Abdallah Fayssoil

Les myopathies d’origine génétique sont des pathologies musculaires en rapport avec des anomalies génétiques. Les myopathies sont à l’origine d’un handicap physique majeur et affectent souvent la fonction respiratoire et parfois le cœur. Nous nous sommes intéressés à la caractérisation myocardique de 4 types de myopathies d’origine génétique à l’aide de l’échocardiographie Doppler : myopathie de Duchenne, sarcoglycanopathies, MELAS syndrome et maladie de Pompe.Nous avons analysé la fonction cardiaque dans 2 modèles murins de dystrophies musculaires: la souris mdx et la souris sgca null. En clinique, nous avons analysé la fonction cardiaque des sujets atteints de myopathie de Duchenne, de sarcoglycanopathies, de MELAS syndrome et de maladie de Pompe en échocardiographie Doppler.Dans les modèles animaux, nous avons retrouvé des anomalies myocardiques chez la souris mdx et chez la souris sgca null. Chez l’homme, l’atteinte myocardique est sévère chez les sujets atteints de myopathie de Duchenne et certains patients présentent un asynchronisme ventriculaire soulevant les indications éventuelles de resynchronisation myocardique. Les sujets atteints de gamma sarcoglycanopathies présentent de façon significative des anomalies de contraction du ventricule gauche comparativement aux sujets atteints d’alpha-sarcoglycanopathies. La fonction ventriculaire droite et gauche est préservée chez les sujets atteints de maladie de Pompe. Les sujets atteints de MELAS présentent des hypertrophies du ventricule gauche. L’analyse génétique retrouve une corrélation significative entre le taux d’hétéroplamie et la survenue d’événements cliniques.

Muscular dystrophies can affect the heart and the respiratory system. Right ventricular‒pulmonary artery (RV‒PA) coupling may reflect right ventricular adaptation to respiratory status. Since RV function is very sensitive to afterload, evaluating RV function coupled with pulmonary circulation is more relevant for assessing clinical issues in patients. The aim of this study was to assess the prognostic value of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP), an index of RV–PA coupling, in patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and sarcoglycanopathies. The study included retrospectively, from 2015 to 2023, patients with DMD, BMD and sarcoglycanopathies, who were followed in Pitié-Salpêtrière Hospital and Raymond-Poincaré Hospital (France) and who benefited from echocardiography that included a measurement of TAPSE/sPAP. The primary goal was to assess the prognostic value of the TAPSE/sPAP in terms of predicting cardiac events. The study included 113 patients (median age 28 years): DMD (n = 60, 53%), BMD (n = 33, 29%) and sarcoglycanopathies (n = 20, 18%). Home mechanical ventilation was present in 51 patients (46%), and 69% of the patients were wheelchair bound. Left ventricular systolic dysfunction (LVEF < 50%) was present in 37% of the patients. The median sPAP was 22 mmHg [19–27], whereas the median TAPSE was 16 mm [13–18]. Using a Cox model, we found that the TAPSE/sPAP*10 was significantly associated with cardiac events; the higher the TAPSE/sPAP, the better was the outcome (HR 0.33, 95% CI [0.16–0.69], p 0.003). According to the Youden criterion, the cutoff TAPSE/sPAP*10 was 5.3 mm/mmHg. RV–PA coupling, defined by the TAPSE/sPAP, may be a prognostic biomarker in patients with muscular dystrophies.

Background: Respiratory muscle function can be affected in patients with heart failure. Ultrasound can be used to assess diaphragm, the main inspiratory muscle. Speckle tracking imaging is an imaging technology providing the evaluation of tissue deformation during contraction. We aimed to evaluate the contribution of traditional echography and 2D speckle tracking imaging in the evaluation and monitoring of patients with acute heart failure (AHF). Case summary: We report a series of four cases of AHF. Diaphragm ultrasound coupled with diaphragm 2D speckle tracking imaging was performed at admission and after decongestive therapy, in cardiac intensive care unit. Patients, at admission, disclosed higher diaphragm 2D strain value and higher diaphragm inspiratory motion value in the context of higher cardiac loading that significantly decrease after decongestive therapy, except for one patient. Diaphragm motion remained less than 10 mm (weakness), despite medical therapy in Cases 2, 3, and 4. Among them, 3 months later, one patient (Case 3) experienced an episode of AHF. Discussion: Diaphragm ultrasound coupled with diaphragm 2D speckle tracking imaging is feasible and may be used to monitor respiratory status patients with AHF.

Background: Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results: We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow‐up with an odds ratio of 4.5 ( P =0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09–22.6]; P =0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan–Meier curves (log‐rank P =0.045). Conclusions: RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration: URL: https://www.clinicaltrials.org ; unique identifier: NCT02501083.

Nucleic acid-based therapeutics hold great promise for the treatment of numerous diseases, including neuromuscular disorders, such as Duchenne muscular dystrophy (DMD). Some antisense oligonucleotide (ASO) drugs have already been approved by the US FDA for DMD, but the potential of this therapy is still limited by several challenges, including the poor distribution of ASOs to target tissues, but also the entrapment of ASO in the endosomal compartment. Endosomal escape is a well recognized limitation that prevents ASO from reaching their target pre-mRNA in the nucleus. Small molecules named oligonucleotide-enhancing compounds (OEC) have been shown to release ASO from endosomal entrapment, thus increasing ASO nuclear concentration and ultimately correcting more pre-mRNA targets. In this study, we evaluated the impact of a therapy combining ASO and OEC on dystrophin restoration in mdx mice. Analysis of exon-skipping levels at different time points after the co-treatment revealed improved efficacy, particularly at early time points, reaching up to 4.4-fold increase at 72 h post treatment in the heart compared to treatment with ASO alone. Significantly higher levels of dystrophin restoration were detected two weeks after the end of the combined therapy, reaching up to 2.7-fold increase in the heart compared to mice treated with ASO alone. Moreover, we demonstrated a normalization of cardiac function in mdx mice after a 12-week-long treatment with the combined ASO + OEC therapy. Altogether, these findings indicate that compounds facilitating endosomal escape can significantly improve the therapeutic potential of exon-skipping approaches offering promising perspectives for the treatment of DMD.