Skip to content
Book Appointment
Multimodality imaging reference

Unexplained left ventricular hypertrophy: separating HCM from its phenocopies

Sarcomeric HCM compared against cardiac amyloidosis, Fabry disease, athlete’s heart and hypertensive heart disease across the echo, CMR, nuclear, electrical and biochemical parameters that change management. Every figure is marked to show whether it is a guideline threshold, a cohort proportion, a laboratory-dependent value or a supportive finding.

Reviewed by Dr Reza Moazzeni, MD FRACP·Consultant Cardiologist·Published 30 July 2026·Updated 30 July 2026

A specialist aide-mémoire for the assessment of unexplained LV hypertrophy in adults, not a diagnostic protocol. Aortic stenosis is treated as a coexistence problem rather than a competing diagnosis, because the clinical question it raises is whether a second myocardial disease is present alongside the valve lesion.

What is unexplained left ventricular hypertrophy?

Unexplained LV hypertrophy is increased left ventricular wall thickness that is not accounted for by the loading conditions present — hypertension, aortic valve disease or athletic training. Clinically relevant unexplained thickening can sit below any diagnostic cut-off. For the diagnosis of HCM in an adult, the conventional threshold is a maximal wall thickness of 15 mm or more on any imaging modality, or 13 mm or more where there is an affected first-degree relative or a pathogenic sarcomere variant.12

The label is a starting point, not a diagnosis. Sarcomeric hypertrophic cardiomyopathy is the commonest cause, but roughly one in ten patients referred with an initial diagnosis of HCM has a phenocopy — most often cardiac amyloidosis, less often Fabry disease, a glycogen storage disorder, a RASopathy or mitochondrial disease.21 Because several of these now have disease-modifying therapy, and because the athlete and the hypertensive patient need to be excluded rather than labelled, the distinction has moved from academic interest to a treatment decision.

On this page

Highest-yield discriminators

If only one finding per diagnosis can be pursued, these carry the most weight. None is diagnostic alone.

Diagnosis Single highest-yield finding What confirms or supports it
Sarcomeric HCM Integrated phenotype after exclusion of loading and of phenocopy features — no single morphological finding discriminates SAM and dynamic LVOT obstruction, characteristic mitral–papillary abnormalities, an affected pedigree or a concordant pathogenic sarcomere variant each increase confidence. Remains a clinical and imaging diagnosis; the panel informs the family rather than establishing the diagnosis
Cardiac amyloidosis Markedly raised ECV with abnormal myocardial nulling on the TI scout, or voltage-to-mass discordance on ECG Grade 2–3 bone scintigraphy with SPECT plus a negative monoclonal screen; otherwise histology with amyloid typing
Fabry disease Low native T1 with normal ECV, or basal inferolateral mid-wall LGE Men: deficient α-galactosidase A activity with a pathogenic or likely pathogenic GLA variant and concordant phenotype. Women: a pathogenic or likely pathogenic GLA variant with phenotypic and biochemical concordance. A VUS alone is not diagnostic
Athlete’s heart Dilated cavity proportionate to wall thickness, with normal or low ECV and no LGE Geometric indices, functional reserve on exercise testing, and partial regression with detraining
Hypertensive heart disease Concentric geometry proportionate to a documented blood pressure burden Regression of hypertrophy with sustained BP control supports a loading mechanism; failure to regress does not exclude hypertensive heart disease

How to read the numbers

A formal diagnostic cut-off and a proportion drawn from a single referral cohort carry very different weight at the bedside, and are easily read as equivalent when they sit side by side. Every figure in the chart below is therefore tagged, and numerical claims are referenced individually.

Marker G

Guideline threshold

A formal diagnostic or management cut-off from a current society document. Use as written, in the context the guideline specifies.

Marker C

Cohort figure

A proportion or prevalence from a defined study population. Carries that study’s selection, modality and definition. Not a population rate.

Marker L

Laboratory-dependent

Varies with scanner, field strength, sequence and vendor. Interpret against your own laboratory’s reference range, ideally as a z-score.

Marker S

Supportive only

Shifts probability. Does not establish or exclude a diagnosis on its own, and should not be a hard branch point in an algorithm.

The differential chart

Scroll the table horizontally for all five columns. Highlighted cells are the most discriminating finding in that row.

