Cardiomyopathy - restrictive
Description
- Stiff, non-compliant ventricle -> impaired diastolic filling with normal or near-normal EF and normal/small cavity size
- Haemodynamic signature: steep rise in ventricular pressure for a small volume increase
- -> inc filling pressures -> biatrial enlargement with normal-sized ventricles
- -> fixed, low stroke volume; cardiac output falls with tachycardia and with loss of atrial kick
- The rarest of the classical cardiomyopathies, but the one most often missed - "HFpEF that does not behave like HFpEF"
The picture
- Marked right-sided congestion out of proportion to left-sided symptoms
- Small ventricles + huge atria on echo = the pattern to recognise
- Wall thickening with LOW voltage on ECG = infiltration (a thickened wall should give big voltages; if it does not, the wall is full of something that is not myocyte)
Epidemiology
- <5% of all cardiomyopathies in developed countries
- Endomyocardial fibrosis is the commonest cause worldwide - tropical Africa, India, South America
- In Australia: cardiac amyloidosis dominates
- ATTR-wt - men, age >70, often with carpal tunnel and spinal stenosis; present in ~13% of HFpEF admissions >60 and ~15% of severe AS referred for TAVI
- AL - median age 63, associated plasma cell dyscrasia
- ATTRv (variant) - V122I in ~3-4% of people of West African ancestry; T60A Irish
Aetiopathogenesis
Classification by site
A. Infiltrative (between myocytes)
- Amyloidosis - AL (light chain), ATTR wild-type, ATTRv. The commonest cause in Australia
- Sarcoidosis (can be restrictive, dilated or arrhythmogenic)
- Gaucher, Hurler
B. Storage (within myocytes)
- Haemochromatosis (often restrictive early, dilated late; reversible with venesection if treated early)
- Fabry disease (alpha-galactosidase A) - LVH phenocopy; look for angiokeratoma, cornea verticillata, neuropathic pain, proteinuria
- Glycogen storage (Pompe, Danon), Niemann-Pick
C. Non-infiltrative
- Idiopathic, familial (desmin, filamin C, troponin I, myopalladin)
- Scleroderma, diabetic cardiomyopathy
- Pseudoxanthoma elasticum
D. Endomyocardial
- Endomyocardial fibrosis (tropical)
- Loffler endocarditis - hypereosinophilic syndrome; eosinophil granule proteins -> necrosis -> thrombosis -> fibrosis
- Carcinoid (right-sided plaques, TR and PS)
- Radiation, anthracyclines, serotonergic drugs (methysergide, ergotamine), hydroxychloroquine
- Metastatic infiltration
Mechanism
- Interstitial or endocardial deposition -> dec ventricular compliance
- -> early rapid filling that stops abruptly ("square root"/dip-and-plateau)
- -> inc atrial pressures -> biatrial dilatation -> AF -> thromboembolism
- -> pulmonary hypertension, then RV failure
- -> later, systolic function and strain decline even while EF is preserved
Diagnosis
Clinical
- Right heart failure dominates: raised JVP, peripheral oedema, ascites, hepatomegaly, pulsatile liver
- Kussmaul sign may be positive (shared with constriction)
- Fatigue and exertional intolerance from fixed low output
- S3 gallop; AF common
- Red flag combination: HF with preserved EF + low ECG voltage + thick walls
ECG
- Low voltage (or voltage inappropriate for wall thickness)
- Pseudo-infarct Q waves in anterior leads (amyloid)
- AV block, AF, non-specific T changes
- Sarcoid: high-grade AV block in a patient <60
Echo
- Normal/small ventricular cavities, normal or increased wall thickness, biatrial enlargement
- Grade III (restrictive) diastolic filling: E/A >2, short deceleration time (<150 ms), E/e' >14
- Reduced global longitudinal strain with apical sparing ("cherry on top" bull's-eye) = amyloid
- Granular sparkling myocardium, thickened valves and interatrial septum, small pericardial effusion
- Dilated IVC, inc estimated PASP
Cardiac MRI
- Diffuse subendocardial or transmural late gadolinium enhancement with abnormal gadolinium kinetics = amyloid
- inc native T1 and inc extracellular volume (ECV) - amyloid
- dec native T1 - Fabry and iron overload; *T2 <20 ms** = myocardial iron
- Patchy mid-wall/basal septal LGE - sarcoid
Establishing the cause
- Serum free light chains + serum and urine immunofixation - to exclude AL before anything else. Three-test screen has >99% sensitivity
- 99mTc-DPD/PYP/HMDP bone scintigraphy - Perugini grade 2-3 uptake with negative plasma cell screen = diagnostic of ATTR without biopsy
- A positive scan with a positive light-chain screen does NOT establish ATTR - AL also takes up tracer. Biopsy
- TTR genotyping in all ATTR - separates wild-type from variant (family implications)
- Ferritin/transferrin saturation, ACE, eosinophil count, alpha-galactosidase A (males) / GLA genotyping (females)
- Endomyocardial biopsy - gold standard where non-invasive work-up is unrevealing; Congo red with apple-green birefringence, mass spectrometry typing
*Restriction vs constriction - the central discrimination*
| Restrictive cardiomyopathy | Constrictive pericarditis | |
