Infiltrative Cardiomyopathies

Think
Infiltrative

LVH + LOW voltage Wall thickness up, QRS voltage low/normal — the classic discordance. This is chiefly an amyloid clue; Fabry and other storage phenotypes may have normal or high voltage, so do not generalize it to all storage disease.

Restrictive physiology Biatrial enlargement, small/normal LV cavity, ↑ filling pressures, diastolic ≫ systolic dysfunction early. Differentiate from constriction.

AV block / VT young Unexplained conduction disease or VT <60 yr → image for infiltration: sarcoid, Fabry, storage (PRKAG2/Danon), Chagas.

Multisystem clues Neuropathy/CTS (amyloid·Fabry) · proteinuria (Fabry·amyloid) · eosinophilia (EMF) · transfusions (iron) · myopathy (Danon·Pompe).

01

The shared phenotype

why they look alike

Amyloid expands the interstitium. Fabry and glycogen disorders store material inside cells and can cause true myocyte hypertrophy. Low voltage is not a shared requirement.
Cavity stays small / non-dilated until late; biatrial enlargement from chronic ↑ filling pressures.
Diastolic dysfunction first (restrictive filling); systolic failure later as infiltration/scar advances.

Restrictive vs constrictive

Restrictive (myocardial) no respirophasic septal shift; ↑ both atria; medial e′ low; ↑ BNP.
Constrictive (pericardial) septal bounce, respiratory variation, pericardial thickening/calcification.

02

Workup ladder

cheap → targeted → tissue

1 · ECG + Echo voltage-mass discordance, GLS apical sparing (amyloid), wall thickness, restrictive filling, atrial size.

2 · CMR mapping the pivotal step — LGE + mapping narrow the differential. Confirm with targeted tests.

3 · Targeted PYP (ATTR) · serum FLC + serum/urine IFE (AL) · ferritin/TSAT · α-Gal A/GLA · eosinophils · FDG-PET (sarcoid).

4 · Genetics / biopsy gene panel (familial); EMB when imaging + labs inconclusive or AL / active inflammation suspected.

03

Signature test

test combinations, not single-test labels

Amyloid ATTR Compatible phenotype + grade 2–3 myocardial uptake on PYP-SPECT + negative complete monoclonal screen.
Amyloid AL Serum FLC + serum IFE + urine IFE. A clone needs urgent evaluation and typed tissue.
Sarcoid FDG-PET (active) + LGE; extracardiac biopsy.
Iron cardiac MRI T2* (<20 ms) — not ferritin.
Fabry low native T1 + α-Gal A (♂) / GLA (♀).
Storage LVH + WPW/block (PRKAG2), myopathy (Danon), infantile (Pompe).
EMF / eosinophilic apical thrombus/obliteration. Eosinophilia may be absent in chronic EMF.

▦

Master comparison — red flag · key test · disease-modifying Rx

amyloid & sarcoid have their own cards ↓

Entity	Red flag	Key test	Disease-modifying Rx
Amyloid ATTR/AL	LVH + low voltage, apical sparing, bilateral CTS	PYP-SPECT + complete monoclonal screen	Tafamidis, acoramidis, vutrisiran. AL → chemo → card
Sarcoid	AV block <60, VT, patchy non-coronary WMA	FDG-PET + LGE; extracardiac biopsy	Steroids + steroid-sparing; device → card
Iron overload P.2	Transfusions/thalassemia or HFE; restrictive→dilated	Cardiac MRI T2* <20 ms	Phlebotomy (primary) · chelation (secondary)
Fabry P.3	Concentric LVH, neuropathic pain, cornea verticillata	Low native T1; α-Gal A / GLA	ERT (agalsidase) · oral migalastat
Storage P.4	LVH + WPW/block; myopathy/ID; infantile	Gene panel; GAA enzyme (Pompe)	ERT for Pompe; transplant for Danon
EMF / eosinophilic P.5	Apical obliteration/thrombus ± eosinophilia	Eosinophil count, echo/CMR	Steroids, anticoagulation, surgery

◰

CMR parametric mapping — narrow the differential

native T1 / T2* / ECV narrow the differential

Deposit	Native T1	ECV	T2* / T2	LGE pattern & pearl
Amyloid	HIGH	HIGH (↑↑ interstitium)	—	Global subendocardial → transmural LGE; abnormal gadolinium kinetics (can't null myocardium)
Fabry	LOW	normal	—	Inferolateral mid-wall LGE; low T1 abnormal in ~40% before LVH
Iron	low	normal	*T2 <20 ms** (sev <10)	Usually no LGE; T2* is the load-bearing measure
Sarcoid	↑ (active)	↑ focal	↑ T2 (edema, active)	Patchy non-coronary mid/epicardial LGE (basal septum, RV insertion); FDG-PET for activity
Eosinophilic / EMF	↑ (acute)	↑	↑ T2 (acute)	Endocardial LGE + overlying low-signal thrombus; apical obliteration

