A detailed pathologic examination of heart tissue from three older patients with Anderson–Fabry disease on enzyme replacement therapy

doi:10.1016/j.carpath.2009.05.003

Cardiovascular Pathology

Volume 19, Issue 5, September–October 2010, Pages 293-301

https://doi.org/10.1016/j.carpath.2009.05.003 Get rights and content

Abstract

Background

Cardiac disease causes considerable morbidity and mortality in men and women with Anderson–Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant.

Methods

A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed.

Results

In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts.

Conclusions

This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD.

Introduction

Anderson–Fabry disease (AFD) is an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Until quite recently, AFD was thought to be a rare disease, but studies in patients with unexplained left ventricular hypertrophy (LVH), renal failure, and cryptogenic stroke suggest that it is underdiagnosed in everyday clinical practice [1], [2], [3], [4]. The cardiac manifestations of AFD were first described over 30 years ago; yet, their significance in the natural history of this disease is still debated. Up to 60% of males with classic disease manifestations have cardiac abnormalities, including LVH, valvular dysfunction, and conduction abnormalities [5], [6]. Cardiac disease is also responsible for considerable morbidity and mortality in female heterozygotes, albeit at a later age than affected men [7], [8].

Disease manifestations are presumed to occur as the result of progressive accumulation of glycosphingolipid [predominantly globotriaosylceramide (Gb3)] within different cell types [9]; treatment with recombinant enzyme preparations is designed to attenuate and reverse this accumulation [10], [11]. In this study, we present a detailed examination of three whole hearts from patients with AFD that had received enzyme replacement therapy (ERT) prior to death. The findings highlight the pancardiac nature of the disease; demonstrate the extent of fibrotic changes; and report, for the first time, myocyte disarray, necrosis, and apoptosis. The implications of these findings for the timing and efficacy of ERT are discussed.

Section snippets

Patients

In all three patients, the diagnosis of AFD was made on the basis of low plasma α-galactosidase A activity and was confirmed on mutational analysis. Two patients were identified during screening of LVH. The third patient was diagnosed following renal transplantation. The study was approved by the ethics committee of the Royal Brompton Hospital, London, UK, and was supported by an unrestricted grant from Genzyme, USA.

Pathology

All three hearts were fixed in formalin. A transverse 1-cm-thick slice was

Case 1

This male was diagnosed during family screening for cardiac hypertrophy at the age of 52 years (plasma enzyme activity, 0.64 ng/ml; genotype: Del1223). His only cardiac symptom was palpitations. Echocardiography showed concentric LVH [maximal left ventricular wall thickness (MLVWT), 20 mm]. He was started on agalsidase-beta (Fabrazyme, Genzyme) ERT in June 2001 at a dose of 1 mg/kg 14q. In 2004, he developed end-stage renal failure. He died from sudden arrhythmic death in 2005, 4 years after

Discussion

This study shows that AFD is associated with Gb3 accumulation in all cellular components of the heart, including myocytes throughout the heart, conduction tissue, valvular tissue, endothelial cells, and vascular intimal and smooth muscle cells. The demonstration of extensive Gb3 accumulation and areas of replacement fibrosis in these older patients has major implications for the selection of patients for ERT.

References (31)

RolfsA et al.
Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study
Lancet
(2005)
LinhartA et al.
New insights in cardiac structural changes in patients with Fabry's disease
Am Heart J
(2000)
GoldmanME et al.
Echocardiographic abnormalities and disease severity in Fabry's disease
J Am Coll Cardiol
(1986)
PochisWT et al.
Electrophysiologic findings in Fabry's disease with a short PR interval
Am J Cardiol
(1994)
ShahJS et al.
Prevalence and clinical significance of cardiac arrhythmia in Anderson–Fabry disease
Am J Cardiol
(2005)
KotankoP et al.
Results of a nationwide screening for Anderson–Fabry disease among dialysis patients
J Am Soc Nephrol
(2004)
NakaoS et al.
An atypical variant of Fabry's disease in men with left ventricular hypertrophy
N Engl J Med
(1995)
SachdevB et al.
Prevalence of Anderson–Fabry disease in male patients with late onset hypertrophic cardiomyopathy
Circulation
(2002)
MehtaA et al.
Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey
Eur J Clin Invest
(2004)
MacDermotKD et al.
Anderson–Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males
J Med Genet
(2001)

MacDermotKD et al.

Anderson–Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females

J Med Genet

(2001)

LinhartA et al.

Cardiac manifestations of Anderson–Fabry disease: results from the international Fabry outcome survey

Eur Heart J

(2007)

LinhartA et al.

The heart in Anderson–Fabry disease and other lysosomal storage disorders

Heart

(2007)

SchiffmannR et al.

Enzyme replacement therapy in Fabry disease: a randomized controlled trial

JAMA

(2001)

EngCM et al.

Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry's disease

N Engl J Med

(2001)

Cited by (58)

Clinical and CMR characteristics associated with cardiac events in patients with Fabry disease
2023, International Journal of Cardiology
The assessment of late gadolinium enhancement (LGE) and left ventricular hypertrophy (LVH) by cardiac magnetic resonance (CMR) as diagnostic and prognostic maker in Fabry disease is advancing. We aimed to investigate the impact of clinical characteristics and CMR findings on cardiac outcome in patients with FD.
In this study 55 patients with genetically confirmed FD and available CMR imaging were included. The primary endpoint was defined as a composite of cardiac events including cardiac death, new occurrence of atrial fibrillation, heart failure, ventricular tachycardia and bradycardia requiring device insertion.
During a median follow-up of 4.9 years (IQR 3.7–5.9), 9 patients (16.3%) reached the primary cardiac end point. The global amount of LGE was associated with an increased risk for primary endpoint in the univariate analysis (HR 1.4 per 10% increase in LGE, p = 0.002). However maximal wall thickness (MWT) was the sole independent predictor of the primary endpoint in a stepwise logistic regression model (HR 9.8 per mm increase in MWT, p < 0.0001). Kaplan-Meier analysis revealed significant difference in event free survival rate between patients with and without LVH (Long-rank p = 0.006) and in patients with and without LGE (Long-rank p < 0.001). Patients without LVH and LGE were free of adverse cardiac events.
LVH and LGE detected by CMR were associated with adverse cardiac events in FD. In particular maximal wall thickness can be useful in cardiac risk stratification of FD patients.
Biventricular strain assessment indicates progressive impairment of myocardial contractility in phenotypically negative patients with Fabry's disease
2022, European Journal of Radiology
Citation Excerpt :
The central findings are that (1) FT-based LV and RV GLS can accurately discriminate between HV and phenotypically negative FD patients (absence of LVH and normal T1), and (2) RV-GLS proved to be non-inferior compared to LV strains in detecting FD and (3) a multiparametric approach including biventricular strains, T1 and LVMi was able to further increase diagnostic accuracy in early stages of FD. As previous studies have shown the involvement of RV in sphingolipid deposition [9,22], we hypothesized that such deposition within the thin RV walls might lead to early changes in RV motility with consecutively impaired RV strains. Supporting our hypothesis, significantly increased RVMi was detected already in group I FD patients, indicating the early involvement of the RV.
The accumulation of sphingolipids in Fabry's disease (FD) leads to left ventricular (LV) hypertrophy and shortened T1 in cardiac magnetic resonance (CMR). Early detection of myocardial involvement is essential for the timely initiation and efficacy of enzyme replacement therapy. However, there is a diagnostic gap between the onset of accumulation and detectable myocardial changes. This study aimed to evaluate the diagnostic value of biventricular strain assessment in early FD.
Genetically proven FD patients (n = 58) and healthy volunteers (HV, n = 62) who had undergone 3 T CMR were retrospectively identified and stratified into 3 groups according to disease severity. Biventricular volumetry, global longitudinal strains (GLS), indexed biventricular masses (RVMi/LVMi), and T1 were evaluated. Group comparisons were performed by ANOVA and diagnostic accuracy was evaluated by ROC-analysis.
The study population included 19 group I, 20 group II and 19 group III patients. LV volumetry and T1 showed no significant difference between early FD patients and HV (all p > 0.760). However, RVMi was increased, while RV-GLS and LV-GLS were significantly impaired (p = 0.024 and < 0.001, respectively). Biventricular strains accurately discriminated early FD patients and HV with RV-GLS being non-inferior to LV-GLS (AUC for both 0.83, p > 0.05). Adding strains to the established approach using T1 and LVMi further increased diagnostic accuracy (AUC 0.99, p < 0.05).
Biventricular strains may help detect altered myocardial deformation patterns in phenotypically negative FD patients. These findings may lead to an earlier initiation of therapy, which in turn may slow hypertrophy and the associated long-term risks.
Right ventricular strain in Anderson-Fabry disease
2021, International Journal of Cardiology
2D speckle tracking echocardiography (2DSTE) is superior to standard echocardiography in the assessment of subtle right ventricle (RV) systolic dysfunction. In this study we aimed to: 1) test the hypothesis that 2DSTE may unveil subtle RV systolic dysfunction in patients with Fabry disease; 2) investigate whether the physiologic difference between the 3-segment (RV-FWS) and the 6-segment (RV-GLS) RV strain (∆RV strain) is preserved in Fabry patients.
Standard echocardiography and 2DSTE were performed in 49 Fabry patients and 49 age- and sex-matched healthy controls. Fabry patients were divided in two groups according to the presence/absence of left ventricular hypertrophy (LVH+: left ventricular wall thickness > 12 mm, 49% of total Fabry patients). RV systolic function assessed by standard echocardiography was normal in the majority of Fabry patients (92%) while RV-GLS and RV-FWS were impaired in about 40%. RV-GLS and RV-FWS were significantly worse in patients LVH+ vs LVH- and vs controls (RV-GLS: LVH+ vs LVH-: −18.4 ± −4.3% vs −23.8 ± −3.1% p<0.001; LVH+ vs controls: −18.4 ± −4.3% vs −23.9 ± −2.8% p<0.001; RV-FWS: LVH+ vs LVH-: −21.8 ± −5.3% vs −26.7 ± −3.8% p = 0.002, LVH+ vs controls −21.8 ± −5.3% vs −26.8 ± −3.9% p<0.001). No difference was found between LVH- patients and controls in both RV-GLS (p = 0.65) and RV-FWS (p = 0.79). ∆RV strain was similar among the groups.
In Fabry cardiomyopathy impaired RV-GLS and RV-FWS is a common finding, while RV strain is preserved in Fabry patients without overt cardiac involvement. The physiologic difference between RV-FWS and RV-GLS is maintained in Fabry patients, regardless of the presence of cardiomyopathy.
Fabry disease patients have an increased risk of stroke in the COVID-19 ERA. A hypothesis
2020, Medical Hypotheses
Stroke is a severe and frequent complication of Fabry disease (FD), affecting both males and females. Cerebrovascular complications are the end result of multiple and complex pathophysiology mechanisms involving endothelial dysfunction and activation, development of chronic inflammatory cascades leading to a prothrombotic state in addition to cardioembolic stroke due to cardiomyopathy and arrhythmias. The recent coronavirus disease 2019 outbreak share many overlapping deleterious pathogenic mechanisms with those of FD and therefore we analyze the available information regarding the pathophysiology mechanisms of both disorders and hypothesize that there is a markedly increased risk of ischemic and hemorrhagic cerebrovascular complications in Fabry patients suffering from concomitant SARS-CoV-2 infections.
Atrial Dysfunction Assessed by Cardiac Magnetic Resonance as an Early Marker of Fabry Cardiomyopathy
2020, JACC: Cardiovascular Imaging
Massive accumulation of globotriaosylceramide in various tissues from a Fabry patient with a high antibody titer against alpha-galactosidase A after 6 years of enzyme replacement therapy
2020, Molecular Genetics and Metabolism Reports
Fabry disease is an X-linked metabolic disorder due to a pathogenic mutation of the GLA gene. The accumulation of globotriaosylceramide (Gb3) damages multiple organs, including the heart, kidney and nervous system, especially in classical type Fabry disease. Enzyme replacement therapy (ERT) using recombinant alpha-galactosidase A has been shown to remove Gb3 from organs and to improve the prognosis of Fabry disease. We herein report the case of a 67-year-old classical type Fabry patient who had been treated with ERT for 6 years and who continuously showed a high antibody titer against recombinant alpha-galactosidase A during therapy. A post-mortem examination was performed after sudden death. A histological examination revealed the massive accumulation of Gb3 in various organs, even after long term ERT. In addition to the typical pathological findings as reported in tissue biopsy samples, the serious accumulation of Gb3 in the cardiac conduction system and the endocrine system was detected. Since the start of ERT for this patient might be too late to improve organ damage and prognosis, ERT should be started before the appearance of major organ involvement for the effective elimination of Gb3 and changes in the therapeutic strategy might be considered if the patient shows a high antibody titer against recombinant alpha-galactosidase A.