Scroll for all five columns
  Sarcomeric HCMAutosomal dominant Cardiac amyloidosisATTRwt / ATTRv / AL Fabry diseaseX-linked, GLA Athlete’s heartPhysiological Hypertensive heart diseasePressure overload
Morphology — transthoracic echo and cine CMR
Hypertrophy pattern Asymmetric septal in most; also concentric, mid-ventricular, apical, focal or mass-like. Reverse-curve, sigmoid, neutral and apical morphologies all described. Geometry does not separate amyloid from HCM. In a CMR referral cohort, asymmetric septal hypertrophy was present in 79%C of ATTR (sigmoid 55%, reverse curve 24%) and symmetric concentric in only 18%C; AL was concentric in around 68%C.10 Echo and biopsy series report higher concentric rates — the figures depend on the septal:posterior >1.5 definition and on modality. Look instead at RV free wall, IAS, valve leaflet thickening, biatrial dilatation and small pericardial effusion. Concentric in most; asymmetric septal, mid-cavity and apical forms all reported.4 Papillary muscle hypertrophy is characteristic but not specific — disproportionate papillary mass occurs in sarcomeric HCM too.S20 Symmetric, mild, harmonious with a dilated cavity. Proportionate RV and atrial enlargement. Concentric remodelling or concentric hypertrophy; sigmoid septum common in the elderly. Rarely truly asymmetric.
Maximal wall thickness Adults: ≥15 mmG, or ≥13 mmG with an affected first-degree relative or pathogenic variant. Children: z ≥2.5G if unexplained and isolated, z ≥2G with family history or genotype. ≥30 mmG is an SCD risk marker.12 Typically 14–20 mm, septum and posterior wall, high relative wall thickness. Normal wall thickness does not exclude cardiac amyloidosis — early ATTRv and AL involvement can precede any thickening, so abnormal strain, biomarkers or ECV still warrant workup. Typically 13–20 mm, occasionally >30 mm and phenotypically indistinguishable from HCM. Sex-specific values (>12 mm male, >11 mm female) appear in consensus treatment criteriaG but are not standalone treatment indications — variant pathogenicity, extracardiac organ involvement, fibrosis burden, symptoms and jurisdictional access all bear on the decision.4 ≤12 mm in men, ≤11 mm in womenC, with 13–15 mm reached by male endurance and Black athletes. In one elite CMR cohort 47.5%C of men and 4.1%C of women sat in the 13–16 mm grey zone;23 other cohorts report far lower rates. Usually 12–15 mm. Thickness out of proportion to the BP burden should prompt a search for a second diagnosis.
LV cavity and volumes Small or normal; LVEDD often <45 mm.C Reduced end-systolic cavity, hyperdynamic base. Small cavity, normal or reduced volumes, dilated atria, reduced stroke volume index and myocardial contraction fraction. Normal cavity; EF often normal or supranormal early. LVEDD >55 mm; LV cavity <54 mm favours HCMC.24 On CMR, wall-thickness-to-LVEDVi ratio <0.15 mm·m²/mLC22 and LV mass-to-volume ratio (LVM/LVEDV) <0.82 g/mLC23 both favour physiology. Note these are two different indices with different units — do not interchange them. Normal to small; LA dilated from chronic pressure load.
LVOT obstruction and SAM Frequent — roughly a third obstructive at rest, two-thirds with provocation.C SAM, elongated anterior leaflet, anteriorly displaced or accessory papillary muscles, posteriorly directed MR jet. Dynamic LVOTO is uncommon but well recognised; population prevalence is not firmly established and varies with subtype, referral pattern and definition. Typically sigmoid septum plus volume depletion. Recognise it before escalating diuresis. Recognised, including SAM-related and mid-cavity or papillary obstruction. Reported rates vary widely across series. Obstruction does not argue against Fabry.4 Absent. Dynamic sub-aortic gradient in the elderly with a sigmoid septum and volume depletion — a classic HCM mimic on a single study.
Function — strain topography and diastology