01

Cause & phenotype

where the iron comes from

Two routes to loading

Primary / hereditary HFE C282Y homozygote (commonest); juvenile (HJV/HAMP) more cardiac. GI over-absorption.
Secondary repeated transfusions — β-thalassemia major, MDS, sickle cell; ineffective erythropoiesis.

Cardiac course

Iron in cardiomyocytes → oxidative injury.
Early restrictive + diastolic dysfunction, AF & conduction disease.
Late dilated / systolic failure can still improve with intensive chelation. Severe disease needs urgent specialist treatment.

02

Diagnosis

ferritin is not cardiac iron

Screen

Labs transferrin saturation >45% + ferritin; HFE genotype if primary suspected.
ECG/echo low voltage, arrhythmia; restrictive then dilated pattern.

Cardiac MRI T2* — gold standard

T2* < 20 ms on validated 1.5-T methods = cardiac iron overload; < 10 ms = severe, high arrhythmia/HF risk.
Cardiac T2* is not reliably predicted by serum ferritin or liver iron — measure cardiac iron directly.

<20T2* ms abnormal

<10T2* ms severe

~25%cardiac iron in TM

03

Treatment

deplete the iron

Primary disease

Phlebotomy ferritin target about 50 µg/L for induction, then 50–100 µg/L maintenance. Do not drive iron deficiency to normalize TSAT. Adjust for hemoglobin and tolerance.

Secondary — chelate (can't bleed an anemic patient)

Treat-to-T2*; intensive chelation recovers EF.
Cardiac iron is the leading cause of death in transfusion-dependent thalassemia — yet reversible.

℞

Iron chelators

match agent to severity & tolerance

Agent	Route / schedule	Niche & notes
Deferoxamine (DFO)	SC / IV (parenteral)	Continuous IV for severe cardiac loading / very low T2*; cumbersome but potent rescue.
Deferasirox (DFX)	oral, once daily	Convenient first-line for chronic transfusional overload; monitor renal/hepatic.
Deferiprone (DFP)	oral, formulation-dependent schedule	Effective myocardial iron clearance; combine with DFO for low T2; agranulocytosis* requires label-directed ANC monitoring.

◷

Monitoring & when to refer

titrate to cardiac T2*

Monitor

Cardiac T2* stable >20 ms: about every 2 y. 10–19 ms: yearly. <10 ms: about every 6 mo, individualized to response.
Function LVEF + diastology on echo/CMR; Holter for arrhythmia.
Iron burden ferritin / TSAT trend + liver iron (tracked separately from cardiac).

Refer / escalate when

T2* < 10 ms, falling LVEF, or arrhythmia → cardiology + intensify chelation (combine DFO + deferiprone).
Advanced HF despite chelation → advanced-HF / transplant evaluation.
Coordinate with hematology (transfusion & chelation program).

KEY

Ferritin cannot replace cardiac T2* MRI. Iron cardiomyopathy is reversible with intensive chelation (deferiprone ± deferoxamine) including some patients with systolic failure; phlebotomy is first-line for primary HFE disease.

◷

Cardiac T2* severity bands → action

treat-to-T2*; cardiac iron clears slower than liver

Cardiac T2*	Iron burden	Risk	Action
>20 ms	none / acceptable	low	Maintain regimen. Stable T2*: reassess about every 2 y
10–19 ms	mild–moderate	↑ — subclinical dysfunction	Optimize chelation. Usually yearly, sooner if clinical deterioration
<10 ms	severe	high — HF & arrhythmia; main cause of death in TM	Intensive combination (DFO + deferiprone). T2* about every 6 mo + cardiology

⚑

Hemochromatosis beyond the heart & mimics on the differential

multisystem iron + who else gives restrictive LVH

Systemic iron clues (primary HFE)

Endocrine diabetes ("bronze diabetes"), hypogonadism, hypothyroidism, hypopituitarism.
Liver hepatomegaly → cirrhosis → HCC risk.
Joints / skin arthropathy (2nd/3rd MCP), slate-grey hyperpigmentation.
Pattern juvenile (HJV/HAMP) & transfusional load are the most cardiac.

