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Cardiac Amyloidosis – An Underdiagnosed Cause of Heart Failure with Preserved Ejection Fraction – Updated Diagnosis and Treatment Options

Roxana Cristina Rimbas
Roxana Cristina Rimbas
, 
Anca Balinisteanu
Anca Balinisteanu
, 
Alexandra Maria Chitroceanu
Alexandra Maria Chitroceanu
 y 
Dragos Vinereanu
Dragos Vinereanu
   | 03 may 2022
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Article Category: Review
Publicado en línea: 03 may 2022
Páginas: 283 - 302
DOI: https://doi.org/10.47803/rjc.2021.31.2.283
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© 2021 Roxana Cristina Rimbas et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

Transthoracic echocardiographic images2DE in a 55 years old patient with AL amyloidosis showing Panel A: severe concentric left ventricular (LV) hypertrophy (IVS=17 mm, PWT=16 mm, RWT=0.8, LV mass=157 g/m2), IVS, interventricular septum; PWT, posterior wall thickness; RWT, relative wall thickness, pericardial effusion (white arrow); Panel B: restrictive filling pattern (E/A=4), E=peak of early filling velocity; A=peak of late atrial filling velocity. Left atrial (LA); Panel C: Severely decreased diastolic myocardial velocities by Tissue Doppler imaging (E’=2 cm/s), with high E/E’ ratio; Panel D: Bull’s eye plot by 2D speckle tracking echocardiography (STE) with significantly reduced global longitudinal strain (GLS) (−9.9%) and global altered deformation mainly at the basal and midventricular segments and with a typical “apical sparing” pattern. Panel E: 2D STE at the level of the LA showing significantly decreased LA contractile function (LAct) and also of LA reservoir function, with Panel F: severe dilated LA (107 ml).
Transthoracic echocardiographic images2DE in a 55 years old patient with AL amyloidosis showing Panel A: severe concentric left ventricular (LV) hypertrophy (IVS=17 mm, PWT=16 mm, RWT=0.8, LV mass=157 g/m2), IVS, interventricular septum; PWT, posterior wall thickness; RWT, relative wall thickness, pericardial effusion (white arrow); Panel B: restrictive filling pattern (E/A=4), E=peak of early filling velocity; A=peak of late atrial filling velocity. Left atrial (LA); Panel C: Severely decreased diastolic myocardial velocities by Tissue Doppler imaging (E’=2 cm/s), with high E/E’ ratio; Panel D: Bull’s eye plot by 2D speckle tracking echocardiography (STE) with significantly reduced global longitudinal strain (GLS) (−9.9%) and global altered deformation mainly at the basal and midventricular segments and with a typical “apical sparing” pattern. Panel E: 2D STE at the level of the LA showing significantly decreased LA contractile function (LAct) and also of LA reservoir function, with Panel F: severe dilated LA (107 ml).

Figure 2

2D Speckle tracking echocardiographic imagesPanel A: Bull’s eye plot by 2D STE in a 42 years old patient with ATTR amyloidosis showing significantly reduced global longitudinal strain (GLS) (−10%) with severe altered deformation mainly at the basal and midventricular segments and relatively preserved at the apex, with a typical “apical sparing” strain or “cherry-on-top” pattern. Panel B: Myocardial work analysis plot of the global work index (GWI) showing severe reduction of the GWI, with a similar “apical sparing” pattern, and an important reduction of the global work efficiency (GWE). Panel C: Myocardial work analysis with low global constructive work (CW) (green bars), also with even lower CW at the basal level, and higher wasted work (blue bars); Panel D: Strain – pressure loops representing GWI (red curve) and a comparative lower WI curve in a basal segment (green curve).
2D Speckle tracking echocardiographic imagesPanel A: Bull’s eye plot by 2D STE in a 42 years old patient with ATTR amyloidosis showing significantly reduced global longitudinal strain (GLS) (−10%) with severe altered deformation mainly at the basal and midventricular segments and relatively preserved at the apex, with a typical “apical sparing” strain or “cherry-on-top” pattern. Panel B: Myocardial work analysis plot of the global work index (GWI) showing severe reduction of the GWI, with a similar “apical sparing” pattern, and an important reduction of the global work efficiency (GWE). Panel C: Myocardial work analysis with low global constructive work (CW) (green bars), also with even lower CW at the basal level, and higher wasted work (blue bars); Panel D: Strain – pressure loops representing GWI (red curve) and a comparative lower WI curve in a basal segment (green curve).