Global longitudinal strain Regionally reduced in the hypertrophied segments, worst basal septal. Apical HCM produces apical strain loss — the inverse of amyloid. Relative apical sparingS (apical LS ÷ [basal + mid LS] >1.0; EF-to-GLS ratio >4.1).12 Meta-analytic performance is moderate — around 61% sensitivity and 83% specificityC — and lower again against severe aortic stenosis, with vendor and disease-stage dependency.13 Supportive, never a branch point. Regional loss in the basal inferolateral segments with a relatively preserved septum early — the mirror image of HCM.4 Normal and augments on exercise. Resting GLS at the low-normal end is common and benign. Mild diffuse reduction, basal septal predominant.
Diastolic function and longitudinal indices Impaired relaxation, raised E/e′, dilated LA. Restrictive filling is uncommon and usually indicates advanced disease; it is not confined to end-stage systolic dysfunction. Progressive diastolic dysfunction with raised filling pressures, plus reduced MAPSE and TAPSE <17 mmG reflecting biventricular involvement. A frankly restrictive transmitral pattern (E/A >1.5, DT <150 ms) is an advanced-stage finding, not an entry criterion. Multiparametric echo scores outperform any single index.14 Impaired relaxation; frankly restrictive physiology is unusual. Normal or supranormal: e′ >10 cm/s, E/e′ <8, normal LA function despite LA dilatation. Grade 1–2 dysfunction proportionate to duration of hypertension.
Tissue characterisation — CMR
Native T1 Normal to mildly increasedL, focally, in hypertrophied and fibrosed segments. Considerable overlap with normal. Often markedly elevated and among the highest encounteredL; rises before LVH is apparent. Native T1 tends higher in AL, ECV higher in ATTR.10 T1 mapping outperforms strain-based apical sparing for detection.15 LowL — one of the few causes of a low myocardial T1. Roughly a third are not low at first pass; pseudonormalises with fibrosis and is elevated within the inferolateral scar.18 Also low with iron overload (check T2*) and fat. Normal or low-normal.L Normal to mildly increased.L
ECV Mildly increasedL, regionally heterogeneous. Markedly increased, commonly >0.40 and sometimes >0.50L. Often among the most discriminating tissue-characterisation measures across LVH phenotypes; tracks amyloid burden and predicts outcome. ECV does not type amyloid — it cannot separate ATTR from AL.10 Normal in the storage phase — low T1 with normal ECV is highly suggestive in the right phenotypeS, not diagnostic. Rises in the inferolateral scar. Normal or lowL — hypertrophy is pure myocyte, so the extracellular fraction falls. Normal to mildly increased.L
LGE pattern Patchy mid-wall within the most hypertrophied segments and at the RV insertion points. Extent ≥15% of LV mass carries roughly a two-fold increase in SCD event risk in patients otherwise judged lower-riskC16; LGE extent is used as an arbitrator when ICD decisions remain uncertainG.2 Quantification is not standardised and the optimal threshold is unsettled — a 2024 meta-analysis favoured 10%.C17 Diffuse subendocardial progressing to transmural, with abnormal gadolinium kinetics. RV LGE in around 96%C; atrial wall and valve enhancement; rapid blood-pool washout.10 Extensive subendocardial LGE is not entirely pathognomonic — it is described in long-standing severe hypertension. Basal-to-mid inferolateral mid-wall, subendocardial-sparing. Present in a minority before LVH. Often with raised T2 in the same segment.19 Usually none. Isolated RV insertion-point LGE occurs in trained endurance athletes and is not diagnostic of HCM. None, or minimal mid-wall or insertion-point enhancement.
TI scout Myocardial nulling Normal — myocardium nulls after the blood pool. Abnormal — myocardium nulls before or simultaneously with blood. Difficulty selecting a TI is itself the sign. Normal. Normal. Normal.
T2 mapping and oedema Mildly raised in hypertrophied segments; rarely decisive. Raised, particularly in untreated AL — oedema alongside infiltration. Focally raised in the basal inferolateral wall during the inflammatory stage, often with a troponin rise.19 Normal. Normal.
Beyond the scanner — nuclear, electrical, biochemical
