Cardiac Amyloidosis

Cardiac amyloidosis is the leading infiltrative cause of restrictive cardiomyopathy in the developed world — distinct in mechanism from endomyocardial fibrosis, which produces a similarly restrictive phenotype through disease of the endocardium rather than interstitial infiltration — and it’s genuinely more common than it was once thought to be — recent screening studies found amyloid in roughly 1 in 8 patients referred for TAVI with severe aortic stenosis, in about 12% of HFpEF registries, and in 7% of patients originally diagnosed with hypertrophic cardiomyopathy at tertiary centers. This page draws primarily on the 2023 British Society of Echocardiography guideline — the first dedicated, echo-specific amyloidosis guideline, and a genuine update to how several long-taught signs should actually be used.

Overview: Two Subtypes Account for 95% of Cases

Amyloidosis isn’t a single disease but a family of disorders unified by protein misfolding — insoluble fibrils accumulate in the myocardial interstitium (the extracellular space), producing increased wall thickness that is genuinely pseudohypertrophy rather than true myocyte growth. Amyloid deposits throughout the heart — valves, atrial walls, and ventricular myocardium — though the process is usually most evident in the ventricular walls.

• AL (light chain) amyloidosis — the precursor protein is an abnormal immunoglobulin light chain, usually from abnormal bone marrow plasma cells. The heart is the most commonly involved organ, with over 75% of patients showing cardiac symptoms at diagnosis. Median age at diagnosis is 65. Initial symptoms (weight loss, fatigue) are nonspecific enough to delay diagnosis by more than 6 months in many patients, and 10–15% of cases occur alongside multiple myeloma. AL amyloidosis follows a rapidly progressive course — median survival from diagnosis is only about 4 months with advanced cardiac involvement, versus roughly 2 years with less severe involvement — though newer therapeutic regimens have improved overall survival, particularly when started early.
• ATTR (transthyretin) amyloidosis — transthyretin is a liver-synthesized serum transport protein for thyroxine and retinol. ATTR amyloidosis splits into wild-type (wtATTR), predominantly older men (median age at diagnosis 79) with a much slower, though eventually fatal, course (median survival around 5 years without disease-modifying therapy), and hereditary (hATTR), an autosomal dominant condition from pathogenic TTR gene variants with age-dependent penetrance, presenting earlier. More than 130 amyloidogenic TTR variants are known worldwide; in the UK and Ireland, the two most common disease-causing variants are V142I (formerly V122I) and T80A (formerly T60A).

UK registry data (1987–2019, over 11,000 patients) found AL amyloidosis remains the single most common type overall (55% of cases) — but the referral prevalence of wtATTR-CM specifically has risen dramatically, from under 3% in 1987–2009 to 25% in 2016–2020, reflecting genuinely improved recognition rather than a true change in disease incidence. Regardless of subtype, early suspicion and prompt diagnosis is what actually changes outcomes — randomized trial evidence now shows TTR-directed therapies benefit patients most when started early in the disease course.

The Central Diagnostic Principle: Echo Raises Suspicion, It Doesn’t Make the Diagnosis

This is worth stating as plainly as the guideline does: echocardiography cannot, by itself, diagnose cardiac amyloidosis or distinguish AL from ATTR subtype — the overlap between the two is too great. Its genuine role is raising suspicion in the right clinical context and prompting confirmatory testing (bone scintigraphy, serum/urine free light chain assessment, or biopsy). Treating a “suggestive” echocardiogram as a finished diagnosis, or guessing at subtype from imaging alone, both overstate what the study can actually tell you.

Wall Thickness: A Threshold With a Real Caveat

The hallmark finding is increased LV (or biventricular) wall thickness, ≥12 mm, in the absence of aortic valve disease, significant hypertension, or another plausible cause. This threshold is not sex-specific, and used in isolation — without accounting for a patient’s blood pressure history — it has high sensitivity but low specificity. It needs to be interpreted alongside the other findings below, and alongside clinical red flags such as a history of bilateral carpal tunnel syndrome, which commonly precedes cardiac symptoms by years in ATTR amyloidosis.