Figure 3

Comparative STE evaluation in HFpEF patients.Panel A and C: Bull’s eye plot by 2D STE (A) in a 56-year-old patient with HFpEF and AL amyloidosis showing significantly reduced global longitudinal strain (GLS) (−7%) with typical “apical sparing” strain pattern, by comparison with a 62-year-old patient with risk factors and HFpEF without amyloidosis (C), with reduced GLS (−14%) and a coronary distribution of the decreased deformation, affecting mainly septum, and postero-lateral walls, mainly at the apical level. Panel B and D: Myocardial work analysis plot of the global work index (GWI) showing severe reduction of the GWI, with a similar “apical sparing” pattern in HFpEF with amyloidosis patient, by comparison with a GWI plot with important reduction of the GWI, mainly generated by mid and apical segments, in HFpEF patient without amyloidosis.
Comparative STE evaluation in HFpEF patients.Panel A and C: Bull’s eye plot by 2D STE (A) in a 56-year-old patient with HFpEF and AL amyloidosis showing significantly reduced global longitudinal strain (GLS) (−7%) with typical “apical sparing” strain pattern, by comparison with a 62-year-old patient with risk factors and HFpEF without amyloidosis (C), with reduced GLS (−14%) and a coronary distribution of the decreased deformation, affecting mainly septum, and postero-lateral walls, mainly at the apical level. Panel B and D: Myocardial work analysis plot of the global work index (GWI) showing severe reduction of the GWI, with a similar “apical sparing” pattern in HFpEF with amyloidosis patient, by comparison with a GWI plot with important reduction of the GWI, mainly generated by mid and apical segments, in HFpEF patient without amyloidosis.

Figure 4

Cardiac magnetic resonance in amyloidosis.CMR images in a 42-year-old patient with TTR-CA. Panel A. short axis view showing LV hypertrophy (IVS = 14mm, AWT= 13 mm, LWT= 15 mm, PWT= 14 mm); Panel B and C: Native T1 mapping short view (B) and 4-chamber view (C) increase in LV native T1 (region of interest IVS) consistent with amyloidosis; Panel D and E: contrast-enhanced T1 mapping short view (D) and 4-chamber view (E) showing significantly elevated ECV (region of interest IVS) compatible with amyloidosis; IVS: interventricular septum; AWT: anterior wall thickness; LWT: lateral wall thickness; PWT: posterior wall thickness; ROI: region of interest; ECV: extracellular volume.
Cardiac magnetic resonance in amyloidosis.CMR images in a 42-year-old patient with TTR-CA. Panel A. short axis view showing LV hypertrophy (IVS = 14mm, AWT= 13 mm, LWT= 15 mm, PWT= 14 mm); Panel B and C: Native T1 mapping short view (B) and 4-chamber view (C) increase in LV native T1 (region of interest IVS) consistent with amyloidosis; Panel D and E: contrast-enhanced T1 mapping short view (D) and 4-chamber view (E) showing significantly elevated ECV (region of interest IVS) compatible with amyloidosis; IVS: interventricular septum; AWT: anterior wall thickness; LWT: lateral wall thickness; PWT: posterior wall thickness; ROI: region of interest; ECV: extracellular volume.

Figure 5

Bone scintigraphy with 99mTc-pyrophosphate in cardiac amyloidosis.Panel A. Negative result defined as no cardiac uptake of the radiotracer in a 55-year-old patient with AL amyloidosis. Panel B. Positive result defined as grade 3= high uptake greater than the bone in an 82-year-old patient with ATTR wt.
Bone scintigraphy with 99mTc-pyrophosphate in cardiac amyloidosis.Panel A. Negative result defined as no cardiac uptake of the radiotracer in a 55-year-old patient with AL amyloidosis. Panel B. Positive result defined as grade 3= high uptake greater than the bone in an 82-year-old patient with ATTR wt.

Figure 6

Anatomo-pathological evaluation of amyloidosis.Panel A. Fat pad biopsy images in in a 56-year-old patient with HFpEF and AL amyloidosis showing homogenous extracellular fibrils positive for Congo red staining (black arrow); Panel B. These fibrils are positive for green birefringence, specific for amyloid deposits (black arrow).
Anatomo-pathological evaluation of amyloidosis.Panel A. Fat pad biopsy images in in a 56-year-old patient with HFpEF and AL amyloidosis showing homogenous extracellular fibrils positive for Congo red staining (black arrow); Panel B. These fibrils are positive for green birefringence, specific for amyloid deposits (black arrow).

Figure 7

Algorithm for diagnosis of cardiac amyloidosis subtype.HFpEF: heart failure with preserved ejection fraction; CMR: cardiac magnetic resonance; LV: left ventricle; AV: atrio-ventricular; IV: intraventricular; GLS: global longitudinal strain; IFE: imun-electroforesis; AL: light chain amyloidosis; ATTR: transthyretin amyloidosis.
Algorithm for diagnosis of cardiac amyloidosis subtype.HFpEF: heart failure with preserved ejection fraction; CMR: cardiac magnetic resonance; LV: left ventricle; AV: atrio-ventricular; IV: intraventricular; GLS: global longitudinal strain; IFE: imun-electroforesis; AL: light chain amyloidosis; ATTR: transthyretin amyloidosis.

