No abstract

No abstract

Anderson-Fabry disease (AFD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme α-galactosidase A (α-Gal A). Anderson-Fabry cardiomyopathy is characterized by structural, valvular, vascular and conduction abnormalities, and is now the most common cause of mortality in patients with AFD. Large-scale metabolic and genetic screening studies have revealed AFD to be prevalent in populations of diverse ethnic origins, and the variant form of AFD represents an unrecognized health burden. Anderson-Fabry disease is an X-linked disorder, and genetic testing is critical for the diagnosis of AFD in women. Echocardiography with strain imaging and cardiac magnetic resonance imaging using late enhancement and T1 mapping are important imaging tools. The current therapy for AFD is enzyme replacement therapy (ERT), which can reverse or prevent AFD progression, while gene therapy and the use of molecular chaperones represent promising novel therapies for AFD. Anderson-Fabry cardiomyopathy is an important and potentially reversible cause of heart failure that involves LVH, increased susceptibility to arrhythmias and valvular regurgitation. Genetic testing and cardiac MRI are important diagnostic tools, and AFD cardiomyopathy is treatable if ERT is introduced early.

BackgroundVarious pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).Methods and ResultsThis study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.ConclusionsInflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease ( FD ). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and healthy controls (n=40). Plasma levels of the following markers of inflammation and cardiac remodeling were determined: tumor necrosis factor ( TNF ), TNF receptor 1 ( TNFR 1) and 2 ( TNFR 2), interleukin‐6, matrix metalloprotease‐2 ( MMP ‐2), MMP ‐8, MMP ‐9, galectin‐1, galectin‐3, B‐type natriuretic peptide ( BNP ), midregional pro–atrial natriuretic peptide ( MR ‐pro ANP ), and globotriaosylsphingosine. Clinical profile, cardiac magnetic resonance imaging, and echocardiogram were reviewed and correlated with biomarkers. Patients with FD had elevated plasma levels of BNP , MR ‐pro ANP , MMP ‐2, MMP ‐9, TNF , TNFR 1, TNFR 2, interleukin‐6, galectin‐1, globotriaosylsphingosine, and analogues. Plasma TNFR 2, TNF , interleukin‐6, MMP ‐2, and globotriaosylsphingosine were elevated in FD patients with left ventricular hypertrophy, whereas diastolic dysfunction correlated with higher BNP , MR ‐pro ANP , and MMP ‐2 levels. Patients with late gadolinium enhancement on cardiac magnetic resonance imaging had greater levels of BNP , MR ‐pro ANP , TNFR 1, TNFR 2, and MMP ‐2. Plasma BNP , MR ‐pro ANP , MMP ‐2, MMP ‐8, TNF , TNFR 1, TNFR 2, galectin‐1, and galectin‐3 were elevated in patients with renal dysfunction. Patients undergoing enzyme replacement therapy who have more severe disease had higher MMP ‐2, TNF , TNFR 1, TNFR 2, and globotriaosylsphingosine analogue levels. ...

No abstract

Aims Anderson–Fabry disease (AFD) is an important X‐linked metabolic disease resulting in progressive end‐organ involvement, with cardiac disease being the dominant determinant of survival in a gender‐dependent manner. Recent epidemiological screening for AFD suggests the prevalence is much higher than previously recognized, with estimates of 1:3000. Our aim was to discover novel plasma biomarker signatures in adult patients with AFD. Methods and results We used an unbiased proteomic screening approach to discover novel plasma biomarker signatures. In the discovery cohort of 46 subjects, 14 healthy controls and 32 patients with AFD, we used a mass spectrometry iTRAQ proteomic approach followed by multiple reaction monitoring (MRM) assays to identify biomarkers. Of the 38 protein groups discovered by iTRAQ, 18 already had existing MRM assays. Based on MRM, we identified an eight‐protein biomarker panel (22 kDa protein, afamin, α1 antichymotrypsin, apolipoprotein E, β‐Ala His dipeptidase, haemoglobin α‐2, isoform 1 of sex hormone‐binding globulin, and peroxiredoxin 2) that was very specific and sensitive for male AFD patients. In female AFD patients, we identified a nine‐marker panel of proteins with only three proteins, apolipoprotein E, haemoglobin α‐2, and peroxiredoxin 2, common to both genders, suggesting a gender‐specific alteration in plasma biomarkers in patients with AFD. The biomarkers were validated in plasma samples from 48 subjects using MRM, and they performed inferiorly in patients with heart failure. Conclusions We have identified gender‐specific plasma protein biomarker panels that are specific and sensitive for the AFD phenotype. The gender‐specific panels offer important insight into potential differences in pathophysiology and prognosis between males and females with AFD.

No abstract