Evolving role of cardiac magnetic resonance in cardiac amyloidosis

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.