A genuine exception worth remembering: AL-CM in particular can present with only minimal wall thickness increase and a normal LV mass — the ≥12 mm threshold is a useful anchor, not an absolute requirement, especially early in AL disease.

Asymmetric Hypertrophy Does Not Exclude Amyloidosis

Amyloidosis has historically been taught as a cause of concentric hypertrophy, and this is indeed the more usual pattern in AL-CM — but many ATTR-CM patients develop asymmetric, septal-predominant thickening instead. In a cardiac MRI study of 263 ATTR-CM patients, 79% showed asymmetric hypertrophy, and only 18% were truly concentric (defined as a septal-to-lateral wall thickness ratio under 1.5). Among patients with a ratio over 1.5, 55% had a sigmoidal septal pattern, and a genuinely notable 24% had a reverse septal contour — a morphology traditionally considered characteristic of HCM. The key point: asymmetry alone should never be used to rule out amyloidosis.

Measuring wall thickness correctly: caliper maximal thickness wherever it occurs — septal, anterior, lateral, and inferior walls, at the mitral valve, mid-LV, and apical levels — excluding the RV wall, papillary muscles, trabeculations, and moderator band. Wall thickness alone doesn’t define LVH; that requires indexed LV mass. Relative wall thickness (RWT) should be calculated including the septal measurement — RWT = (IVSd + PWd) ÷ LVIDd, not the posterior-wall-only version sometimes used interchangeably — since septal-predominant thickening in amyloid will otherwise be underestimated. An RWT over 0.42 defines concentric remodeling; ≤0.42 is eccentric.

A Term Worth Retiring: “Granular Sparkling”

The classic “speckled” or “sparkling” myocardial texture has long been taught as a hallmark of amyloidosis — the current guideline specifically recommends not commenting on this finding at all. It lacks diagnostic specificity (the same texture is seen in hypertensive heart disease, chronic kidney disease, HCM, and Pompe disease), and has been further confounded by the routine shift from fundamental to harmonic imaging on modern equipment, which changes how myocardial texture appears regardless of underlying pathology.

A genuinely more useful mismatch to look for: a surprisingly low-voltage QRS on ECG paired with impressively thick walls on echo. This directly reflects the pseudohypertrophy mechanism — since the “hypertrophy” is extracellular infiltration rather than myocyte growth, the heart doesn’t generate the increased electrical voltage true hypertrophy would produce. This mismatch is a far more specific clue than texture, and a key feature that helps separate amyloidosis from sarcomeric HCM.

Strain Imaging: The Single Most Useful Diagnostic Parameter

Performing GLS in every patient with increased LV wall thickness or LVH is critical — not only those already suspected of amyloidosis — since early suspicion directly enables earlier, more effective treatment.

• Longitudinal systolic function is impaired even in the earliest phase of disease, often before any other conventional parameter becomes abnormal.
• A normal (not supranormal) EF alongside diminished longitudinal function is itself a distinguishing pattern. Sarcomeric HCM more often shows a high or frankly supranormal EF — amyloidosis typically doesn’t.
• The apical sparing (“cherry on top”) bullseye pattern — strain severely reduced at the base and mid-ventricle, with relative preservation at the apex — is seen in both AL-CM and ATTR-CM. An apex-to-base strain ratio over 2.1 is 93% sensitive and 82% specific for distinguishing amyloidosis from other causes of LV wall thickening, including hypertension, Fabry disease, and Friedreich’s ataxia, and independently predicts worse prognosis. The proposed mechanism is simply less amyloid deposition at the apex relative to the base, though this remains debated. By contrast, other causes of LVH (aortic stenosis, HCM) more typically show reduced strain specifically in the regions of maximal hypertrophy — the opposite spatial pattern.
• Technical acquisition matters: maintain a frame rate of 40–90 fps at a stable heart rate, with clear endocardial and epicardial definition throughout the cycle. If more than two segments in any single view can’t be adequately tracked, don’t calculate an average GLS; if full tracking fails but the apical four-chamber view is adequate, report four-chamber GLS alone and state the method used.

