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

Rimbas, Roxana Cristina; Balinisteanu, Anca; Chitroceanu, Alexandra Maria; Vinereanu, Dragos

doi:10.47803/rjc.2021.31.2.283

Figures & Tables

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).

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).

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.

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.

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.

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).

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

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

Figures & Tables

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

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

Main therapies for HFpEF in AL and ATTR amyloidosis

Paradigm

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