Carol A. Wittlieb-Weber

Duchenne muscular dystrophy (DMD) is an X‐linked genetic neuromuscular disorder that is caused by a mutation in the dystrophin gene. The disease is characterized by progressive weakness of skeletal muscle, resulting in loss of ambulation and eventually respiratory insufficiency. Cardiac muscle is also involved, and cardiomyopathy is a prominent feature of DMD. The care of patients with DMD has changed in important ways over the past 15 years, with the use of chronic steroid therapy combined with noninvasive respiratory support such as continuous positive airway pressure for home use. More recently, therapies targeting specific genetic mutations in DMD have been approved, using gene‐skipping oligonucleotides, and many other novel therapies are being evaluated in clinical trials, including mini‐dystrophin genes delivered by viral vectors. In view of this new era in care and outcomes, it is appropriate to review the role of advanced cardiac therapies such as ventricular assist devices and heart transplantation in the care of this population. In September 2024, a group of healthcare professionals with expertise in DMD and heart failure convened to review this topic; the consensus opinion of this group (DMD Cardiac Care Consortium) is presented in this manuscript.

Background: A viral vector recombinant gene transfer therapy (GTT) has recently been approved by the FDA for males of all ages with Duchenne Muscular Dystrophy (DMD) without limitations regarding preexisting cardiac impairment. Acute myocarditis is a potential life-threatening short-term complication that has been reported following GTT. This immune mediated response can range from troponin elevation to rapid cardiovascular compromise and death, particularly in those with abnormal cardiac status at baseline. Early detection of cardiac compromise is essential to optimize outcomes. Objectives: The primary objective of this consensus statement is to advocate for caution with DMD GTT patient selection and to initiate preemptive monitoring for those who may be at increased risk for cardiac adverse events. Secondary objective is to deepen our understanding of short and long-term impact of DMD gene therapies on the heart. Methods: A national learning network of pediatric cardiologists with expertise in DMD developed recommendations for cardiac surveillance of DMD males receiving GTT based on available evidence and expert consensus opinion. A monitoring and treatment plan for standard and high cardiac risk patients was developed. Conclusion: Partnership of cardiologists with GTT prescribers is essential to identify patient-specific considerations that might influence risk for adverse cardiac events and alter post infusion monitoring and management plans. Consistency in cardiac surveillance practices across centers will expedite our knowledge regarding potential short- and long-term cardiac effects of GTT for DMD.

Outcomes in patients requiring prolonged inotropes (PI) following surgery for congenital heart disease (CHD) have not been well studied. We aimed to describe the burden of PI use in the immediate postoperative period after CHD surgery and identify risk factors for in-hospital mortality. We conducted a retrospective cohort study using the Pediatric Health Information System® (PHIS) database. Patients 0–18 years with CHD who underwent cardiovascular surgery from 2010 to 2020 were included. Patients who received inotropic medications for > 7 consecutive days after surgery were in the PI group and all others in the control group. Patients who died before 7 days were excluded. Multivariable mixed-effect logistic regression was used to examine risk factors for in-hospital mortality. There were 110,271 patients from 48 centers included, 10,292 in the PI group and 99,979 in the control group. In-hospital mortality was significantly higher in the PI group (24.9% vs. 4.6%, p < 0.001). Ventricular assist device use was rare (1.6%). After adjustment, odds of in-hospital mortality in the PI group was 3.5 (95% CI 3.3–3.8) times higher than in controls. Independent risk factors for in-hospital mortality were age, non-White race, class of CHD, number of complex chronic conditions, preoperative inotrope, preoperative extracorporeal membrane oxygenation, sepsis, stroke, renal failure, number of inotropes at 7 days, and discharge year (p < 0.01 for all). Postoperative PI use in CHD is common and carries a considerable burden of mortality. Additional work is needed to understand which risk factors are modifiable and which patients may benefit from reintervention or advanced heart failure therapies.

Standards of care exist to optimize outcomes in Duchenne and Becker muscular dystrophy (DBMD), caused by alterations in the DMD gene; however, there are limited data regarding health care access in these patients. This study aims to characterize outpatient subspecialty care utilization in pediatric patients with DBMD. This retrospective cohort study used administrative claims data from IBM MarketScan Medicaid and Commercial Claims and Encounters Research Databases (2013-2018). Male patients 1-18 years with an ICD-9/10 diagnosis code for hereditary progressive muscular dystrophy between January 1, 2013, and December 31, 2017, were included. Participants were stratified into 3 age cohorts: 1-6 years, 7-12 years, and 13-18 years. The primary outcome was rate of annual neurology visits. Secondary outcomes included annual follow-up rates in other subspecialties and proportion of days covered (PDC) by corticosteroids. A total of 1,386 patients met inclusion-347 (25.0%) age 1-6 years, 502 (36.2%) age 7-12 years, and 537 (38.7%) age 13-18 years. Heart failure, respiratory failure, and technology dependence increased with age (p for all<0.05). The rate of neurology visits per person-year was 0.36 and did not differ by age. Corticosteroid use was low; 30% of person-years (1452/4829) had a PDC ≥20%. Medicaid insurance was independently associated with a lower likelihood of annual neurology follow-up (OR 0.23; 95% CI 0.18-0.28). The rate of annual neurology follow-up and corticosteroid use in patients with DBMD is low. Medicaid insurance status was independently associated with a decreased likelihood of neurology follow-up, while age was not, suggesting that factors other than disease severity influence neurology care access. Identifying barriers to regular follow-up is critical in improving outcomes for patients with DBMD.

Cardiac dysfunction due to hypertension (CDHTN) in pediatrics is not well described. We aimed to describe the presentation and outcomes of pediatric CDHTN and identify clinical features associated with resolution of dysfunction. A single-center retrospective cohort study of patients ≤ 21 years with CDHTN from January 2005–September 2020 was performed. Patients with systolic dysfunction without another cause, blood pressure > 95th percentile, and physician judgment that dysfunction was secondary to hypertension were included. Demographics, clinical characteristics, echocardiographic findings, and outcomes were examined using Fisher’s exact and Mann–Whitney U tests. Multiple correspondence analysis was used to explore the relationship of resolution of dysfunction to clinical features. Thirty-four patients were analyzed at a median age of 10.9 (IQR 0.3–16.9) years. Patients were divided into groups < 1 year (n = 12) and ≥ 1 year (n = 22). Causes of hypertension were varied by age, with renovascular disease most common in infants (42%) and medical renal disease most common in older patients (77%). Echocardiography demonstrated mild LV dilation (median LV end-diastolic z-score 2.6) and mild LV hypertrophy (median LV mass z-score 2.4). Most patients (81%) had resolution of dysfunction, particularly infants (92%). One patient died and one patient was listed for heart transplant. None required mechanical circulatory support (MCS). No clinical features were statistically associated with resolution of dysfunction. Hypertension is an important but reversible cause of systolic dysfunction in children. Patients are likely to recover with low mortality and low utilization of MCS or transplantation. Further studies are needed to confirm features associated with resolution of dysfunction.