Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction

Abstract

Objectives: This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF).

Background: Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF.

Methods: Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy.

Results: The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size-adjusted heart weight (p = 0.04).

Conclusions: Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

Keywords: aging; amyloid; autopsy; diastole; heart failure with preserved ejection fraction; mass spectrometry-based proteomics; transthyretin.

Figure 1. Prevalence of left ventricular wtTTR amyloid in Control (n=131) and HFpEF (n=109) patients by age

Insert shows the prevalence of left ventricular wtTTR amyloid in males and females by age in Control (top insert panel) and HFpEF (bottom insert panel).

Figure 2. Semi-quantitative characterization of severity of amyloid deposition in sulfated alcian blue (SAB) stained left ventricular sections

Representative examples demonstrate the extent of interstitial (top panels) and vascular (bottom panels) amyloid deposition (green), assessed semi-quantitatively as mild, moderate or severe.

Figure 3. Site and severity of amyloid deposition in Control and HFpEF patients with wtTTR amyloid

The number of patients with no (none), mild, or moderate or severe (M–S) interstitial and vascular wtTTR amyloid is shown. Patients with only vascular deposition (red shading), only interstitial (blue shading) or mixed (grey shading) deposition are illustrated. Sex (M, male or F, female) of patients with M–S deposition is provided.

Figure 4. Assessment of LV fibrosis by whole-field digital microscopy and quantitative analysis in SAB-stained left ventricular (LV) sections

Representative examples of SAB-stained LV sections from HFpEF patients with mild (<5%), moderate (5–10%) and severe (>15%) myocardial fibrosis (ratio of total fibrosis area (deep red) to total tissue area (yellow)) are shown (top panels), along with the corresponding definition of fibrosis (magenta) and myocardial tissue (yellow) by the Definiens® analysis program (bottom panels). Details of the custom analysis algorithm are provided in the online supplement.

Figure 5. Prevalence of any or TTR amyloid at autopsy according to age at HFpEF diagnosis

Frequency of wtTTR amyloid by in patients diagnosed with HFpEF at age <65 (n=21), age 65–79 (n=53) or age ≥ 80 (n=35).