Progression of echocardiographic parameters and prognosis in transthyretin cardiac amyloidosis

Abstract

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly diagnosed disease. Echocardiography is widely utilized, but studies to confirm the value of echocardiography for tracking changes over time are not available. We sought to describe (i) changes in multiple echocardiographic parameters; (ii) differences in rate of progression of three predominant genotypes; and (iii) the ability of changes in echocardiographic parameters to predict prognosis.

Methods and results: We prospectively studied 877 ATTR-CM patients attending our centre between 2000 and 2020. Serial echocardiography findings at baseline, 12 months and 24 months were compared with survival. Overall, 565 patients had wild-type ATTR-CM and 312 hereditary ATTR-CM (201 with V122I; 90 with T60A). There was progressive worsening of structural and functional parameters over time, patients with V122I ATTR-CM showing more rapid worsening of left and right ventricular structural and functional parameters compared to both wild-type and T60A ATTR-CM. Among a wide range of echocardiographic analyses, including deformation-based parameters, only worsening in the degree of mitral (MR) and tricuspid regurgitation (TR) at 12- and 24-month assessments was associated with worse prognosis (change at 12 months: MR, hazard ratio 1.43 [95% confidence interval 1.14-1.80], p = 0.002; TR, hazard ratio 1.38 [95% confidence interval 1.10-1.75], p = 0.006). Worsening in MR remained independently associated with poor prognosis after adjusting for known predictors.

Conclusion: In ATTR-CM, echocardiographic parameters progressively worsen over time. Patients with V122I ATTR-CM demonstrate the most rapid deterioration. Worsening of MR and TR were the only parameters associated with mortality, MR remaining independent after adjusting for known predictors.

Keywords: Cardiomyopathy; Echocardiography; Prognosis; Progression; Restrictive.

Figure 1

Kaplan–Meier curves of mitral (MR) and tricuspid regurgitation (TR) progression from baseline to 12 months showing progression of ‘at least’ one or two grades.

Figure 2

Patients with mitral (MR) and tricuspid regurgitation (TR) with progression. Percentage of patients with MR and TR who progress at 12 and 24 months using progression of ‘at least’ one grade and progression of ‘at least’ two grades. *p = 0.001 for MR progression of ‘at least’ one grade from 12 to 24 months; p < 0.001 value for TR progression of ‘at least’ one grade from 12 to 24 months. **p = 0.058 for MR progression of ‘at least’ two grades from 12 to 24 months; p = 0.319 for TR progression of ‘at least’ two grades from 12 to 24 months.

Figure 3

Transthoracic echocardiogram in a patient with transthyretin amyloid cardiomyopathy: mitral valve. A 78‐year‐old lady with V122I‐associated hereditary transthyretin amyloidosis. (A) Two‐dimensional transthoracic echocardiographic parasternal long‐axis view of the mitral valve with both thickened and markedly shortened posterior mitral leaflet (red arrow). (B) Zoomed parasternal long‐axis view of the mitral valve in diastole where the posterior mitral leaflet appears to be completely ‘disappeared’ (red arrow). (C) Short‐axis view of the mitral valve in systole, confirming a short posterior mitral leaflet (red arrow) in early systole with eccentric posterior coaptation line. (D) Short‐axis view of the mitral valve in diastole, demonstrating the ‘disappeared’ posterior mitral leaflet as fixed and englobed into the posterior wall (red arrow).

Figure 4

Transthoracic echocardiogram in a patient with transthyretin amyloid cardiomyopathy: mitral and tricuspid valves. A 69‐year‐old lady with hereditary transthyretin amyloidosis associated with V122I TTR variant. (A) Two‐dimensional transthoracic echocardiographic four‐chamber view of both atrio‐ventricular valves, markedly thickened. Septal tricuspid valve leaflet (thick red arrow) and posterior mitral valve leaflet (thin red arrow) also appear restricted (reduced mobility). (B) Colour Doppler of moderate mitral regurgitation, posteriorly directed due to thickened and restricted posterior mitral valve leaflet. (C) Colour Doppler of extremely eccentric tricuspid regurgitation due to thickened and restricted septal tricuspid valve leaflet.

Figure 5

Histological appearances of the mitral and tricuspid valve. Native heart of a 44‐year‐old lady with hereditary transthyretin amyloid cardiomyopathy associated with the Ser23Asn variant. Left panel: Mitral valve posterior leaflet. (A–D) Amyloid deposits within the fibrous annulus (arrowheads). (A) Macroscopic specimen; (B) Azan Mallory (AM) trichrome, original magnification (OM) 25x; (C) AM trichome, OM 50x; (D) Congo red (CR) staining, OM 50x. (E–H) Fibrosis is increased and distributed along the ventricular side (G, asterisk); loose connective tissue rich in glycosaminoglycans evident in the atrial side (G, arrow). (E) Macroscopic specimen; (F) scanned slide; (G) AM trichrome, OM 25x; (H) AM trichrome, OM 25x. Middle panel: Macroscopic view of atrio‐ventricular valves with stiffened annulus, thickened leaflets, loss of normal scallop segmentation. Right panel: (A) Macroscopic specimen of the anterior leaflet of the tricuspid valve, which appears swollen and stiffened, due to numerous nodular amyloid deposits (B–D) (arrowheads) and fibrous tissue. Tendinous cords are markedly thickened (B, arrow). (E,F) The apex of papillary muscle indicates fibrosis in blue and multiple amyloid deposits (arrows). (B) Scanned slide; (C) AM trichrome, OM 25x; (D) CR staining, OM 25x; (E) AM trichrome, OM 25x; (F) CR staining, OM 25x.

Figure 6

Histological appearance of the mitral valve in wild‐type transthyretin amyloid cardiomyopathy (wtATTR‐CM). Native heart of a 64‐year‐old male with wtATTR‐CM. (A) Macroscopic specimen of mitral valve posterior leaflet. (B–E) Extensive amyloid deposits in both annulus (B,C, arrows) and valve cusp leaflet (D,E, asterisks). (F) Glycosaminoglycan pooling along the free edge (arrow). (B) Scanned slide; (C) Congo red staining (CR), original magnification (OM) 25x; (D) haematoxylin‐eosin, OM 25x; (E,F) CR staining, OM 25x.