Cardiac Amyloidosis (Tc-99m-PYP/DPD/HMDP)
Noninvasive diagnosis of transthyretin cardiac amyloidosis with bone-avid tracers
Quick Answer
Bone-avid Tc-99m tracers (PYP in the US; DPD/HMDP in Europe) accumulate in transthyretin (ATTR) cardiac amyloid deposits, allowing noninvasive diagnosis without biopsy when interpreted correctly. Positivity is graded by the Perugini visual score (0–3) and the heart-to-contralateral (H/CL) ratio. Crucially, a positive scan is only diagnostic of ATTR after excluding a monoclonal protein (to rule out AL amyloidosis, which can also take up tracer). SPECT is mandatory to prove uptake is myocardial rather than blood pool or bone.
Definition
Cardiac amyloidosis is infiltration of the myocardial interstitium by misfolded amyloid fibrils, producing a restrictive/infiltrative cardiomyopathy. The two dominant cardiac types are transthyretin (ATTR) — wild-type (ATTRwt) or hereditary/variant (ATTRv) — and immunoglobulin light-chain (AL) amyloidosis. Bone-scintigraphy imaging specifically identifies ATTR.
Synonyms
ATTR cardiomyopathy (ATTR-CM); senile systemic amyloidosis (older term for ATTRwt); hereditary/familial (mutant) transthyretin amyloidosis (ATTRv); primary/light-chain (AL) amyloidosis; "PYP scan," "bone-tracer cardiac amyloid imaging."
Epidemiology
ATTRwt is increasingly recognized as an under-diagnosed cause of HFpEF in older adults, with a strong male predominance. ATTRv varies by inherited TTR variant and ancestry (e.g. the V122I variant carried by a meaningful fraction of people of West-African descent; endemic V30M in some populations). AL amyloidosis is rarer but rapidly progressive and is a plasma-cell disorder. Wider availability of bone-tracer imaging has driven a large rise in ATTR diagnoses.
Etiology & Genetics
- ATTRwt: age-related misfolding of normal transthyretin (no mutation).
- ATTRv: autosomal-dominant TTR point mutations (e.g. V122I, V30M, T60A) — genetic testing defines the variant, informs phenotype (cardiac vs neuropathic), and enables family screening.
- AL: a clonal plasma-cell dyscrasia producing amyloidogenic light chains (linked to MGUS/myeloma) — a hematologic, not genetic, cause.
Pathophysiology
Misfolded precursor proteins (transthyretin tetramer dissociation in ATTR; free light chains in AL) deposit as β-pleated-sheet amyloid in the interstitium, increasing wall thickness and stiffness → restrictive physiology, diastolic dysfunction, and low-flow/low-gradient states. Conduction-system infiltration causes AV block/arrhythmia. Bone-tracer avidity in ATTR is thought to relate to microcalcification associated with the deposits (greater in ATTR than AL, though AL can still be avid).
Histopathology
Congo-red staining shows apple-green birefringence under polarized light; immunohistochemistry/mass spectrometry types the fibril (ATTR vs AL vs others) — essential when imaging/screening is discordant. Endomyocardial (or surrogate fat-pad) biopsy is reserved for cases not resolved noninvasively.
Clinical Presentation
Heart failure with preserved ejection fraction (HFpEF), exertional dyspnea, and, later, low-output symptoms. Characteristic "red flags": unexplained increased wall thickness with low-voltage ECG (discordance), bilateral carpal-tunnel syndrome and lumbar spinal stenosis (ATTR, often preceding cardiac disease), peripheral/autonomic neuropathy (ATTRv, AL), intolerance of standard heart-failure drugs (ACE inhibitors/beta-blockers), and unexplained AV block. AL may show periorbital purpura, macroglossia, and renal/multi-organ involvement.
Laboratory Findings
- Monoclonal-protein screen — mandatory: serum and urine immunofixation and serum free light chains (κ/λ ratio). This defines whether a positive scan means ATTR.
- Cardiac troponin and NT-proBNP (prognosis/staging).
- Genetic TTR testing to separate ATTRwt from ATTRv (and enable family screening).