Emerging Composite and Scoring Parameters

• EFSR (EF-to-GLS ratio) was the single best discriminating deformation parameter in one comparison of amyloidosis, HCM, and hypertensive heart disease (AUC 0.80).
• Myocardial contraction fraction (MCF) — the ratio of stroke volume to myocardial mass — showed the highest diagnostic accuracy in a larger ATTR-CM cohort.
• An ESC-endorsed “increased wall thickness” (IWT) score, combining RWT, E/e′, TAPSE, GLS, and the septal apex-to-base strain ratio, reached an AUC of 0.87 for ATTR-CM at a threshold of 8 points; a separate AL score using RWT, E/e′, GLS, and TAPSE reached an AUC of 0.90 for AL-CM at a threshold of 5 points. Neither score has been externally validated, and the BSE guideline explicitly does not endorse a formal scoring model — see the reporting framework below for what it recommends instead.
• EFSR and MCF, while useful, are not part of the BSE minimum dataset.

Diastolic Function and Doppler Findings

Diastolic parameters are often markedly abnormal from myocardial stiffening — but the single most important caveat here is that a clear-cut restrictive mitral inflow pattern is rarely seen until late in the disease, while early diastolic dysfunction and signs of raised filling pressure can be among the very first signs, and are actually more sensitive for early detection than waiting for a classic restrictive pattern to appear. See LV Diastolic Function for the general grading framework this fits into.

• Tissue Doppler: mitral annular e′ is usually under 6 cm/s in amyloidosis — a stricter threshold than the general RCM figure — with biatrial dilation and systolic blunting of pulmonary vein flow (in the absence of significant MR) supporting elevated filling pressure.
• E/e′ (averaged septal and lateral) becomes abnormal early in the disease course, at a threshold around 13 — rising further as disease advances.
• Reductions in TDI systolic and diastolic indices typically precede the appearance of traditional restrictive Doppler findings, making tissue Doppler a genuinely useful subclinical marker when amyloidosis is suspected but not yet confirmed on more conventional parameters.
• A reduced-amplitude mitral A wave suggests poor atrial mechanical function and a correspondingly higher risk of atrial thrombus formation — worth noting specifically given the embolic implications.

Associated Findings

• Left ventricular cavity size and stroke volume: usually normal or small, and progressive amyloid infiltration increases myocardial mass while the cavity becomes progressively smaller — producing low stroke volume despite a normal EF, particularly early in the disease. This creates a state of effectively fixed end-diastolic volume, where cardiac output becomes critically dependent on heart rate — valve infiltration causing mitral and tricuspid regurgitation further limits forward stroke volume on top of this. Stroke volume should be measured directly via LVOT diameter and VTI, using an inner-edge-to-inner-edge LVOT diameter measured immediately below the aortic cusp insertion — a technical point that differs from the older practice of measuring up to 1 cm below the cusps.
• Valve thickening: mitral, tricuspid, and aortic valve thickening are common accompanying findings, graded simply as normal, mild, moderate, or severe — nonspecific on their own, but a frequent supporting feature.
• Mitral regurgitation: quantification can be genuinely limited when the PISA dome merges with turbulent LVOT flow (amyloid can occasionally cause LVOT obstruction too, though far less often than HCM — still worth checking for, since finding it helps separate the two conditions). When quantitation is precluded, an E velocity under 1.3 m/s with an E/A ratio under 1 is a reasonable indicator that MR is not severe.
• Biatrial dilation, left atrial stasis with spontaneous echo contrast, interatrial septal thickening, and pericardial or pleural effusion are all recognized accompanying features.
• RV free wall hypertrophy strongly suggests an infiltrative process specifically, since true (sarcomeric) LV hypertrophy rarely involves meaningful RV wall thickening — a useful, quick discriminator. RV cavity size is typically normal. See Evaluation of the Right Ventricle for the standard assessment approach. Reduced TAPSE and reduced RV tissue Doppler s′ are specifically early indicators of cardiac involvement in AL amyloidosis — not merely late prognostic findings.