Don't mistake it for…

Amyloid — also low voltage + restriction, but high T1/ECV & apical sparing (not low T2*).
Fabry / storage — concentric LVH but normal T2*; check native T1, enzymes.
Other siderosis — verify with cardiac T2*, not ferritin, before committing to chelation.
Pitfall normal liver iron / ferritin does not exclude cardiac iron.

01

Biology & heart

GLA → Gb3 storage

X-linked GLA mutation → α-galactosidase A deficiency → globotriaosylceramide (Gb3) in myocytes, podocytes, endothelium, neurons.
Males hemizygous, classic/severe. Females heterozygous — variable, can be fully affected.
Later-onset "cardiac variant" GLA mutations can be heart-limited.
Concentric LVH (mimics HCM/HTN/amyloid); short PR then conduction disease, AF; papillary muscle hypertrophy; inferolateral LGE.

02

Diagnosis

CMR + enzyme/gene

CMR signature — LOW native T1

Low T1 supports storage but is scanner/sequence-dependent. Fibrosis can pseudonormalize T1. Normal T1 does not exclude Fabry.
Abnormal in ~40% before LVH (early marker); ECV normal (storage, not interstitial).

Confirm

Males plasma/leukocyte α-Gal A activity (low).
Females GLA sequencing (enzyme can be normal) ± plasma lyso-Gb3.

03

Therapy

treatable storage disease

Enzyme replacement (ERT)

Agalsidase beta or pegunigalsidase alfa are US-approved ERT options. Agalsidase alfa is used in other jurisdictions. Choose with a Fabry specialist.

Oral chaperone

Migalastat for amenable GLA missense mutations — phase 3 placebo-controlled (FACETS); comparable renal outcomes over 18 mo (ATTRACT).
Treat early — before extensive LGE/fibrosis.

⚑

Extracardiac red flags & who to screen

Fabry is multisystem — the clues are outside the heart

Multisystem features → suspect

Neuro childhood acroparesthesias (burning hands/feet), early stroke/TIA.
Skin / eye angiokeratomas, cornea verticillata, hypohidrosis.
Renal proteinuria → progressive CKD/ESRD.
Other GI cramping/diarrhea, hearing loss, fatigue.

Screen these populations

Unexplained concentric LVH — especially with low native T1 or a short PR.
Cryptogenic stroke in the young; unexplained proteinuria / ESRD.
Any family member of a known proband (X-linked cascade).

KEY

Concentric LVH + low native T1 + multisystem clues = test for Fabry — X-linked and treatable (ERT or oral migalastat for amenable mutations).

℞

Choosing therapy & monitoring

ERT vs oral chaperone · what to track

Feature	ERT — check regional label	Migalastat (oral chaperone)
Route	IV infusion every 2 weeks	123 mg every other day, fasting 2 h before/after
Eligibility	Confirmed Fabry disease. Product age/indication limits apply	Adults with pathogenic GLA variants listed as amenable. Not recommended if eGFR <30
Evidence	multi-organ benefit (heart · kidney · nervous system)	FACETS placebo-controlled; ATTRACT: comparable renal-function outcomes at 18 mo
Caveats	infusion reactions; anti-drug antibodies	nonsense / large variants → use ERT instead

Monitor on therapy plasma lyso-Gb3 trend · eGFR + urine protein · echo/CMR (LV mass, native T1, LGE) · ECG / Holter for conduction disease & arrhythmia. Start before irreversible fibrosis (LGE) develops.

⊕

Differential of concentric LVH — how Fabry stands out

low native T1 + ECG & multisystem flags split the field

Cause	Native T1	Discriminator	Confirm
Fabry	LOW	Acroparesthesias, cornea verticillata, short PR, inferolateral LGE	α-Gal A (♂) · GLA + lyso-Gb3 (♀)
Amyloid	HIGH	Low voltage, apical sparing, bilateral CTS	PYP scan · serum FLC + serum/urine IFE
Sarcomeric HCM	normal / ↑	Asymmetric septum, SAM/LVOT gradient, FHx SCD	Sarcomere gene panel
Hypertensive / AS	normal / ↑	BP history; valve gradient; regresses with load relief	Echo + clinical context
PRKAG2 / Danon	normal	Pre-excitation (WPW), conduction block, myopathy	Gene panel (see P.4)

Published Fabry CMR showing concentric wall thickening and inferolateral midwall late enhancement — **Fabry can leave inferolateral scar.** Source panels e/h mark typical midwall LGE. Other patterns also occur. Deva et al., 2016, Fig. 5. © The authors. Source figure · CC BY 4.0. Unmodified. Select image to enlarge.