Bone scintigraphy ⁹⁹ᵐTc-DPD / PYP / HMDP No disease-specific myocardial uptake expected. Incidental and false-positive uptake can occur. Perugini grade 2–3 with a negative monoclonal protein screen is diagnostic of ATTR-CM without biopsy.G9 Any grade, including grade 3, can occur in AL. If serum or urine immunofixation or the serum free light-chain assessment is abnormal, scintigraphy cannot establish the amyloid type: haematology assessment with histological confirmation and definitive typing is generally required. SPECT is mandatory to separate myocardial from blood-pool uptake. Timing is tracer-specific: DPD and HMDP at around 3 h; PYP conventionally at 1 h with delayed 3 h imaging if blood pool persists.G711 No disease-specific myocardial uptake expected. Not applicable. No disease-specific myocardial uptake expected.
ECG High voltage with strain, deep T-wave inversion, pathological Q waves. Giant negative T waves in apical HCM. Voltage high relative to mass. Voltage-to-mass discordance is the useful concept — frank low voltage occurs in only 25–40%C. Pseudo-infarct Q waves, AF, PR prolongation, AV and intraventricular conduction disease. Short PR without a delta wave early, high voltage, then progressive AV block, chronotropic incompetence and RBBB.4 Sinus bradycardia, early repolarisation, isolated voltage criteria, incomplete RBBB. Anterior TWI beyond V2 generally warrants assessment, except the recognised Black-athlete pattern (V1–V4 preceded by J-point or ST elevation) and the juvenile pattern under 16.G8 Lateral or inferolateral TWI is abnormal in any athlete. LVH with strain, LA abnormality.
Biomarkers NT-proBNP modestly raised, roughly tracking obstruction and diastolic burden. NT-proBNP and hs-troponin disproportionately and persistently elevated for the degree of hypertrophy; both feed ATTR and AL staging. Free light chain ratio rather than absolute levels — and the ratio is distorted by renal impairment.6 α-galactosidase A activity: markedly reduced activity in males is powerful, but GLA sequencing is still required for confirmation, variant classification, cascade screening and treatment selection. In females enzyme activity and lyso-Gb3 may be normal, so sequencing is essential.4 Normal NT-proBNP and troponin at baseline; transient rises occur after prolonged or intense exercise, so time sampling away from training. Variable, generally modest.
Extracardiac red flags Family history of HCM or premature SCD; autosomal dominant pedigree with male-to-male transmission. Bilateral carpal tunnel syndrome (typically years earlier), lumbar spinal stenosis, spontaneous biceps tendon rupture, autonomic neuropathy, orthostatic hypotension, unexplained intolerance of beta-blockers or ACE inhibitors. Periorbital purpura and macroglossia strongly favour AL. Nephrotic-range proteinuria is typical of AL but also occurs in hereditary amyloidoses with renal predominance. X-linked pedigree with no male-to-male transmission, acroparaesthesia, hypohidrosis, angiokeratoma, cornea verticillata, CKD or proteinuria, early cryptogenic stroke and white-matter lesions, tinnitus, GI symptoms.4 High training volume, sport type and duration. Phenotype may partially regress with detraining; failure to regress does not establish HCM. Documented hypertension, retinopathy, CKD, LVH regression with BP control.
Why the label matters
Consequence of getting it right SCD risk stratification and ICD decisions; cardiac myosin inhibitors for symptomatic obstruction; septal reduction therapy; cascade family screening. Exercise participation is a shared decision after expert assessment, not automatic restriction.G2 ATTR: tafamidis, acoramidis and vutrisiran are all disease-modifying options with no established superiority and no routine combination strategy; availability is jurisdiction-specific — check TGA registration and PBS criteria before counselling. Benefit is greatest early. Sequence TTR in every patient after a non-biopsy diagnosis, at any age, to separate hereditary from wild-type. AL: haematological emergency. Both: HF therapy individualised, with MRAs and SGLT2 inhibitors increasingly used where BP, renal function and congestion permit.6 Enzyme replacement, or oral chaperone therapy only for an amenable GLA variant, with better outcomes started before fibrosis; renal and neurological co-management; obligatory family cascade screening.4 Reassurance and continued participation. A false HCM label brings unnecessary restriction, repeated testing, risk stratification, possible device consideration, and family screening that was never indicated. Blood pressure control with demonstrable LVH regression.