Imaging Findings by Modality
- Echocardiography: increased wall thickness, granular/sparkling myocardium, biatrial enlargement, restrictive filling, and characteristic apical-sparing ("cherry-on-top") longitudinal-strain pattern.
- Cardiac MRI: diffuse subendocardial/transmural late gadolinium enhancement, abnormal gadolinium kinetics, and elevated native T1 and extracellular volume (ECV).
- Bone-tracer SPECT (Tc-99m-PYP/DPD/HMDP): myocardial uptake grading and quantification — the ATTR-specific test.
- Amyloid PET (investigational): ¹⁸F-florbetapir/-benzothiazole ligands can bind cardiac amyloid (including AL), a research avenue.
Radiopharmaceutical Uptake Mechanisms
Bone-avid diphosphonates/pyrophosphate localize to ATTR myocardial deposits (probably via associated microcalcification), giving greater and more consistent uptake in ATTR than AL. Because AL can also be avid, imaging is diagnostic for ATTR only with a negative monoclonal screen. SPECT discriminates true myocardial uptake from residual blood pool and overlying rib/sternum.
Typical SPECT / PET Tracers
| Tracer | Role |
|---|---|
| ⁹⁹ᵐTc-PYP (US) | ATTR cardiac imaging (planar + SPECT), 1 h ± 3 h |
| ⁹⁹ᵐTc-DPD / HMDP (Europe) | ATTR cardiac imaging equivalent |
| (research) ¹⁸F-amyloid PET | Binds cardiac amyloid incl. AL (investigational) |
Protocol (Step by Step)
- Screen for a monoclonal protein (serum/urine immunofixation, serum free light chains) — first or in parallel; this is not optional.
- Inject Tc-99m-PYP (or DPD/HMDP); image at 1 hour (± 3 hours per local protocol).
- Acquire planar chest images and SPECT (or SPECT/CT) — SPECT is required to prove uptake is myocardial, not blood pool or overlying rib.
- Grade visually (Perugini 0–3) and quantify the H/CL ratio.
- Integrate with echo/CMR and the monoclonal screen for the final diagnosis.
Perugini Visual Grade
| Grade | Cardiac uptake vs bone (ribs) |
|---|---|
| 0 | No cardiac uptake (normal bone uptake) |
| 1 | Cardiac uptake less than bone |
| 2 | Cardiac uptake equal to bone |
| 3 | Cardiac uptake greater than bone, with mild/absent bone uptake |
Grade 2–3 with a negative monoclonal screen is highly specific for ATTR; grade 1 is equivocal and needs further evaluation.
Heart-to-Contralateral (H/CL) Ratio
A circular ROI over the heart is divided by a mirror-image ROI over the contralateral chest. H/CL ≥ 1.5 at 1 hour supports ATTR; a lower cutoff (~1.3) applies at 3 hours as blood pool clears. Grade 2–3 uptake with a negative monoclonal screen is reported (Gillmore) as > 99% specific for ATTR cardiac amyloidosis. SPECT confirmation is decisive when planar/quantitative results are borderline or blood pool is retained.
Therapy Indications
Confirmed ATTR-CM is treated by cardiology with disease-modifying therapy: TTR stabilizers (tafamidis — the ATTR-ACT trial showed reduced mortality/hospitalization; acoramidis), and TTR gene silencers/knockdown (patisiran, vutrisiran, and emerging CRISPR approaches), plus heart-failure and arrhythmia management. AL amyloidosis requires urgent plasma-cell-directed therapy (a hematologic emergency). Nuclear medicine's role is accurate, timely diagnosis and grading.
Differential Diagnosis
- AL amyloidosis (can be tracer-avid; a positive scan with a positive monoclonal screen mandates biopsy/typing — never an ATTR label).
- Hypertensive / hypertrophic cardiomyopathy and other causes of increased wall thickness.
- Blood-pool retention (early imaging, renal failure) and rib/sternal overlap — false-positive planar appearances resolved by SPECT.
- Prior myocardial infarction (dystrophic calcification) as a focal mimic.
Reporting Checklist
- State the monoclonal-protein screen result — a positive-uptake scan is not ATTR-diagnostic without it.
- Report Perugini grade, H/CL ratio (with timing), and explicit SPECT confirmation of myocardial (not blood-pool/bone) uptake.
