Treatment of hypertrophic cardiomyopathy caused by cardiospecific variants of Fabry disease with chaperone therapy

Müntze, Jonas; Salinger, Tim; Gensler, Daniel; Wanner, Christoph; Nordbeck, Peter

doi:10.1093/eurheartj/ehy072

Cited by 15 publications

(13 citation statements)

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“…Pathophysiological explanation might be provided in a current study using cMRI T2 mapping, showing that (chronic) inflammation might contribute to the development of LE in FD 28. In line with these findings, we could just recently show that LE is not necessarily progressive, but might even regress slightly under appropriate therapy 29. These observations might not be specific or limited to FD, since similar phenomena were evidenced recently also in patients with aortic stenosis undergoing aortic valve replacement 30…”

Section: Discussionsupporting

confidence: 89%

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease

et al. 2018

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ObjectivesCurrent guidelines highlight important therapy implications of cardiac fibrosis in patients with Fabry disease (FD). However, association between morphological and functional impairments with cardiac fibrosis in hereditary cardiomyopathies remains elusive. We investigated the association between echocardiography-determined cardiac dysfunction and cardiac MRI (cMRI)-detected myocardial fibrosis (late gadolinium enhancement, LE) in patients with FD with preserved left ventricular ejection fraction (≥50%).Methods146 patients with FD (aged 39±14 years, 57 men) were analysed, all receiving echocardiography and cMRI within a 1 week interval. Longitudinal systolic strain (LS_sys), strain rate (LSr_sys) and diastolic strain rate (LSr_E/LSr_A) were assessed using speckle-tracking imaging. Receiver operating characteristic (ROC) analysis was performed to identify the diagnostic performance of various markers for LE.ResultsLE was detected in 57 (39%) patients with FD. LV wall thickness, left atrial volume, septal E/e′, diastolic dysfunction grade, global LS_sys and E/LSr_E, mid-lateral LS_sys and LSr_E, as well as N-terminal pro-brain natriuretic peptide were all associated with LE independent of age, sex, body mass index, New York Heart Association functional class and kidney function. In ROC curve analysis, septal E/e′ performed best (area under the curve=0.86, 95% CI=0.79 to 0.92). Septal E/e′>14.8 was strongly associated with LE (specificity=97.8% and sensitivity=49.1%). In 9% of patients, localised LE was present even though no other cardiac or kidney abnormalities were detected.ConclusionsEchocardiography-derived diastolic dysfunction is closely linked to LE in FD. Septal E/e′ ratio is the best echocardiographic marker suggestive of LE. Diastolic dysfunction is not a prerequisite for LE in FD, since LE can be detected in the absence of measurable cardiac functional impairments.Trial registration numberClinicalTrials.gov Identifier (NCT03362164).

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Section: Discussionsupporting

confidence: 89%

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease

et al. 2018

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“…This currently degrades the actual clinical relevance of the value that should be solved by additional examinations in a higher number of patients (including cardiac magnetic resonance imaging and other advanced techniques), which is planned for the medium‐term future. This will allow confirmation of the actual trend of myocardial mass reduction and can increase our understanding of our current clinical findings . In the past, both hs‐troponin T and NT‐ProBNP have been described as useful clinical markers for predicting cardiac involvement in patients with FD .…”

Section: Discussionmentioning

confidence: 82%

“…This will allow confirmation of the actual trend of myocardial mass reduction and can increase our understanding of our current clinical findings. 27 In the past, both hs-troponin T and NT-ProBNP have been described as useful clinical markers for predicting cardiac involvement in patients with FD. 28,29 ERT did not lead to substantial changes in either of these biomarkers.…”

Section: Cardiac Biomarkers and Myocardial Mass Indexmentioning

confidence: 99%

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Müntze

Gensler

Maniuc

et al. 2019

Clin Pharma and Therapeutics

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Long‐term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single‐center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open‐label migalastat therapy, patients showed significant changes in alpha‐galactosidase‐A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m 2 ; P = 0.037), and serum creatinine (0.94–1.0 mg/ dL ; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m 2 ; P = 0.012). The enzymatic increase correlated with myocardial mass reduction ( r = −0.546; P = 0.044) but not with renal function ( r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy‐naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme‐replacement therapy. These first real‐world data show that migalastat substantially increases alpha‐galactosidase‐A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.

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“…In real world conditions, Muntze et al reported one patient with an improvement of LV mass, LGE, troponin, and NT-proBNP after 12 months of treatment with migalastat [ 53 ]. Later, the same authors showed that, in 14 patients treated with migalastat for 1 year, LV mass index significantly decreased, while plasma lyso-GB3 significantly decreased in naïve patients and remained stable in patients switched from ERT.…”

Section: Migalastatmentioning

confidence: 99%

Fabry Disease Therapy: State-of-the-Art and Current Challenges

Azevedo

Gago

Miltenberger-Miltényi

et al. 2020

IJMS

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Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.

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Treatment of hypertrophic cardiomyopathy caused by cardiospecific variants of Fabry disease with chaperone therapy

Cited by 15 publications

References 0 publications

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Fabry Disease Therapy: State-of-the-Art and Current Challenges

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