Aortic stenosis: a coexistence problem, not a differential

Significant aortic stenosis is an established loading cause of LV hypertrophy, but it does not automatically explain all increased wall thickness, nor its distribution. Assess whether the magnitude and pattern of hypertrophy are proportionate to valve severity, and consider concomitant ATTR cardiac amyloidosis, HCM or another myocardial disorder when the phenotype, ECG, biomarkers or CMR findings are discordant. Low-flow states make gradient alone an incomplete measure of severity, which is precisely the setting in which the overlap is most enriched.

The overlap

Why it matters

Cardiac amyloidosis was found in 26 of 200 patients (13%)C aged 75 or over referred for TAVI in a blinded prospective screening study,25 with prospective series overall reporting roughly 8–16%.C26 The overlap is enriched in the low-flow, low-gradient phenotype with preserved ejection fraction.

What it changes

Usually not the decision to treat the valve. It reframes the prognostic conversation, opens access to disease-modifying therapy, and informs expectations about symptomatic gain. Do not unnecessarily delay an otherwise indicated valve intervention solely to complete amyloid testing — sequence investigation and treatment through individualised Heart Team assessment.3

Screen before intervention

Triggers

  • Wall thickness or distribution out of proportion to valve severity
  • Low-flow, low-gradient severe AS with preserved EF
  • Voltage-to-mass discordance on ECG
  • Relative apical sparing on strainS — noting this performs less well against AS than in other settings
  • RV free wall thickening, reduced TAPSE, thickened IAS
  • NT-proBNP disproportionate to the valve lesion
  • Poor tolerance of afterload reduction or unexplained hypotension
  • Bilateral carpal tunnel release, spinal stenosis, biceps tendon rupture

Working sequence

Six steps
  1. Confirm the hypertrophy is unexplained. Reconcile wall thickness against loading conditions: BP history and home readings, aortic valve severity including flow state, training volume and sport type, renal function. Phenocopies and pressure-overload LVH become increasingly important competing diagnoses with advancing age.
  2. Read the ECG against the mass. High voltage with a thick wall shifts probability toward HCM, Fabry or hypertensive disease. Normal or low voltage with a thick wall shifts probability toward amyloid. Short PR without pre-excitation shifts probability toward Fabry. Voltage alone cannot reliably separate them, and in athletes the international criteria apply rather than a single voltage rule.
  3. Use the strain map as a topographic clue. Apical sparing suggests amyloid; basal inferolateral loss suggests Fabry; loss confined to the thickest segments suggests HCM; normal and augmenting suggests an athlete. Treat all four as supportive, and check the apex with contrast, because apical HCM is an important mimic of the sparing pattern.
  4. Screen for the treatable infiltrative causes in parallel. Serum free light chain assessment with serum and urine immunofixation, alongside bone scintigraphy with SPECT if there is any amyloid signal — interpreted together, never in isolation. If any monoclonal test is abnormal, scintigraphy cannot type the amyloid: refer for haematology assessment and histological confirmation with definitive typing, since MGUS is common in the age group affected by ATTR. For Fabry, use otherwise unexplained LVH as the trigger rather than concentric geometry — asymmetric, apical and mid-cavity phenotypes all occur. Send α-Gal A and GLA sequencing in men; sequencing regardless in women.
  5. CMR for tissue characterisation and for risk. Native T1 and ECV first, LGE second, against local reference ranges.5 In HCM the specific questions are LGE burden and apical aneurysm — both change ICD decisions and neither is reliably answered by echo.
  6. Genotype, then the family. A pathogenic or likely pathogenic variant concordant with the phenotype establishes a molecular diagnosis and enables appropriately counselled cascade testing. A variant of uncertain significance must not be used to establish causality or for predictive testing. A pathogenic TTR variant establishes hereditary risk but does not by itself confirm that current LVH represents cardiac amyloid deposition — phenotypic evidence is still required. A negative sarcomere panel neither excludes HCM nor argues for a phenocopy; atypical age, morphology, extracardiac findings, biomarkers or tissue characterisation do.

