Treatment of hypertrophic cardiomyopathy caused by cardiospecific variants of Fabry disease with chaperone therapy.
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ABSTRACT:
SUBMITTER: Muntze J
PROVIDER: S-EPMC5963304 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Treatment of hypertrophic cardiomyopathy caused by cardiospecific variants of Fabry disease with chaperone therapy.
Müntze Jonas J Salinger Tim T Gensler Daniel D Wanner Christoph C Nordbeck Peter P
European heart journal 20180501 20
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Project description:Hypertrophic obstructive cardiomyopathy can be the phenotype of storage disorders as Fabry disease cardiomyopathy. In this instance, its recognition through GLA gene analysis and preventive administration of enzyme replacement therapy may reduce heart failure risk of surgical septal myectomy (SSM). A 59-year-old man was referred for SSM as dyspnoea and low threshold muscle fatigue associated to severe left ventricular outflow obstruction (gradient of 100 mmHg) due to both interventricular septal hypertrophy and mitral leaflet systolic anterior motion were not controlled by metoprolol 100 mg bid. Electrocardiogram showed sinus rhythm and a complete left bundle branch block. Cardiac magnetic resonance imaging showed a preserved left ventricular (LV) contractility (ejection fraction 70%) but failed to reveal reduced T1 mapping and fibrosis of postero-lateral LV wall suggesting Fabry disease cardiomyopathy. Cardiac catheterization and coronary angiography documented increased LV end-diastolic pressure but normal coronary arteries. SSM was followed by acute renal and heart failure with left ventricular ejection fraction declining to 35%. Histology of SSM showed regularly arranged severely enlarged cardiomyocytes containing extensive vacuoles that were intensely positive to immunofluorescence with anti-Gb3 antibodies and appeared at electron microscopy to consist of myelin bodies suggesting the diagnosis of FD. This entity was confirmed by low blood levels of alpha-galactosidase A (0.8 nmol/mL/h; NV > 1), high values of Lyso-Gb3 (5.85 nmol/L; NV < 2.3), and the presence of the pathogenic mutation c.644A>G in the exon 5 of GLA gene. This study emphasizes the importance of a genetic screening for FD before SSM be considered for hypertrophic obstructive cardiomyopathy.
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Project description:Based on evidence that FHL2 (four and a half LIM domains protein 2) negatively regulates cardiac hypertrophy we tested whether FHL2 altered expression or variants could be associated with hypertrophic cardiomyopathy (HCM). HCM is a myocardial disease characterized by left ventricular hypertrophy, diastolic dysfunction and increased interstitial fibrosis and is mainly caused by mutations in genes coding for sarcomeric proteins. FHL2 mRNA level, FHL2 protein level and I-band-binding density were lower in HCM patients than control individuals. Screening of 121 HCM patients without mutations in established disease genes identified 2 novel (T171M, V187L) and 4 known (R177Q, N226N, D268D, P273P) FHL2 variants in unrelated HCM families. We assessed the structural and functional consequences of the nonsynonymous substitutions after adeno-associated viral-mediated gene transfer in cardiac myocytes and in 3D-engineered heart tissue (EHT). Overexpression of FHL2 wild type or nonsynonymous substitutions in cardiac myocytes markedly down-regulated α-skeletal actin and partially blunted hypertrophy induced by phenylephrine or endothelin-1. After gene transfer in EHTs, force and velocity of both contraction and relaxation were higher with T171M and V187L FHL2 variants than wild type under basal conditions. Finally, chronic phenylephrine stimulation depressed EHT function in all groups, but to a lower extent in T171M-transduced EHTs. These data suggest that (1) FHL2 is down-regulated in HCM, (2) both FHL2 wild type and variants partially protected phenylephrine- or endothelin-1-induced hypertrophy in cardiac myocytes, and (3) FHL2 T171M and V187L nonsynonymous variants induced altered EHT contractility. These findings provide evidence that the 2 novel FHL2 variants could increase cardiac function in HCM.
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Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disease and is defined by otherwise unexplained left ventricular hypertrophy. The main complications include heart failure and arrhythmias such as atrial fibrillation and ventricular arrhythmias. Current treatment rests on septal reduction therapies, prevention of sudden cardiac death through implantable cardioverter defibrillator, and use of drugs such as beta-blockers, calcium antagonists, or amiodarone. In the last years, new pharmacological agents specifically targeting the pathophysiology of the disease have been developed with encouraging results in terms of functional capacity and symptoms improvement from clinical trials. In this review, we summarize the possible treatment approaches for each phase of the natural history of the disease: pre-phenotype expression, classic phenotype, adverse remodelling, and overt dysfunction.
