Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat model.

Duchenne muscular dystrophy (DMD) is a muscle wasting disorder caused by mutations in the gene encoding dystrophin. Gene therapy using micro-dystrophin (MD) transgenes and recombinant adeno-associated virus (rAAV) vectors hold great promise. To overcome the limited packaging capacity of rAAV vectors, most MD do not include dystrophin carboxy-terminal (CT) domain. Yet, the CT domain is known to recruit α1- and ß1-syntrophins and α-dystrobrevin, a part of the dystrophin-associated protein complex (DAPC), which is a signaling and structural mediator of muscle cells. In this study, we explored the impact of inclusion of the dystrophin CT domain on ΔR4-23/ΔCT MD (MD1), in DMDmdx rats, which allows for relevant evaluations at muscular and cardiac levels. We showed by LC-MS/MS that MD1 expression is sufficient to restore the interactions at a physiological level of most DAPC partners in skeletal and cardiac muscles, and that inclusion of the CT domain increases the recruitment of some DAPC partners at supra-physiological levels. In parallel, we demonstrated that inclusion of the CT domain does not improve MD1 therapeutic efficacy on DMD muscle and cardiac pathologies. Our work highlights new evidences of the therapeutic potential of MD1 and strengthens the relevance of this candidate for gene therapy of DMD.

Celsior® crystalloid cardioplegia versus standard hyperkalemic normothermic blood cardioplegia: Analysis of myocardial protection in elective mitral valve repair.

INTRODUCTION: With the increase and refinement of video assisted mitral valve surgery, cristalloïd cardioplegia started regaining popularity. The aim of our study was to evaluate the effectiveness of Celsior®, a crystalloid cardioplegic solution, on myocardial protection in elective surgical mitral valve repair in comparison to blood based hyperkalemic cardioplegia. METHODS: In this observational retrospective study, all consecutive elective isolated surgical mitral valve repair where Celsior® or normothermic hyperkalemic blood cardioplegia were used were included. Primary endpoint was any sign of myocardial protection failure (troponin levels, need for inotropic or mechanical support, rhythm disturbances, mortality). Secondary endpoint was Celsior® safety (allergic reactions, bleeding, organ toxicities). RESULTS: From January 2009 to August 2016, 382 patients underwent elective isolated mitral valve repair in whom normothermic hyperkalemic blood cardioplegia (n = 181) or Celsior® (n = 201) were used. There were no statistically significant differences in baseline characteristics including Euroscore 2. Peak troponin (pg/ml) release and 30-days mortality were not statistically different. Need for cardioversion was significantly more frequent in the Celsior® group (47% vs 13%, p < 0.001). There was no statistical difference in post-operative atrial fibrillation, permanent pacemaker implantation, reoperation for bleeding, transfusion, acute kidney injury, haemoglobin at discharge or length of stay. No allergic reaction to Celsior® occurred. CONCLUSION: Effective myocardial protection was achieved with the Celsior® cardioplegic solution with no unexpected toxicity. Celsior® may be an efficacious and safe cardioprotective strategy in mitral valve repair.

Impact of age on outcomes of patients assisted by veno-arterial or veno-venous extra-corporeal membrane oxygenation: 403 patients between 2005 and 2015.