Do not stop at the imaging clue

Confirm with enzyme testing in males and GLA sequencing in both sexes. Normal enzyme activity in a female does not exclude Fabry.

Offer genetic counseling and targeted family testing after a pathogenic variant is established. Follow cardiac, renal and neurologic involvement.

Low T1 and inferolateral LGE are clues. Neither substitutes for biochemical/genetic confirmation.

These mimic HCM but are metabolic storage diseases — myocytes are vacuolated and glycogen-filled, with no sarcomeric disarray. Clues it isn't sarcomeric HCM: ventricular pre-excitation (WPW), conduction block, skeletal myopathy / ↑CK, X-linked pattern, intellectual disability, retinopathy, very high LV mass.

P

Pompe

GAA deficiency · AR

Defect acid α-glucosidase (GAA) deficiency → lysosomal glycogen.
Infantile massive HCM, hypotonia, respiratory failure, death <1 yr untreated.
Late-onset limb-girdle and respiratory weakness. Significant cardiomyopathy is uncommon.
Dx GAA enzyme (dried blood spot) + GAA gene.
Rx — ERT alglucosidase alfa q2 wk: 99% ↓ death risk, 92% ↓ death-or-ventilation vs historical (infantile).

G

PRKAG2

AMPK γ2 · AD

Triad LVH + ventricular pre-excitation (WPW) + progressive conduction block.
Histology glycogen vacuoles, no myofibrillar disarray.
Course Penetrance and pacing need vary by family/variant. Serial ECG and rhythm assessment remain essential.
Rx supportive; ablation for pre-excitation; pacemaker for block.

D

Danon

LAMP2 · X-linked

Defect LAMP2 → impaired autophagy, glycogen vacuoles.
Triad HCM + skeletal myopathy + intellectual disability (± retinopathy); males severe & early.
Course rapidly progressive — advanced HF / arrhythmia by young adulthood.
Rx supportive → early transplant referral; LAMP2 gene therapy emerging.

▲

Storage vs sarcomeric HCM — how to tell

when LVH is "too much" or has the wrong company

Feature	Points to storage / metabolic	Typical sarcomeric HCM
Pre-excitation (WPW)	PRKAG2, Danon, Pompe	absent
Conduction block	PRKAG2, Danon (also LMNA/Fabry)	uncommon early
Skeletal myopathy / ↑CK	Danon, Pompe (late-onset)	absent
Inheritance / extra clues	X-linked (Danon/Fabry); retinopathy, ID	autosomal dominant, isolated
LV mass	often extreme	asymmetric septal, variable

⊕

Other metabolic & storage mimics

send a metabolic panel when LVH keeps odd company

Friedreich ataxia (frataxin / FXN) — concentric HCM + ataxia, diabetes, scoliosis; autosomal recessive.
Mucopolysaccharidoses (Hurler / Hunter) — LVH + valve thickening / regurgitation; coarse features.
Mitochondrial (e.g., MELAS) — HCM/DCM + deafness, lactic acidosis, myopathy; maternal inheritance.
Others oxalosis & rare deposits — pursue when the phenotype + family pattern don't fit sarcomeric HCM.

KEY

LVH + WPW/block (PRKAG2), + myopathy/ID (Danon), or infantile HCM + hypotonia (Pompe) → glycogen storage, not sarcomeric HCM. Pompe is treatable (ERT); refer Danon early for transplant.

⌗

Gene · inheritance · diagnostic test · therapy at a glance

one panel for the metabolic / storage mimics

Disease	Gene · MOI	Heart & clue	Test	Therapy
Pompe	GAA · AR	Infantile massive HCM + hypotonia; late-onset limb-girdle	GAA enzyme (DBS) + gene	ERT alglucosidase alfa q2 wk
PRKAG2	PRKAG2 · AD	LVH + WPW + progressive block	Gene panel (glycogen, no disarray)	Supportive; ablation; pacemaker
Danon	LAMP2 · XL	HCM + myopathy + ID ± retinopathy; males early/severe	LAMP2 gene; muscle biopsy	Supportive → early transplant; gene therapy emerging
Fabry	GLA · XL	Concentric LVH, low T1 (see P.3)	α-Gal A / GLA + lyso-Gb3	ERT · migalastat
Friedreich	FXN · AR	Concentric HCM + ataxia, DM, scoliosis	FXN GAA-repeat expansion	Supportive; HF therapy
MPS (Hurler/Hunter)	IDUA / IDS · AR / XL	LVH + valve thickening/regurgitation; coarse features	Urine GAGs + enzyme/gene	ERT ± HSCT (type-specific)

RX

Genotype changes management. Confirm the gene before labeling "HCM": it determines treatability (Pompe/Fabry/MPS have enzyme therapy), device need (PRKAG2/Danon block), transplant timing (Danon), and cascade screening of relatives. A negative sarcomere panel with extreme LVH + extracardiac clues should trigger a metabolic/storage work-up.