View all citing articles on Scopus

: The study was approved by the ethics committee of the Royal Brompton Hospital, London, and UK and was supported by an unrestricted grant from Genzyme, USA.

: The total amount of funding received from Genzyme Corp for this project was £2000.

View full text

Original ArticleA detailed pathologic examination of heart tissue from three older patients with Anderson–Fabry disease on enzyme replacement therapy

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Pathology

Case 1

Discussion

Lancet

Am Heart J

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Results of a nationwide screening for Anderson–Fabry disease among dialysis patients

J Am Soc Nephrol

An atypical variant of Fabry's disease in men with left ventricular hypertrophy

N Engl J Med

Prevalence of Anderson–Fabry disease in male patients with late onset hypertrophic cardiomyopathy

Circulation

Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey

Eur J Clin Invest

Anderson–Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males

J Med Genet

Anderson–Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females

J Med Genet

Cardiac manifestations of Anderson–Fabry disease: results from the international Fabry outcome survey

Eur Heart J

The heart in Anderson–Fabry disease and other lysosomal storage disorders

Heart

Enzyme replacement therapy in Fabry disease: a randomized controlled trial

JAMA

Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry's disease

N Engl J Med

Original Article
A detailed pathologic examination of heart tissue from three older patients with Anderson–Fabry disease on enzyme replacement therapy