Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week.

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.

Characteristics of Vascular Phenotype in Fabry Patients.

Fabry disease is a rare X-linked lysosomal disorder. Alpha-galactosidase A deficiency caused by mutation leads to accumulation of glycosphingolipids predominantly in endothelial cells, leading to impairment of vascular wall morphology and function. We assessed vascular wall hypertrophy (carotid artery intima-media thickness, cIMT), endothelial function (brachial artery flow-mediated dilation, FMD), presence of atherosclerotic plaques in the carotid and femoral arteries, and levels of endothelial adhesion and inflammatory biomarkers in 33 Fabry patients compared with 66 healthy matched controls. Fabry patients had thicker cIMT (0.07 ± 0.02 vs 0.06 ± 0.02 cm; P = .021), as well as dilated common carotid arteries (0.80 ± 0.12 vs 0.70 ± 0.06 cm; P < .001), and aortic annulus than controls (3.07 ± 0.48 vs 2.7 ± 0.48 cm; P = .001). Flow-mediated dilation was reduced (4.48 ± 8.80 vs 10.67 ± 8.72%; P = .001) and atherosclerotic plaques were less present in Fabry patients (9.10% vs 43.94%; P < .001). Vascular cell adhesion molecule-1, interleukin-6, tumor necrosis factor α, and high-sensitivity CRP were significantly higher and E-selectin lower in Fabry patients. Our results suggest that a complex vascular phenotype is present in Fabry patients. This represents a challenge for further research that could have important clinical applications.

Matrix metalloproteinase-3 gene polymorphism (rs3025058) affects markers atherosclerosis in type 2 diabetes mellitus.

BACKGROUND: The study was designed to test the possible association between either polymorphisms of the matrix metalloproteinase-9 (MMP-9) gene (rs17576, rs3918242) or the MMP-3 5A/6A gene polymorphism (rs3025058) with markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The second aim of the study was to demonstrate an association between either the rs17576, rs3918242 or rs3025058 and subclinical markers of coronary artery disease in the same subset of patients with T2DM. PATIENTS AND METHODS: A total of 595 subjects with T2DM and 200 subjects without T2DM (control group) were enrolled in the prospective study. Subclinical markers of carotid atherosclerosis were assessed ultrasonographically. Additionally, in a subset of subjects with T2DM a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of all three polymorphisms (rs17576, rs3918242, rs3025058) was performed with real-time PCR systems. RESULTS: The comparison of atherosclerosis parameters was performed with regard to different genotypes of MMP-9 rs17576, rs3918242, and MMP-3 rs3025058 polymorphisms upon enrolment and during follow-up. In our study, we found an association between the MMP-3 rs3025058 and CIMT at the time of recruitment. Multiple linear regression analysis revealed the association of either the A- allele or the A- genotypes of the rs3025058 (MMP-3) with carotid intima media thickness (CIMT) progression in a 3.8-year follow-up. We demonstrated the effect of the rs3025058 on subclinical markers of coronary atherosclerosis (coronary calcium score, number of coronary arteries with more than 50 % stenosis, and presence of at least one vessel with more than 50 % stenosis). CONCLUSIONS: We found an association between the MMP-3 rs3025058 and subclinical markers of carotid (CIMT) and coronary atherosclerosis at the time of recruitment. Moreover, we demonstrated the effect of the MMP-3 rs3025058 on CIMT progression in the 3.8-year follow-up in patients with T2DM.

C-reactive protein as a marker of progression of carotid atherosclerosis in subjects with type 2 diabetes mellitus.

BACKGROUND: This prospective study was designed to evaluate the effect of inflammatory markers on the presence and progression of subclinical markers of carotid atherosclerosis in a 3.8-year follow-up period in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A total of 595 subjects with T2DM were enrolled. Subclinical markers of carotid atherosclerosis (carotid intima media thickness (CIMT), plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment and again after 3.8 years. Subjects with T2DM were divided into 2 groups according to the plasma high sensitive C-reactive protein (hs-CRP) levels (subjects with hs-CRP ≥ 2 mg/L and subjects with hs-CRP below 2 mg/L). RESULTS: Subjects with T2DM and hs-CRP levels ≥ 2 mg/L had higher CIMT in comparison with subjects with T2DM and hs-CRP levels below 2 mg/L, and higher incidence of plaques/unstable plaques in comparison with subjects with T2DM and hs-CRP levels below 2 mg/L. Multivariate logistic regression analysis found the association between the HDL cholesterol level and presence of plaques, whereas the inflammatory marker hs-CRP was not associated with subclinical markers of progression of carotid atherosclerosis. Multiple linear regression analysis found the association between the hs-CRP levels and either CIMT progression rate or a change in the number of sites with plaques in a 3.8-year follow-up. CONCLUSIONS: We demonstrated an association between the inflammatory marker hs-CRP and either CIMT or incidence of plaques/unstable plaques at the time of recruitment in Caucasians with T2DM. Moreover, we found the association between hs-CRP levels and either CIMT progression rate or a change in the number of sites with plaques in a 3.8-year follow-up in subjects with T2DM.

Polymorphism rs5498 of the ICAM-1 gene affects the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: Adhesion molecules are involved in the development of atherosclerosis. An increased level of the ICAM 1 molecule is associated with numerous inflammatory diseases including atherosclerosis of carotid arteries. The rs5498 (K469E) polymorphism of the ICAM-1 gene leads to an increase in the level of serum ICAM. We investigated the association between the rs5498 (K469E) polymorphism of the ICAM-1 gene and the progression of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). METHODS: The study included 595 patients with T2DM and 200 subjects in the control group without T2DM. The control examination was made 3.8 years after the initial examination. Indicators of atherosclerosis (carotid intima-media thickness (CIMT), total plaque sum and sum of the plaques thickness) were detected by ultrasound examination. Genetic analyses of the polymorphism rs5498 of the ICAM-1 gene were made by RT-PCR. RESULTS: The distribution of genotypes and frequencies of rs5498 polymorphism was not significantly different between the group with type 2 diabetes ( T2DM) and the control group. Genotype EE K469E polymorphism is associated with a statistically significant annual plaques growth. CONCLUSION: The EE genotype of the rs5498 of the ICAM-1 gene was associated with a more rapid progression of carotid atherosclerosis in patients with T2DM in comparison with other genotypes.