a patient with a transthyretin mutation is found to have a positive biopsy
for amyloid, he or she should undergo evaluation for liver transplantation, with
the goal to receive the transplant as early in the disease as possible
• If an amyloid cardiomyopathy is present with significant HF, isolated liver
transplantation is contraindicated, and consideration should be given to a
combined liver-heart transplant or just heart alone.

Investigational
Agents
• Patisiran is an anti-TTR small interfering ribonucleic
acid (siRNA) formulation of lipid nanoparticles.
• A randomized trial comparing Patisiran with
placebo in patients with ATTRm amyloidosis with
polyneuropathy found that Patisiran significantly
reduced symptoms and impairment from
neuropathy and improved quality of life.
• In a cardiac subgroup, Patisiran significantly
reduced NT-pro BNP levels and LV wall thickness
and reduced worsening longitudinal strain. The
drug was generally well tolerated

Investigational
Agents
• Inotersen is an antisense oligonucleotide
construct that inhibits hepatic production
of TTR
• A randomized trial comparing inotersen
with placebo found that inotersen
significantly reduced symptoms and
impairment from neuropathy and
improved quality of life
• The most frequent serious adverse events
were glomerulonephritis and severe
thrombocytopenia.

Patient PM
Suspected Red flags for ATTR-CA
•Male above the age of 70, HFpEF with LV wall
thickening, Atrial Fibrillation diagnosis, presented
to the ED with lower extremity edema and
dyspnea.
Future Management
•Utilize more sensitive and specific diagnostic test
to assess for potential ATTR cardiac amyloidosis
•Upon diagnosis: Reevaluate use of
antihypertensive medications due to no benefit
to mortality or morbidity and hypotension.
•Upon diagnosis: Evaluate NYHA staging to
recommend for addition of TTR stabilizer
Tafamidis

References
• Fontana, F. (2022). Amyloid Cardiomyopathy: Treatment and Prognosis Uptodate. Retrieved November 22, 2022, from: thttps://www-
uptodate-com.uri.idm.oclc.org/contents/cardiac-amyloidosis-epidemiology-clinical-manifestations-and-
diagnosis?search=cardiac%20amyloidosis&source=search_result&selectedTitle=1~89&usage_type=default&display_rank=1#H264978019
0
• Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC Heart Fail. 2019 Dec;6(6):1128-
1139. doi: 10.1002/ehf2.12518. Epub 2019 Sep 25. PMID: 31553132; PMCID: PMC6989279.
• Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR Amyloidosis: Current and Emerging Management
Strategies: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2021 Oct 19;3(4):488-505. doi:
10.1016/j.jaccao.2021.06.006. PMID: 34729521; PMCID: PMC8543085.
• Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural History of Wild-
Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016 Sep 6;68(10):1014-20.
doi: 10.1016/j.jacc.2016.06.033. Erratum in: J Am Coll Cardiol. 2017 Jun 13;69(23):2882. PMID: 27585505.
• Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman
BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT
Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep
13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27. PMID: 30145929.

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