Exosome COVID-19 mRNA vaccine (Capricor)

In the modern era, in which early initiation of corticosteroids and noninvasive respiratory support have become widespread in the treatment of Duchenne muscular dystrophy (DMD), life expectancy has increased to the late 20s. This has unmasked the clinical significance of DMD-associated cardiomyopathy, which contributes to death in 30%–50% of patients in the current era [1, 2]. Despite these advances, analyses from multicenter observational studies and clinical surveys have shown that the indications for initiation of medical therapy are highly variable [3-5]. The Care Considerations and American Heart Association (AHA) Guidelines previously provided some guidance in the late 2010s, albeit with recommendations generally based on expert consensus given longitudinal data was scant [6, 7]. The topic of when to initiate medical therapy, especially therapy with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) has become especially relevant in the current era. ACEi are the best-studied class of cardiac medications in DMD and have been associated with slower progression of both systolic dysfunction and left ventricular scarring in randomized trials [8, 9]. More recently, an analysis of the French multicenter DMD registry described an association between prophylactic ACEi use and improved overall survival with lower cumulative risk of heart failure hospitalization [10]. While there are fewer trials of ARBs, ACEi and ARBs have been shown to have similar cardiac benefits in early cardiomyopathy when compared head-to-head [11]. In a recent issue of Muscle and Nerve, Conway et al. [12] analyzed the relationship between prophylactic ACEi/ARB use and long-term clinical outcomes in the US population-based Muscular Dystrophy Surveillance Tracking and Research network (MD STARnet) between 1982 and 2009. This retrospective cohort study included 325 males with DMD and compared the long-term survival among patients treated prophylactically with an ACEi or ARB prior to the onset of left ventricular systolic dysfunction and those who were not. Twenty-eight percent of patients were treated prophylactically, with the frequency of prophylactic use generally increasing over time. Prophylactic ACEi/ARB was associated with longer survival after adjusting for corticosteroid use, scoliosis surgery, noninvasive ventilation use, ventricular dysfunction, and loss of ambulation. The association also persisted when excluding the earliest cohort of patients. The median age of survival was 26.4 years in patients treated prophylactically compared to 23.3 years among those untreated. This study continues to expand on the work of Porcher et al. [10] demonstrating the association between early ACEi use and improved long-term outcomes in DMD. The work of Conway et al. is especially notable because it confirms similar benefits in a new cohort. In particular, the Conway work includes a much larger proportion of patients on corticosteroid therapy (61% vs. 27%). Both ACEi and corticosteroids have been shown to positively impact long-term cardiac mortality individually, but we now have growing evidence for the additive effects of these treatments. The steroid experience is also instructive and raises the question of whether ACEi therapy should parallel the approach for early introduction of steroids to preserve muscle. Since the publication of the AHA guideline and Care Considerations, new histologic and cardiac magnetic resonance imaging data have demonstrated that late gadolinium enhancement (LGE), which was previously characterized as fibrosis, is rather fibrofatty [13, 14]. Furthermore, these studies have shown that late stages of the disease are characterized by near complete, irreversible fatty replacement of cardiac tissue in a phenotype that appears similar to the skeletal muscle phenotype [15]. When one considers these long-term natural history data and overlays previous data noting LGE is present in 15%–20% of patients before age 10 years, it makes the case that the recommendation for initiation at age 10 years should be revisited [16]. The preponderance of data suggests the next set of questions the field needs to ask is not whether we should begin prophylactic ACEi/ARB therapy earlier than age 10 years, but rather, how much earlier should we begin and how do we ensure widespread and equitable delivery of guideline-based therapy? The challenges with the delivery of guideline-directed care in DMD have been shown to be subspecialty independent, associated with socioeconomic determinants of health, and parallel the challenges of care delivery in non-DMD heart failure [17-19]. While the field has made strides in developing novel therapies, the science behind care delivery in DMD is generally lacking. Thus, the work of Conway et al. is important as it not only provides multicenter clinical data regarding ACEi/ARB prophylaxis, but also because it underscores the need to integrate implementation science into DMD care. The topic of care delivery is especially relevant as the life expectancy of individuals with DMD increases, care delivery shifts to adult-based providers with limited DMD experience, and care becomes more complicated in the era of multiple therapeutic options. Eleanor Greiner: conceptualization, writing – original draft, writing – review and editing. Chet R. Villa: conceptualization, writing – original draft, writing – review and editing. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. C.R.V. has received support from, and/or has served as a paid consultant for PTC Therapeutics, Pfizer, Sarepta, Capricor, Antisense, Solid Bioscience, Fibrogen, and Edgewise. He has also received funding from Parent Project Muscular Dystrophy. E.G. declares no conflicts of interest. Data sharing not applicable-no new data generated.