Practical points worth carrying

Clinical pearls
  1. Geometry is close to useless for separating amyloid from HCM. Asymmetric septal hypertrophy is the commonest ATTR morphology in CMR series, and sigmoid septum is its commonest subtype. Right-heart and extracardiac structural involvement — RV free wall thickness, IAS, valve leaflets, atrial size, TAPSE — often strengthens suspicion for amyloidosis where geometry cannot.
  2. Low ECG voltage is a late and insensitive sign of amyloid. Voltage-to-mass discordance is the usable concept: a 17 mm wall with unremarkable voltage is abnormal even when no low-voltage criterion is met.
  3. Never interpret a bone scan without the monoclonal screen. Any Perugini grade — including grade 3 — can occur in AL. The non-biopsy diagnosis of ATTR requires grade 2–3 uptake plus a negative light chain screen plus SPECT confirmation. AL misdiagnosed as ATTR is a preventable death.
  4. A positive monoclonal screen does not exclude ATTR — it disqualifies the non-invasive pathway. MGUS is common in this age group and can coexist with ATTR. Abnormal immunofixation or an abnormal light-chain ratio means the amyloid type must be established histologically, not inferred from the scan.
  5. Know your tracer’s clock. DPD and HMDP at around three hours; PYP conventionally at one hour with a delayed three-hour acquisition if the blood pool is still in the way. Imaging at the wrong time is how equivocal scans are generated.
  6. Apical HCM is an important mimic of apical sparing — and the sparing ratio is a supportive finding with roughly 61% sensitivity, not a branch point. Confirm apical morphology before acting on the bull’s-eye.
  7. Low native T1 with a normal ECV is highly suggestive of Fabry in the right phenotype, but a normal T1 does not exclude it: about a third are not low at first pass, women pseudonormalise earlier, and the inferolateral segment runs the opposite way. Check T2* — iron lowers T1 too.
  8. The TI scout is free diagnostic information. If the radiographer struggles to null the myocardium, or nulls it before the blood, raise amyloid before the LGE images are reconstructed.
  9. Normal wall thickness does not exclude cardiac amyloidosis. Early ATTRv and AL involvement can precede thickening, which matters when strain, biomarkers or ECV are abnormal and the walls are not yet thick.
  10. Bilateral carpal tunnel release in an older patient with LVH is a cardiology referral. The musculoskeletal prodrome precedes heart failure by years — exactly the window in which stabilisers and silencers do most good.
  11. In the athlete’s grey zone the cavity is more informative than the wall. LVEDD >55 mm, wall-thickness-to-LVEDVi ratio <0.15 mm·m²/mL, LVM/LVEDV <0.82 g/mL, normal or low ECV, e′ above 10 cm/s and a peak VO₂ above 120% of predicted all favour physiology. Detraining for one to three months is a legitimate test, but incomplete regression does not establish HCM and detraining is not always practical.
  12. Papillary muscle hypertrophy is a Fabry clue, not a Fabry sign. Disproportionate papillary mass is described in sarcomeric HCM in the same CMR series.
  13. Phenocopies coexist with the common diseases. ATTR with AS, ATTR in HFpEF, hypertension on top of genuine HCM. Finding one explanation does not close the question when the phenotype is out of proportion.
  14. Beyond the five columns: Danon disease (young males, massive LVH, pre-excitation, intellectual disability, retinopathy), PRKAG2 (pre-excitation with progressive AV block), Noonan and the RASopathies, Friedreich ataxia, mitochondrial disease. Worth a thought whenever LVH sits alongside pre-excitation, conduction disease or syndromic features.

Traps

Avoidable errors
  • Diagnosing HCM in an elderly hypertensive with a sigmoid septum and a resting gradient. Volume status and afterload reproduce most of the phenotype. Reassess after optimising both.
  • Ordering scintigraphy without light chains, or reading it without SPECT. The scan is only interpretable alongside the monoclonal screen, and only after myocardial uptake is separated from blood pool.
  • Calling ATTR on a positive scan when a monoclonal protein is present. The non-invasive criteria no longer apply; the amyloid type must be established histologically.
  • Using a variant of uncertain significance to explain the phenotype or to screen relatives. A VUS establishes neither causality nor predictive risk, and cascade testing on that basis causes harm.
  • Working up a Black athlete for anterior T-wave inversion that is a recognised normal variant. V1–V4 preceded by J-point and ST elevation is physiological. Lateral and inferolateral TWI is not.
  • Restricting Fabry screening to concentric hypertrophy. Asymmetric, apical and mid-cavity phenotypes all occur; use otherwise unexplained LVH with clinical, ECG and CMR red flags as the trigger.
  • Treating a normal α-Gal A level as excluding Fabry in a woman, or as sufficient in a man. Sequence GLA either way.
  • Assuming a negative sarcomere panel points away from HCM. A large share of clinically definite HCM is genotype-negative. The panel informs the family, not the diagnosis.
  • Offering an oral chaperone without checking variant amenability. Migalastat works only for amenable GLA variants.
On thresholds

Every native T1 and ECV figure above carries an L for a reason. Use your own laboratory’s normal ranges and, where possible, a z-score against local controls rather than an absolute value quoted from a paper acquired on a different scanner.

Common questions

Does left ventricular hypertrophy always mean hypertrophic cardiomyopathy?

No. Most increased wall thickness is explained by loading — hypertension, aortic valve disease or athletic training. HCM is the commonest cause once those are excluded, but roughly one in ten patients referred with a working diagnosis of HCM has a phenocopy, most often cardiac amyloidosis. The diagnosis rests on integrating morphology, tissue characterisation, ECG, biomarkers, extracardiac features and, where appropriate, genotype.