Types of amyloidosis and affected organs16,20,21,22,23,24,25,26,27,28,29,30,31,32,33

Type of Amyloidosis Organs Affected Responsible Protein Cardiac involvement Frequency Important additional info amyloidosis
Primary (AL) Heart, kidneys, liver, peripheral and autonomic nervous system, GI tract Monoclonal light chains (clonal or frankly malignant plasma cells) 49%

death within 6–12 months of symptom onset

multiple myeloma

non-Hodgkin’s lymphoma

Waldenstrom’s macroglobulinemia

diagnostic sensitivity of fat aspiration 84%
Senile systemic (ATTRwt) Heart, peripheral and autonomic nervous system Wild-type transthyretin 40%

without underling diseases

diagnostic sensitivity of fat aspiration 15% (11–20%)
Hereditary (ATTRv) Heart, peripheral and autonomic nervous System, GI tract Mutant transthyretin (more than 120 mutations) 10%

death within 5–15 years of symptom onset

without underling diseases

inherited in an autosomal dominant fashion

diagnostic sensitivity of fat aspiration 45% (36–54%), but dependent on mutation (Val122Ile 33%, Thr60Ala 67%)
Secondary (AA) Kidneys, GI tract, heart Serum amyloid A <1%

infectious, inflammatory, or neoplastic insults

rheumatoid arthritis

ankylosing spondylitis

severe gout

tuberculosis, bronchiectasis

osteomyelitis

inflammatory bowel disease

Hodgkin’s disease

renal-cell carcinoma

diagnostic sensitivity of fat aspiration - not analyzed
Dialysis-related (Aβ2M) Osteoarticular tissue, GI tract, circulatory system, heart β2-microglobulin unknown

renal failure with dialysis

effective treatment is renal transplantation
Isolated atrial (AANF) Heart, atrium Atrial natriuretic factor unknown

abnormal heart rhythms
Hereditary (ALys) Kidneys, liver Lysozyme unknown

without underling diseases
Hereditary (AFib) Kidneys, liver Mutant fibrinogen A α unknown

without underling diseases
Hereditary (AApoA1, 2) Heart, kidneys, liver, peripheral nervous system, skin Principal component of high-density lipoprotein- <1%

without underling diseases

Red Flag clinical findings for diagnosis of amyloidosis39,40,41,42,43,44,45,46,47,48,49

Cardiac amyloidosis Systemic involvement
Biventricular HF especially with HFpEF Macroglossia and periorbital purpura (AL type)
Newly diagnosed HCMP in elderly patients Carpal tunnel syndrome, particularly if bilateral
HFpEF associated with nephrotic syndromes Spinal stenosis (mainly ATTR wt)
Low normal blood pressure with previous history of hypertension Autonomic signs and symptoms (orthostatic hypotension, alternating constipation/diarrhea, sweating abnormalities) associated with peripheral neuropathy (both types)
Intolerance to beta blocker, ACEi, or ARB, ARNI Spontaneous biceps tendon rupture
Unexplained conduction block needing pacemaker AV block + increased LV wall thickness Nephrotic syndrome/non-diabetic proteinuria (mainly AL type)
Newly diagnosed low flow, low gradient aortic stenosis in elderly patients Hepatic alteration/hepatomegaly disproportionated to HF status (mainly AL type)

Main therapies for HFpEF in AL and ATTR amyloidosis

General therapeutic principles for cardiac symptoms and complications in amyloidosis AL amyloidosis therapies ATTR amyloidosis therapies

Diuretic therapy

Conventional heart failure treatment (use with caution)

Anticoagulation

Devices and ablation therapy

Cardiac assist devices

Heart transplantation

Conventional chemotherapy: alkylating agents, proteasome inhibitors, immunomodulators, immunotherapy

High-dose chemotherapy and autologous stem cell transplantation

Drugs that stabilize the transthyretin tetramer: Tafamidis, Diflunisal

Drugs that inhibit TTR gene expression: Inotersen, Patisiran

Drugs that inhibit oligomer aggregation and tetramer dissociation: Epigallocatechin-3-gallate

Drugs that affect degradation and reabsorption of amyloid fibers: Doxycycline, Tauroursodeoxycholic acid, Miridesap, Dezamizumab

Orthotopic liver transplantation

Liver-heart transplantation
eISSN:
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Calendario de la edición:
4 veces al año
Temas de la revista:
Medicine, Clinical Medicine, Internal Medicine, Cardiology, Pediatrics and Juvenile Medicine, Paediatric Cardiology, Surgery, Cardiac Surgery
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