Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) in older adults, resulting from myocardial deposition of misfolded transthyretin (TTR) or pre-albumin. Characteristic patterns of echocardiography and cardiac magnetic resonance can strongly suggest the disease but are not diagnostic. The diagnosis can be made with noninvasive nuclear imaging when there is no evidence of a monoclonal protein. Amyloid fibril formation results from a destabilizing mutation in hereditary ATTR amyloidosis (hATTR) or from an aging-linked process in wild-type ATTR amyloidosis (wtATTR). Recent studies have suggested that up to 10% to 15% of older adults with HF may have unrecognized wtATTR. Associated features, including carpal tunnel syndrome and lumbar spinal stenosis, raise suspicion and may afford a means for early diagnosis. Previously treatable only by organ transplantation, pharmaceutical therapy that slows or halts ATTR-CM progression and favorably affects clinical outcomes is now available. Early recognition remains essential to afford the best treatment efficacy.

Keywords: amyloidosis; cardiomyopathy; transthyretin.

Central Illustration:. Transthyretin Cardiac Amyloidosis:

llustrates the present ad future of ATTR-CM with respect to epidemiology diagnostic approach and treatment.

Figure 1.. Pathobiology of ATTR:

The mechanism of TTR protein dissociation, misfolding and aggregation as amyloid fibrils is illustred with resultant end-organ dysfunction.

Figure 2.. Echocardiography in ATTR-CM:

Two patients genopositive for TTR Val122Ile : 73-year-old male patient in Panels A, B, and C. Panel A is a 4-chamber view with the corresponding longitudinal strain map in panel B. Panel C shows the map of all myocardial segments. Note the reduced global longitudinal strain (GLS) at −10.3% and apical sparing (> 2:1 apical:basal ratio or “cherry on top”) pattern. A 65-year-old male with Val122Ile genotype and hypertension (Tc^99m-PYP scan showing grade 1 uptake) is illustrated in Panels C, D, and E. the bullseye map shows the absence of apical sparing and GLS is normal at −21.6%.

Figure 3.. Cardiac MRI of ATTR-CM:

An 82 year old female with wtATTR-CM is illustrated in panels A and B and a 76 year old male with hypertension is illustrated in panels C and D. Phase sensitive inversion recovery (PSIR) late gadolinium enhancement (LGE) images taken in the 4-chamber plane are seen in panels A and C. Diffuse LGE (arrows) in ATTR-CM (panel A), but absence of LGE and normal myocardial signal suppression in HTN (panel C). Panels B and D show corresponding short axis extracellular volume fraction (ECV) maps taken at the mid-ventricle with regions of interest drawn over the septum. The ECV in panel B was 60% consistent with ATTR-CM, whereas the ECV in panel D was 27% (normal).

Figure 4.. Gross and histopathology of ATTR-CM:

Autopsy specimen reveals biventricular thickening, biatrial dilatation, and thickening of both mitral and tricuspid valves (A), hemotoxylin and eosin staining showing diffuse amyloid deposition (B), characteristic “apple green” birefringence on polarized light microscopy (C), and immunohistochemistry for typing of amyloid (D). Mass spectrometry (not illustrated) can also be peformed for typing and is considered the gold-standard. Reproduced with permission by the author.

Figure 5.. Nuclear imaging of ATTR-CM with bone avid tracers:

A typical patient with ATTR-CM is depicted with grade 3 tracer uptake on planar imaging (A), increased heart to contralateral chest ratio of 1.79 (B), and multiplanar single photon emission computed tomography (SPECT) showing myocardial (and not blood pool) tracer uptake, with some heterogeneity in uptake intensity. Coronary artery disease was excluded by angiography.

Figure 6.. Diagnostic algorithm for evaluation of suspected ATTR-CM:

A proposed flow diagram is illustrated demonstrating the critical requirement to exclude light-chain amyloidosis by serum/urine testing and concomitant use of of nuclear scintigraphy to identify the presence of ATTR-CM. It is emphasized that serum free light-chains and serum/urine immunofixation electrophoresis are the appropriate tests to exclude a monoclonal gammopathy, which also may be present in patients with ATTR-CM. Nuclear imaging can also be performed concurrent to light-chain assessment, even in the case of a detected monoclonal gammopathy, for additive information. IHC - immunohistochemistry; PYP, DPD, HMDP - Tc^99m associated tracers.

Figure 7.. Therapies available or in development to treat ATTR-CM:

Therapeutic strategies for ATTR-CM are illustrated with agents either presently approved, under review, or in development. * TTR silencers patisiran and inotersen are not presently approved for ATTR-CM but rather for hATTR polyneuropathy (with or without cardiomyopathy). ***The agent tafamidis is undergoing FDA review for an ATTR-CM indication. **Diflunisal may be used off-label in selected patients with ATTR-CM but only with careful monitoring. †Combination of doxycycline and tauro-deoxycholic acid can be used in conjunction with other strategies and is being evaluated in clinical trial. †† AG10, a TTR stabilizer, and PRX004, a monoclonal antibody that binds and potentially removes ATTR deposits, are both in development.