How much wall thickness is required to diagnose HCM?

In adults, a maximal wall thickness of 15 mm or more on echocardiography, CMR or CT, not explained by loading conditions. The threshold falls to 13 mm where there is an affected first-degree relative or a pathogenic sarcomere variant. In children the criterion is a z-score of 2.5 or more when unexplained and isolated, or 2 or more with a family history or established genotype.

Can hypertension cause asymmetric septal hypertrophy?

It can, particularly a sigmoid or basal septal bulge in older patients, and this may generate a dynamic sub-aortic gradient when the patient is volume-depleted. That combination is a recognised HCM mimic on a single study. Reassess after optimising blood pressure and volume status before committing to a cardiomyopathy label.

Does apical sparing on strain diagnose cardiac amyloidosis?

No. It is a supportive finding. Meta-analytic sensitivity is around 61% with specificity around 83%, and performance falls further in severe aortic stenosis. It is also vendor- and stage-dependent, and apical HCM produces a pattern that can be misread as sparing. Treat it as something that shifts probability, and confirm apical morphology before acting on the bull’s-eye plot.

What if the monoclonal protein screen is positive?

The non-invasive diagnostic pathway for ATTR no longer applies. Positive bone scintigraphy cannot establish the amyloid type in the presence of a monoclonal protein, and any Perugini grade — including grade 3 — can occur in AL amyloidosis. MGUS is also common in the age group affected by ATTR, so the two can coexist. Haematology assessment with histological confirmation and definitive amyloid typing is generally required.

Can Fabry disease occur with a normal native T1?

Yes. Roughly a third are not low at first assessment. Native T1 pseudonormalises as fibrosis develops and is actually elevated within the inferolateral scar, women pseudonormalise earlier than men, and iron overload lowers T1 independently. A normal T1 does not exclude the diagnosis where the clinical picture, pedigree or extracardiac features are suggestive.

Does negative genetic testing exclude HCM?

No. A substantial proportion of clinically definite HCM is genotype-negative on current sarcomere panels. A negative result neither excludes HCM nor argues for a phenocopy. Its main value is that it limits the usefulness of predictive cascade testing in relatives, who then require clinical surveillance instead.

Key takeaways

In brief
  • Exclude loading before labelling. Age raises the prior probability of both amyloid and hypertensive hypertrophy.
  • Read the ECG against the mass, not in isolation; voltage-to-mass discordance is the most usable amyloid signal.
  • Bone scintigraphy is interpretable only alongside a monoclonal screen and only with SPECT. A positive monoclonal screen mandates histological typing.
  • Use otherwise unexplained LVH, not concentric geometry, as the Fabry screening trigger. Sequence GLA in women regardless of enzyme activity.
  • Only a pathogenic or likely pathogenic variant concordant with the phenotype supports cascade testing. A VUS does not.

