Evolving role of cardiac magnetic resonance in cardiac amyloidosis

Table 1 Core cardiac magnetic resonance imaging tissue characterization parameters in cardiac amyloidosis

Parameter	Normal range	Cardiac amyloidosis	Clinical utility	Ref.	Strength of supporting evidence
Native T1 (1.5T)	Approximately 950-1000 ms	Markedly elevated, often > 1100-1150 ms	Among the highest sensitivity/specificity of any CMR marker; rises before LGE in early disease	[7,12]	Moderate-High, multiple concordant cohort studies and meta-analyses
Native T1 (3T)	Approximately 1200-1300 ms	Markedly elevated, often > 1300-1400 ms	Same diagnostic role; absolute thresholds are field-strength and sequence dependent	[7,12]	Moderate-High, multiple concordant cohort studies and meta-analyses
ECV	Approximately 25%-28%	Frequently > 40%, can exceed 50%-60%	Strongest single prognostic CMR parameter; tracks amyloid burden and treatment response	[8,9,11]	High, consistently the strongest single prognostic/diagnostic parameter across multiple meta-analyses
LGE pattern	Absent	Diffuse subendocardial → transmural; atrial, RV, valvular involvement	Historic diagnostic anchor; correlates with disease stage and biomarkers	[2,3,15]	High, long established diagnostic anchor across large cohorts
Native myocardial T2	Normal	Usually normal to mildly elevated unless acute decompensation	Helps exclude active myocarditis/edema as an LVH mimic	[13]	Low-Moderate, smaller, more heterogeneous evidence base, primarily single/few-centre studies

Normal and disease-range values shown are representative of published cohorts; absolute thresholds vary by scanner vendor, field strength, and mapping sequence and should be interpreted against each site’s local reference ranges. CMR: Cardiac magnetic resonance; LGE: Late gadolinium enhancement; ECV: Extracellular volume; RV: Right ventricle; LVH: Left ventricular hypertrophy.

Table 2 Comparison of different imaging modalities in cardiac amyloidosis

Modality	Sensitivity	Specificity	Cohort and reference standard	Primary role	Key limitation
Bone scintigraphy - Perugini grade ≥ 2[19]	90%	97%	1217 patients with suspected cardiac amyloidosis at specialist centres: 857 with histologically proven amyloid (374 by endomyocardial biopsy) and 360 with confirmed non-amyloid cardiomyopathy. Figures are for grade 2-3 uptake alone; adding a negative monoclonal screen raises specificity and positive predictive value to 100% (95%CI: 98.0-100). Addresses discrimination of ATTR from AL in patients already suspected of amyloidosis, not detection in an unselected population	Non-biopsy diagnosis of ATTR-CM	Valid only with negative serum and urine immunofixation and free light chains. Uptake of any grade is more sensitive (> 99%) but far less specific (86%), with false positives almost exclusively from AL-CA
Bone scintigraphy - pooled diagnostic accuracy, all tracers[20]	92.2% (95%CI: 89%-95%)	95.4% (95%CI: 77%-99%)	Bivariate meta-analysis of 6 studies comprising 529 patients with suspected cardiac ATTR. Differs from the row above because it pools unselected cohorts without the negative clonal screen requirement	Screening and diagnosis of ATTR-CM	Accuracy varies by tracer (DPD > PYP > HMDP); wide specificity confidence interval reflects few non-amyloid comparators; poor discriminator for AL-CA
CMR - ECV[21]	90%	91%	Meta-analysis of 18 diagnostic studies comprising 2015 patients	Diagnosis, quantification, prognostication, monitoring	Requires gadolinium; least validated in significant chronic kidney disease. Diagnostic odds ratio 84.6 (95%CI: 30.3-236.2), significantly higher than LGE
CMR - native T1 mapping[21]	87%	88%	Same meta-analysis as the row above; sensitivity and specificity did not differ significantly from LGE	Contrast-free diagnostic alternative	Vendor- and sequence-dependent (MOLLI/ShMOLLI/SASHA); absolute values are not interchangeable across field strengths
CMR - LGE[21]	85%	92%	Same meta-analysis as the two rows above; diagnostic odds ratio 20.1 (95%CI: 9.1-44.1) vs 84.6 (95%CI: 30.3-236.2) for ECV	Diagnosis, prognostication	Qualitative and pattern-based; myocardial nulling becomes difficult in advanced disease
Echocardiography - apical sparing of longitudinal strain[22]	72%	66%	544 patients with confirmed cardiac amyloidosis (375 ATTR, 169 AL) and 200 controls in whom amyloidosis was suspected but excluded, from 12 centres in 4 countries, plus 174 healthy subjects. Diagnosis by endomyocardial biopsy with mass spectrometry, or grade 2-3 Tc99-PYP uptake without monoclonal gammopathy; controls excluded by biopsy or by negative scintigraphy and light chains. Apical sparing ratio cut-off 1.67, AUC 0.74	First-line screening (widely available, low cost)	Specificity, rather than sensitivity, is the principal weakness: Apical sparing was present in 32% of clinically similar control patients and in 6% of healthy subjects, giving a negative predictive value of 0.50. Accuracy is further reduced in chronic kidney disease
Cardiac amyloid PET (11C-PiB, 18F-florbetapir/florbetaben)[23]	78% (91% for 11C-PiB)	95% (97% for 11C-PiB)	Derived from the PET subset of a meta-analysis of 31 articles comprising 37 studies and 2585 patients across CMR, SPECT and PET; the pooled PET figure is not drawn from all 31 articles	Emerging; AL-CA detection, particularly with negative or equivocal scintigraphy	Varies substantially by tracer; the best-performing tracer (11C-PiB) has a 20-minute half-life limiting routine use; not yet in guideline algorithms; no FDA-approved cardiac indication