INTRODUCTION: To assess the impact of age on early outcomes and mortality in veno-arterial extra-corporeal membrane oxygenation and veno-venous extra-corporeal membrane oxygenation recipients, and to investigate predictors of mortality. METHODS: Single-center retrospective study on prospectively collected data including all patients treated by veno-venous extra-corporeal membrane oxygenation and veno-arterial extra-corporeal membrane oxygenation (January 2005-July 2015). Outcomes were compared among two subgroups: aged less than 65 years (Group 1) versus more than 65 years (Group 2) and by type of support (veno-arterial extra-corporeal membrane oxygenation or veno-venous extra-corporeal membrane oxygenation). RESULTS: Among 403 patients, 20.3% were treated by veno-venous extra-corporeal membrane oxygenation and 79.7% by veno-arterial extra-corporeal membrane oxygenation. Veno-arterial extra-corporeal membrane oxygenation group: 76.6% were included in Group 1 and were more severe (pH 7.30 ± 0.19 vs. 7.35 ± 0.13 in Group 2, p = 0.003; lactates 7.5 ± 5.6 mmol/L vs. 5.8 ± 4.5 mmol/L in Group 2, p = 0.003). Weaning rate was higher in Group 1 (63.8% vs. 45.3%, p = 0.0043). The 30-day survival was higher in Group 1 (52.0% vs. 25.3%, p < 0.001). Univariate analysis identified higher Simplified Acute Physiology Score II (p = 0.02) and noradrenaline (p = 0.04) to be associated with mortality. Veno-venous extra-corporeal membrane oxygenation group: 80.5% were in Group 1. Mean PaO2 was 73.5 ± 42.9 mm Hg versus 100.8 ± 80.3 mm Hg (p = 0.24); FiO2 90.1% ± 18% versus 89.4% ± 16.4% (p = 0.89); and 30-day survival 56.1% versus 25.0% (p = 0.048). CONCLUSION: Patients older than 65 years have higher mortality after veno-arterial extra-corporeal membrane oxygenation or veno-venous extra-corporeal membrane oxygenation. This therapeutic strategy is feasible in the elderly, but comorbidities and clinical presentation have a major impact on prognosis and need to be seriously considered to avoid futile treatment.

Carotid versus femoral access for transcatheter aortic valve replacement: comparable results in the current era.

OBJECTIVES: The carotid approach for transcatheter aortic valve replacement (TAVR) has been shown to be feasible and safe. The goal of this study was to compare the 30-day outcomes of trans-carotid (TC) and transfemoral (TF) TAVR. METHODS: This retrospective study enrolled 500 consecutive patients treated by TC-TAVR (n = 100) or TF-TAVR (n = 400) with percutaneous closure between January 2018 and January 2020 at the Nantes University Hospital. The primary end-point was the occurrence of cardiovascular death and cerebrovascular events at 30 days. RESULTS: The mean age was 79.9 ± 8.1 in the TC group and 81.3 ± 6.9 (P = 0.069) in the TF group. The TC group had more men (69% vs 50.5%; P = 0.001) and more patients with peripheral vascular disease (86% vs 14.8%; P < 0.0001). Cardiac characteristics were similar between the groups, and the EuroSCORE II was 3.8 ± 2.6% vs 4.6 ± 6.0%, respectively (P = 0.443). The 30-day mortality was 2% in the TC group versus 1% in the TF group (P = 0.345). TC-TAVR was not associated with an increased risk of stroke (2% vs 2.5%; P = 0.999) or major vascular complications (2% vs 4%; P = 0.548). More permanent pacemakers were implanted in the TF group (14.9% vs 5.6%; P = 0.015), and no moderate or severe aortic regurgitation was observed in the TC group (0 vs 3.3%; P = 0.08). TC-TAVR was not associated with an increased risk of mortality or stroke at 30 days (odds ratio 1.32; 95% confidence interval 0.42-4.21; P = 0.63) in the multivariable analysis. CONCLUSIONS: No statistically significant differences between TC-TAVR and TF-TAVR were observed; therefore, TC-TAVR should be the first alternative in patients with anatomical contraindications to the femoral route.

Structural valve deterioration of bioprosthetic aortic valves: An underestimated complication.

OBJECTIVES: Structural valve deterioration (SVD) remains a major bioprosthesis-related complication, as recently described for the Mitroflow valve (models LX and 12A) (LivaNova, London, United Kingdom). The real incidence of the SVD risk remains unclear, often due to methodologic pitfalls by systematically using the Kaplan-Meier estimator and/or the Cox model. In this report, we propose for the first time a precise statistical modeling of this issue. METHODS: Five hundred sixty-one patients who underwent aortic valve replacement with the aortic Mitroflow valve between 2002 and 2007 were included. We used an illness-death model for interval-censored data. Median follow-up was 6.6 years; 103 cases of SVD were diagnosed. RESULTS: The 4-year and 7-year SVD cumulative incidences after the first anniversary of surgery were 15.2% (95% confidence interval, 11.9-19.1) and 31.0% (95% confidence interval, 25.8-37.2), respectively. Female gender, dyslipidemia, chronic obstructive pulmonary disease, and severe patient-prosthesis mismatch were significant risk factors of SVD. The occurrence of SVD was associated with a 2-fold increase in the risk of death. CONCLUSIONS: Appropriate statistical models should be used to avoid underestimating the SVD complication associated with worse long-term survival.