References

  1. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503–3626. doi:10.1093/eurheartj/ehad194
  2. Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation 2024;149:e1239–e1311. doi:10.1161/CIR.0000000000001250
  3. Praz F, Borger MA, Lanz J, et al. 2025 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2025;46:4635–4736. doi:10.1093/eurheartj/ehaf194
  4. Cameli M, Pieroni M, Pastore MC, et al. The role of cardiovascular multimodality imaging in the evaluation of Anderson–Fabry disease: from early diagnosis to therapy monitoring. A clinical consensus statement of the ESC Working Group on Myocardial and Pericardial Diseases and the EACVI. Eur Heart J Cardiovasc Imaging 2025;26:814–829. doi:10.1093/ehjci/jeaf038
  5. Role of multimodality cardiac imaging in the management of patients with hypertrophic cardiomyopathy in 2025. A clinical consensus statement of the EACVI of the ESC. Eur Heart J Cardiovasc Imaging 2025. doi:10.1093/ehjci/jeaf282
  6. Kittleson MM, Ruberg FL, Ambardekar AV, et al. Transthyretin cardiac amyloidosis evaluation and management: 2025 ACC concise clinical guidance. J Am Coll Cardiol 2026;87:549–565.
  7. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis, Parts 1 and 2. Circ Cardiovasc Imaging 2021;14:e000029 and e000030.
  8. Sharma S, Drezner JA, Baggish A, et al. International recommendations for electrocardiographic interpretation in athletes. Eur Heart J 2018;39:1466–1480. doi:10.1093/eurheartj/ehw631
  9. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–2412. doi:10.1161/CIRCULATIONAHA.116.021612
  10. Martinez-Naharro A, Treibel TA, Abdel-Gadir A, et al. Magnetic resonance in transthyretin cardiac amyloidosis. J Am Coll Cardiol 2017;70:466–477. doi:10.1016/j.jacc.2017.05.053 — source of the hypertrophy-geometry proportions and the RV LGE figure quoted above; septal-to-posterior ratio >1.5 definition.
  11. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–1084.
  12. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 2012;98:1442–1448.
  13. Vetter S, et al. Diagnostic accuracy of the apical sparing ratio for detecting cardiac amyloidosis in left ventricular hypertrophy and severe aortic stenosis: a systematic review and meta-analysis. Echocardiography 2026;43:e70474.
  14. Boldrini M, Cappelli F, Chacko L, et al. Multiparametric echocardiography scores for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 2020;13:909–920.
  15. Korthals D, Chatzantonis G, Bietenbeck M, et al. CMR-based T1 mapping offers superior diagnostic value compared to longitudinal strain-based assessment of relative apical sparing in cardiac amyloidosis. Sci Rep 2021;11:15521.
  16. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130:484–495. doi:10.1161/CIRCULATIONAHA.113.007094 — source of the ≥15% LV mass two-fold SCD risk figure.
  17. Quantitative late gadolinium enhancement cardiac magnetic resonance and sudden death in hypertrophic cardiomyopathy: a meta-analysis. JACC Cardiovasc Imaging 2024;17:489–497. — pooled odds ratio 4.9; best-performing extent threshold 10% of LV mass.
  18. Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson–Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 2013;6:392–398.
  19. Augusto JB, Nordin S, Vijapurapu R, et al. Myocardial oedema, T2 mapping and inflammation in Fabry disease. Circ Cardiovasc Imaging 2020;13:e010171.
  20. Kozor R, Callaghan F, Tchan M, et al. Insight into hypertrophied hearts: a cardiovascular magnetic resonance study of papillary muscle mass and T1 mapping. Eur Heart J Cardiovasc Imaging 2017;18:1034–1040. — disproportionate papillary mass in both Fabry disease and sarcomeric HCM.
  21. Limongelli G, Masarone D, Verrengia M, et al. Diagnostic clues for the diagnosis of nonsarcomeric hypertrophic cardiomyopathy (phenocopies): amyloidosis, Fabry disease, and mitochondrial disease. J Cardiovasc Echogr 2018;28:120–123. doi:10.4103/jcecho.jcecho_2_18
  22. Petersen SE, Selvanayagam JB, Francis JM, et al. Differentiation of athlete’s heart from pathological forms of cardiac hypertrophy by means of geometric indices derived from cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2005;7:551–558. — wall-thickness-to-LVEDVi ratio <0.15 mm·m²/mL.
  23. Czimbalmos C, Csecs I, Toth A, et al. The demanding grey zone: sport indices by cardiac magnetic resonance imaging differentiate hypertrophic cardiomyopathy from athlete’s heart. PLoS One 2019;14:e0211624. doi:10.1371/journal.pone.0211624 — source of the 47.5% and 4.1% grey-zone proportions and the LVM/LVEDV cut-off. The published abstract labels the LVM/LVEDV cut-off in mm·m²/mL; a mass-to-volume ratio is dimensionally g/mL, and that unit is used here.
  24. Caselli S, Maron MS, Urbano-Moral JA, et al. Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy. Am J Cardiol 2014;114:1383–1389. — LV cavity <54 mm.
  25. Scully PR, Patel KP, Treibel TA, et al. Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation. Eur Heart J 2020;41:2759–2767. doi:10.1093/eurheartj/ehaa170
  26. Nitsche C, Scully PR, Patel KP, et al. Prevalence and outcomes of concomitant aortic stenosis and cardiac amyloidosis. J Am Coll Cardiol 2021;77:128–139. doi:10.1016/j.jacc.2020.11.006
Referrals

Unexplained LV hypertrophy in your patient?

Heartcare Sydney provides transthoracic echocardiography with strain imaging at Westmead, with onward CMR, nuclear and genetic pathways where the phenotype does not fit the loading conditions. Referrals are required for all consultations.

Refer a patient
0
Would love your thoughts, please comment.x
()
x