ATTR-CM: Transthyretin amyloid cardiomyopathy; AL-CM: Immunoglobulin light-chain amyloid cardiomyopathy; ATTR: Transthyretin amyloidosis; AL: Immunoglobulin light-chain amyloidosis; CI: Confidence interval; DPD: ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid; PYP: ^99mTc-pyrophosphate; HMDP: ^99mTc-hydroxymethylene diphosphonate; CMR: Cardiac magnetic resonance; ECV: Extracellular volume; LGE: Late gadolinium enhancement; MOLLI: Modified Look-Locker inversion recovery; ShMOLLI: Shortened modified Look-Locker inversion recovery; SASHA: Saturation recovery single-shot acquisition; AUC: Area under the curve; PET: Positron emission tomography; ¹¹C-PiB: Carbon-11 Pittsburgh compound B; ¹⁸F: Fluorine-18; SPECT: Single-photon emission computed tomography; FDA: United States Food and Drug Administration.

Table 3 Simplified educational diagnostic and monitoring pathway incorporating cardiac magnetic resonance

Step	CMR finding	Next step
1 Unexplained LVH/HFpEF	Concentric LVH, reduced strain, small pericardial effusion	Proceed to tissue characterization
2 Tissue characterization	Diffuse subendocardial/transmural LGE + elevated native T1/ECV	High suspicion for cardiac amyloidosis
3 Subtype triage	Bone-avid tracer scintigraphy (Tc-99m PYP/DPD/HMDP) + serum/urine free light chains	Grade 2-3 uptake + negative clonal screen = ATTR (no biopsy needed); any clonal positivity requires hematologic work-up ± biopsy
4 Baseline severity/prognosis	Quantify ECV, LGE extent, strain, NT-proBNP/troponin	Risk-stratify and stage per ATTR or AL staging systems
5 Therapy and follow-up	Serial CMR (ECV) on disease-modifying therapy	Track treatment response; stable/falling ECV favors disease stabilization

CMR: Cardiac magnetic resonance; LVH: Left ventricular hypertrophy; HFpEF: Heart failure with preserved ejection fraction; LGE: Late gadolinium enhancement; ECV: Extracellular volume; ATTR: Transthyretin amyloidosis; Tc-99m: Technetium-99m; PYP: ^99mTc-pyrophosphate; DPD: 3,3-diphosphono-1,2-propanodicarboxylic acid; HMDP: Hydroxymethylene diphosphonate; NT-proBNP: N-terminal pro-B-type natriuretic peptide.