Incidence and Characterization of Concealed Cardiac Amyloidosis Among Unselected Elderly Patients Undergoing Post-mortem Examination

Abstract

Background: The prevalence of cardiac amyloidosis (CA) is unknown. Aims and Methods: We sought to (a) determine the prevalence of CA in unselected patients ≥75 years undergoing autopsy, (b) characterize cardiological profiles of CA and non-CA patients by providing clinical-histological correlations, and (c) compare their cardiological profiles. After dedicated staining, the localization (interstitial or vascular) and the distribution (non-diffuse or diffuse) of amyloid deposition were analyzed. Cardiological data at last evaluation were retrospectively assessed for the presence of CA red-flags. Results: CA (50% light chains, 50% transthyretin) was found in 43% (n = 24/56) of the autopsied hearts. Atria were involved in 96% of cases. Amyloid localized both at the perivascular and interstitial levels (95.5 and 85%, respectively) with a slightly predominant non-diffuse distribution (58% of cases). Compared to the other patients, CA patients had a more frequent history of heart failure (HF) (79 vs. 47%, p = 0.014), advanced NYHA functional class (III-IV 25 vs. 6%, p = 0.047), atrial fibrillation (68 vs. 36%, p = 0.019), discrepancy between QRS voltage and left ventricular (LV) thickness (70 vs. 12%, p < 0.001), thicker LV walls (15 vs. 11 mm, p < 0.001), enlarged left atrium (49 vs. 42 mm, p = 0.019) and restrictive filling pattern (56 vs. 19%, p = 0.020). The presence of right ventricular amyloidosis seemed to identify hearts with a higher amyloid burden. Among the CA patients, >30% had ≥3 echocardiographic red-flags of disease. Conclusion: CA can be found in 43% of autopsied hearts from patients ≥75 years old, especially in patients with HF, LV hypertrophy and atrial fibrillation.

Keywords: amyloidosis; diagnosis; epidemiology; histology; light chain (AL) amyloidosis; red flags; transthyretin (ATTR) amyloidosis.

Figure 1

Gross evaluation of unfixed heart and histological characterization with dedicated staining. Left Top: massive cardiac hypertrophy of the left ventricle involving the subvalvular aortic region extending to the right ventricle, the papillary muscles and the inter-atrial septum. The heart exhibits a heterogeneous color with pale areas and faint yellowish tone. Bottom: increased atrial wall thickness with diffuse granulations on the endocardial surface and nodular deposits of amyloid. Right: left column (optical field 10×) and right column (optical field 20×): H&E, severe amyloid infiltration in the interstitium and vessels with degeneration of myocytes; Congo Red and polarized light microscope, Congo Red binding to amyloid fibrils showing the typical apple-green birefringence and revealing predominant interstitial infiltration; amyloid infiltration involves the interstitial space and vessel walls, including the sinoatrial nodal artery; IHC for TTR and FLCs, positivity of transthyretin (left, 40×) and immunoglobulin light chain Kappa (right, 20×) in advanced cases of cardiac amyloidosis. H&E, Hematoxylin and Eosin; FLCs, Free Light Chains; IHC, Immunohistochemistry; TTR, Transthyretin.

Figure 2

Study design. Flow-chart showing selection of the final population.

Figure 3

Prevalence of CA (any site) at autopsy according to age at death. %, percentage; CA, Cardiac Amyloidosis.

Figure 4

Localization and severity of amyloid deposition in the patients with CA. The number of patients with no (none), mild, moderate or severe interstitial and vascular amyloid is shown. Patients with only vascular deposition (red), only interstitial (blue), or mixed (green) deposition are illustrated. Sex [male (M) or female (F)] of patients with moderate and severe deposition is provided.