01

Spectrum & stages

eosinophil-driven endocardial disease

Related phenotypes, different etiologies

Löffler endocarditis temperate; hypereosinophilic syndrome (clonal / reactive / idiopathic) — granule proteins are endocardial toxins.
Tropical EMF endemic tropics; a major endemic restrictive cardiomyopathy. Eosinophilia is not required, and its pathogenesis is incompletely defined.

The three stages

1 · Necrotic acute eosinophilic myocarditis — myocardial necrosis, troponin rise.

2 · Thrombotic mural thrombus over damaged endocardium → embolism.

3 · Fibrotic endocardial fibrosis, apical obliteration, AV-valve tethering (MR/TR), restrictive physiology.

Eosinophil count is dissociated from cardiac progression — keep cardiac follow-up even after the blood eosinophilia is controlled.

02

Diagnose & treat

cause · clot · fibrosis

Diagnose

Labs eosinophil count/trend; evaluate cause (FIP1L1-PDGFRA myeloid, reactive, idiopathic HES).
Echo apical obliteration, mural thrombus, restrictive filling, AV-valve involvement.
CMR endocardial LGE + thrombus; EMB in the acute phase.

Treat

Cause corticosteroids (reactive/idiopathic); imatinib if FIP1L1-PDGFRA; hydroxyurea.
Clot anticoagulation for mural thrombus.
Fibrotic stage HF therapy; endocardial resection ± valve repair/replacement — symptom-mitigating, not curative; poor prognosis untreated.

EMFgeographically variable

19.8%one Mozambique community, 2008

3stages

+

Complications & the restrictive-CM differential

what EMF causes · what else mimics it

Complications to anticipate

Thromboembolism apical / mural thrombus → stroke & systemic emboli — anticoagulate.
AV-valve regurgitation chordal & leaflet tethering by fibrosis → MR / TR.
Restrictive HF ascites, edema, low output; atrial arrhythmias (AF).
Apical obliteration cavity loss → low stroke volume.

Other restrictive CMs to exclude

Amyloid (PYP-SPECT + complete monoclonal screen), sarcoid (FDG-PET), iron (T2*), Fabry (low T1) — see the other pages.
Radiation heart disease; carcinoid (right-sided); idiopathic RCM.
Constrictive pericarditis — the key non-myocardial mimic (septal bounce, pericardial thickening).

◑

Acute vs chronic · Löffler vs tropical

tempo changes the priority

Acute (necrotic) — an emergency

Fulminant eosinophilic myocarditis → high-dose corticosteroids urgently; treat the eosinophilia driver.
Cardiogenic shock → supportive care ± temporary MCS; EMB confirms the diagnosis.

Löffler vs tropical EMF

Löffler temperate; overt hypereosinophilia; often biventricular; steroid / imatinib-responsive early.
Tropical EMF endemic; eosinophilia may have waned by presentation; chronic fibrotic disease — surgery for advanced cases.

℞

Hypereosinophilia: find the cause, target the driver

cause-directed therapy + endocardial protection

Driver	Clue	Targeted therapy
Myeloid (clonal)	FIP1L1-PDGFRA fusion; ↑ B12/tryptase	Imatinib (dramatically responsive)
Lymphocytic / idiopathic HES	aberrant T-cell clone or no cause found	Corticosteroids first-line; mepolizumab (anti-IL-5) steroid-sparing
Reactive / secondary	parasites, drug, allergy, EGPA, malignancy	Treat the cause. Urgent steroids for organ-threatening disease require attention to Strongyloides exposure and infection risk

Endocardial protection: anticoagulate established mural thrombus; CMR (endocardial LGE + low-signal thrombus) tracks damage better than the eosinophil count, which is dissociated from cardiac progression — keep cardiac surveillance after the blood count normalizes.

KEY

Eosinophilia + restrictive heart + apical thrombus = eosinophilic / EMF. Treat active eosinophilic disease and its cause, anticoagulate thrombus, assess surgery for advanced fibrosis — and follow the heart even after the eosinophils normalize.