- Note blood-pool retention, rib overlap, or prior-MI calcification if present.
- Integrate echo/CMR red flags and recommend genetic TTR testing to separate ATTRwt from ATTRv.
Prognosis
ATTR-CM is progressive but its trajectory has improved with disease-modifying therapy, making early diagnosis high-impact. Staging systems combine NT-proBNP and troponin (± eGFR). Untreated AL cardiac amyloidosis has a poor short-term prognosis and demands urgent hematologic treatment — one reason the monoclonal screen is non-negotiable.
Board Pearls
Bone-tracer cardiac uptake is only diagnostic of ATTR after excluding a monoclonal gammopathy (serum/urine immunofixation + serum free light chains) — AL amyloidosis can also be avid, and mislabeling AL as ATTR is dangerous. Grade 2–3 uptake + negative monoclonal screen ≈ ATTR without biopsy (> 99% specific).
SPECT is non-negotiable: it separates true myocardial uptake from blood pool and rib/sternal activity that confound planar images.
Quantify with the H/CL ratio (≥ 1.5 at 1 h; ~1.3 at 3 h) alongside the Perugini grade, and beware early-imaging blood-pool retention (renal failure) and prior-MI dystrophic calcification as pitfalls. Confirmed ATTR is now treatable (tafamidis/acoramidis stabilizers; patisiran/vutrisiran silencers) — so an accurate, timely scan changes management, and genetic testing separates ATTRwt from hereditary ATTRv for family screening.
Related Pages
- Tracer: Tc-99m-PYP (labeling, imaging protocol, blood-pool caveat).
- Related cardiac: Cardiac sarcoidosis and nuclear cardiology overview.
- Pitfalls: Pearls, pitfalls & normal variants.
Figure / Diagram Suggestions
- A diagnostic algorithm: HFpEF + red flags → PYP + monoclonal screen → grade/H-CL → ATTR vs (screen-positive) biopsy/typing.
- The Perugini 0–3 visual-grade plate (cardiac vs rib uptake).
- Planar vs SPECT teaching pair showing blood-pool mimicry resolved by SPECT.
Common Pitfalls
- A negative bone-tracer scan does not exclude AL amyloidosis — AL is often non-avid or only faintly avid, so cardiac amyloidosis can still be present; pursue biopsy/typing if clinical suspicion remains high.
- Grade 1 uptake is equivocal, not negative — SPECT is needed to decide whether faint activity is truly myocardial; dismissing it as normal can miss early ATTR.
- Applying the 1-hour H/CL cutoff (~1.5) to 3-hour images (or vice versa) — thresholds differ because blood pool clears over time.
- Poor contralateral ROI placement or inclusion of sternal/rib activity can spuriously inflate the H/CL ratio.
- Focal mimics such as recent rib fracture, valvular calcification, or overlying breast/soft-tissue attenuation distorting the visual grade.
Self-Check (Board-Style)
Q1. A grade-3 PYP scan is obtained. What single result must be checked before diagnosing ATTR, and why?
Answer: The monoclonal-protein screen (serum/urine immunofixation + serum free light chains). AL amyloidosis can also take up tracer; a positive screen mandates biopsy/typing rather than an ATTR label.
Q2. Planar images suggest cardiac uptake but SPECT shows the activity is in the blood pool and overlying ribs. Interpretation?
Answer: This is a false-positive planar appearance — SPECT (mandatory) shows the uptake is not myocardial. Retained blood pool (e.g. early imaging/renal failure) is a classic cause.
Q3. What does Perugini grade 2 with a negative monoclonal screen indicate?
Answer: Findings consistent with ATTR cardiac amyloidosis — grade 2–3 with a negative screen is highly specific (>99%) and can establish ATTR without biopsy.
Q4. Why has accurate ATTR diagnosis become higher-stakes in recent years?
Answer: ATTR-CM is now treatable with disease-modifying therapy (TTR stabilizers like tafamidis/acoramidis and silencers like patisiran/vutrisiran), so timely noninvasive diagnosis directly changes management and outcomes.
Evidence & sources
https://nuc.med/cardiac-amyloidosis/ Report an issue