|---|---|---|
| Problem | Myocardium | Pericardium |
| Ventricular interdependence | ABSENT | PRESENT - the key discriminator |
| Respiratory variation in mitral inflow | Normal (<25%) | Exaggerated (>25%) |
| JVP descents | Prominent y | Prominent x AND y ("M"/"W") |
| Septal bounce | No | Yes |
| Tissue Doppler e' | Reduced (<8 cm/s) | Normal or high ("annulus paradoxus") |
| Mitral annular e' | Lateral > septal | Septal > lateral ("annulus reversus") |
| Catheter: LVEDP vs RVEDP | LVEDP exceeds RVEDP by >5 mmHg | Equalisation (within 5 mmHg) |
| Systolic area index | <1.1 | >1.1 |
| RVSP | Often >55 mmHg | Usually <55 |
| Pericardium on CT/MR | Normal | Thickened >4 mm, calcified (20% have normal thickness) |
| BNP | Markedly elevated | Mildly elevated |
| Treatment | Medical, of the cause | Pericardiectomy - curable |
Management
A. Treat the specific cause - this is where the prognosis is won
- AL amyloid - urgent haematology referral; daratumumab-CyBorD (bortezomib, cyclophosphamide, dexamethasone) +/- autologous stem cell transplant
- Time-critical: cardiac AL has the worst prognosis of any amyloid
- ATTR-CM - tafamidis (TTR stabiliser) is the only disease-modifying agent approved in Australia
- ATTR-ACT: dec all-cause mortality and CV hospitalisation; benefit greatest in NYHA I-II - refer early
- Internationally approved second-generation agents: acoramidis (stabiliser), vutrisiran (siRNA silencer); eplontersen in phase III
- Haemochromatosis - venesection or chelation (cardiac iron responds; reverse early)
- Fabry - enzyme replacement (agalsidase) or migalastat
- Sarcoid - corticosteroid +/- steroid-sparing agent; ICD for high-grade block or ventricular arrhythmia
- Loffler / hypereosinophilic - corticosteroids, imatinib if FIP1L1-PDGFRA positive, anticoagulation
- Endomyocardial fibrosis - endocardectomy with valve repair in selected
B. Symptomatic - congestion
- Loop diuretic, carefully - these patients are preload-dependent; over-diuresis drops cardiac output precipitously
- Salt and fluid restriction, daily weights
- Aldosterone antagonist for congestion
C. What NOT to do - this is examinable
- *Standard HFrEF therapy is poorly tolerated in cardiac amyloid*
- Beta blockers: output is rate-dependent (fixed stroke volume) -> bradycardia causes decompensation
- ACEi/ARB/ARNI: profound hypotension, autonomic neuropathy
- *Digoxin: binds amyloid fibrils -> toxicity at therapeutic levels. Avoid or use with extreme care*
- Non-dihydropyridine CCBs: same binding problem, negative inotropy
- Avoid rate-slowing agents generally; maintain sinus rhythm - atrial kick matters more than usual
D. Arrhythmia and thromboembolism
- AF is poorly tolerated - prioritise rhythm control (amiodarone is the safest agent here)
- *Anticoagulate cardiac amyloid with AF regardless of CHA2DS2-VA score* - very high atrial thrombus rate
- Consider TOE before cardioversion even with adequate anticoagulation - atrial mechanical failure
- Pacing for conduction disease; ICD benefit less clear than in other cardiomyopathies (death is often electromechanical dissociation, not VT)
E. Advanced
- Cardiac transplantation - for selected patients: ATTR, non-systemic AL after haematological response, idiopathic
- Combined heart-liver transplant in ATTRv
- Mechanical support poorly tolerated (small ventricles)
- Early palliative care involvement
Associations
- Carpal tunnel syndrome (often bilateral, 5-10 years before cardiac presentation), lumbar spinal stenosis, biceps tendon rupture, spontaneous ATTR red flags
- Macroglossia and periorbital purpura - specific for AL, not ATTR
- Nephrotic-range proteinuria (AL), autonomic neuropathy, peripheral neuropathy
- Low-flow low-gradient aortic stenosis - ATTR present in ~15% of TAVI referrals
- Hypereosinophilic syndrome, carcinoid, scleroderma
- Family history - ATTRv, desmin and filamin C cardiomyopathies
Natural history & complications
- Progressive: diastolic failure -> pulmonary hypertension -> RV failure -> low-output state
- Untreated cardiac AL amyloid: median survival ~6 months; ATTR-wt ~3-5 years; ATTRv variable by mutation
- Haemochromatosis and Fabry can be substantially reversed if treated early
- Idiopathic RCM in adults: ~50% 5-year survival; poor in children
Complications
- Refractory right heart failure, ascites, cardiac cachexia
- AF with thromboembolism (high intracardiac thrombus rate)
- Conduction disease and sudden death
- Mural thrombus (endomyocardial forms)
- Valve regurgitation from endocardial involvement
- Diuretic-refractory congestion with rising creatinine - the usual terminal picture
Prognostic staging
- Mayo staging for AL: NT-proBNP, troponin, difference in free light chains
- NAC/Gillmore ATTR staging: NT-proBNP and eGFR
- Rising NT-proBNP and troponin drive prognosis more than EF in all restrictive disease
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