| S-EPMC10132571 | biostudies-literature
Project description:Ultrasound myocardial cavitation-enabled treatment was applied to the SS-16BN rat model of hypertrophic cardiomyopathy for proof of the principle underlying myocardial reduction therapy. A focused ultrasound transducer was targeted using 10-MHz imaging (10 S, GE Vivid 7) to the left ventricular wall of anesthetized rats in a warmed water bath. Pulse bursts of 4-MPa peak rarefactional pressure amplitude were intermittently triggered 1:8 heartbeats during a 10-min infusion of a microbubble suspension. Methylprednisolone was given to reduce initial inflammation, and Losartan was given to reduce fibrosis in the healing tissue. At 28 d post therapy, myocardial cavitation-enabled treatment significantly reduced the targeted wall thickness by 16.2% (p?<0.01) relative to shams, with myocardial strain rate and endocardial displacement reduced by 34% and 29%, respectively, which are sufficient for therapeutic treatment. Premature electrocardiogram complexes and plasma troponin measurements were found to identify optimal and suboptimal treatment cohorts and would aid in achieving the desired impact. With clinical translation, myocardial cavitation-enabled treatment should fill the need for a new non-invasive hypertrophic cardiomyopathy therapy option.
| S-EPMC5960614 | biostudies-literature
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| S-EPMC4862597 | biostudies-literature
Project description:Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and β or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.
| S-EPMC10797794 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is a common myocardial disease characterized by otherwise unexplained left ventricular hypertrophy. The main cause of disabling symptoms in patients with HCM is left ventricular outflow tract (LVOT) obstruction. This phenomenon is multifactorial, determined both by anatomical and functional abnormalities: myocardial hypercontractility is believed to represent one of its major determinants. The anatomical anomalies are targeted by surgical interventions, whereas attenuating hypercontractility is the objective of old and new drugs including the novel class of allosteric myosin inhibitors. This review summarizes the current treatment modalities and discusses the emerging therapeutical opportunities focusing on the recently developed cardiac myosin ATPase inhibitors Mavacamten and CK-274. Novel surgical and interventional approaches are also discussed.
| S-EPMC7957690 | biostudies-literature
Project description:Enzyme replacement therapy (ERT) has been widely used for the treatment of Fabry disease, a rare X-linked recessive disorder due to absent or reduced activity of lysosomal enzyme ?-galactosidase A. It is still unclear why some patients under ERT show disease progression typically with renal, cardiovascular and cerebrovascular dysfunctions. Here, we investigated the involvement of drug absorption, distribution, metabolism, and excretion gene variants in response variability to ERT, genotyping 37 patients with the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET) Plus microarray. We found three single nucleotide polymorphisms in human alcohol dehydrogenase (ADH)4 gene (rs1126670, rs1126671, rs2032349) and one in ADH5 gene (rs2602836) associated with disease progression (p < 0.05). Our data provide a basic tool for identification of patient with ERT non-response risk that may represent a framework for personalized treatment of this rare disease.
| S-EPMC5746088 | biostudies-literature
Project description:Fabry disease is a progressive X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the α-galactosidase lysosomal enzyme. The partial or complete deficiency of the lysosomal enzyme leads to an accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues throughout the body. In the heart, glycosphingolipids deposition causes progressive left ventricular hypertrophy (LVH). We report a case of Fabry disease which was suspected based upon two-dimensional echocardiographic finding of LVH. A 44-year-old man was admitted to evaluation of aggravated exertional dyspnea of two weeks duration. He had been diagnosed with end-stage renal disease of unknown etiology at age 41 followed by renal transplantation that year. He had been treated with oral immunosuppressive agents. On hospital day two, transthoracic echocardiography revealed concentric LVH. Left ventricular systolic function was preserved but diastolic dysfunction was present. Fabry disease was confirmed by demonstration of a low plasma α-galactosidase A (α-Gal A) activity. Analysis of genomic DNA showed α-Gal A gene mutation. The patient was diagnosed with Fabry disease.
| S-EPMC3611116 | biostudies-literature
Project description:Fabry's disease is an X-linked lysosomal storage disease most often associated with renal dysfunction and death due to renal failure in patients' fourth and fifth decades of life. However, cardiac manifestations including arrhythmias, angina and heart failure are common and probably underrecognized. Furthermore, Fabry's disease is now recognised as also affecting female carriers, who manifest signs later than males. A variant of Fabry's has been identified that only affects cardiac tissue, which presents as an unexplained hypertrophy of the left ventricle in middle-aged patients, possibly with women more affected than men. Given that epidemiological studies report a prevalence of Fabry's cardiomyopathy among middle-aged patients with cardiac hypertrophy to be anywhere from one to 12%, it is reasonable to screen these patients for alpha-galactosidase A deficiency. Although mortality data is lacking from randomised, controlled trials of galactosidase replacement therapy, there are some reports of improvement in cardiac endpoints. Therefore patients with known Fabry's disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed.
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