Amyloid and Low-Flow, Low-Gradient Aortic Stenosis

A genuinely important overlap population: patients with amyloid and severe aortic stenosis frequently present with parameters consistent with low-flow, low-gradient AS despite a preserved EF, since amyloid’s own limited stroke volume reserve — often compounded by concomitant MR or atrial fibrillation — keeps aortic valve velocity and mean gradient low regardless of true valve severity. No echo feature reliably distinguishes amyloid-with-severe-AS from lone severe AS, though LV wall thickening disproportionate to the degree of AS is a useful clue. A proposed clinical scoring system (AUC 0.85) combines limited echo findings (septal thickness over 18 mm, E/A over 1.4) with non-echo findings weighted more heavily — specifically a history of carpal tunnel syndrome and RBBB on ECG. Importantly, aortic valve intervention still benefits patients with symptomatic severe AS and concomitant ATTR-CM — the presence of amyloid is not, by itself, a reason to withhold treatment for the valve disease.

How Echocardiography Should Be Reported

Rather than endorsing a formal numeric score, the BSE guideline recommends a three-tier, likelihood-based interpretation:

Category	Criteria
Not suggestive	Normal LV wall thickness, normal atrial size, septal or lateral e′ over 10 cm/s, normal GLS, no apical sparing pattern
Equivocal	Mixed parameters
Suggestive	Increased LV wall thickness, reduced GLS with a typical apical sparing pattern, restrictive mitral inflow, restrictive mitral annular tissue Doppler

Even a “suggestive” report cannot reliably distinguish AL-CM from ATTR-CM — the overlap between the two is considerable — so the recommendation is to report likelihood only, without commenting on subtype.

Prognosis and Serial Assessment

Several echocardiographic parameters correlate with CMR-derived extracellular volume, a robust marker of amyloid burden, and follow a recognizable staging pattern: GLS and E/e′ tend to become abnormal early, at lower amyloid burden, while atrial size and EF become abnormal only later, at higher burden — a useful mental model for placing a given patient’s findings along the disease continuum.

• In ATTR-CM, baseline stroke volume index, GLS, E/e′, and right atrial area index are all independently associated with mortality.
• In AL-CM, baseline GLS and stroke volume index predict survival; after chemotherapy, patients achieving improvement in both GLS and NT-proBNP survive longer than those improving NT-proBNP alone — a reason to track echo response alongside biomarkers, not as a secondary consideration.
• In a large cohort (565 wtATTR-CM and 312 hATTR-CM patients), among a wide range of echo parameters including strain-based measures, only worsening mitral and tricuspid regurgitation was independently associated with adverse prognosis — a genuinely specific finding worth knowing, since it elevates valve assessment above many more commonly emphasized parameters for this particular purpose.
• The optimal interval for repeat echocardiography isn’t established and should be individualized based on subtype and treatment response.

Screening At-Risk Relatives

For relatives known to carry a pathogenic TTR variant, echocardiography — alongside CMR and bone scintigraphy — forms part of structured clinical surveillance, assessing pre-symptomatic carriers functionally over time. Current guidance recommends offering cardiac assessment within 10 years of the predicted age of onset for the specific variant involved — typically over age 50 for the two most common UK and Ireland variants, V142I and T80A.

Clinical Importance

Cardiac amyloidosis rewards recognizing a pattern rather than chasing a single sign — the granular texture once taught as diagnostic is now actively discouraged, concentric hypertrophy is the less reliable assumption in ATTR disease specifically, and a fully restrictive Doppler pattern is a late finding rather than an early one. What actually works is the combination: strain imaging in every patient with unexplained wall thickening, the ECG-echo voltage mismatch, disproportionate wall thickening in the context of low-flow low-gradient AS, and early tissue Doppler abnormality — assembled into a likelihood judgment that triggers the right downstream test, rather than a definitive diagnosis echocardiography was never positioned to make alone.