Taking ACTION to detect myocarditis related to recombinant gene transfer therapy for Duchenne Muscular Dystrophy;Consensus recommendations for cardiac surveillance

Abstract

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.

Keywords

duchenne muscular dystrophy genetic therapy myocarditis cardiac adverse event expert consensus

Introduction

Recombinant gene transfer therapy (GTT) utilizing viral vector delivery of gene products is being developed for several monogenetic disorders.¹ Adeno-associated virus (AAV)-mediated GTT for DMD designed to restore functional dystrophin protein are in advanced stages of development with relatively rapid clinical dissemination under FDA rare disease approval pathways.^{2, 3} The first AAV GTT containing a micro-dystrophin transgene, delandistrogene moxeparvovec-rokl (ELEVIDYS) was FDA approved in June 2023 for 4–5 year olds with DMD.⁴ On 6/20/2024 the FDA granted traditional approval to ELEVIDYS for ambulatory DMD patients and accelerated approval to ELEVIDYS for non-ambulatory DMD. This expanded the labeled indication to include all individuals with DMD who are at least 4 years of age with the only contraindication being those with deletions in exon 8 or exon 9 in the DMD gene.⁵

The endpoints for these GTT clinical trials have largely focused on impact in skeletal muscle strength and function, with limited cardiac evaluations for safety. While pre-clinical data in a DMD^mdx rat model treated with delandistrogene moxeparvovec has reported dystrophin expression in the heart with increased cardiac function,⁶ the impact on potential changes in manifestation of DMD related cardiomyopathy (CM) in humans is not yet characterized. As there is the potential for both beneficial as well as adverse impact on cardiac function related to viral gene delivery into cardiac myocytes, expedited understanding of short and long-term effect of these therapies is essential. Known toxicities related to AAVs include hepatotoxicity, acquired hemolytic uremic syndrome, neurotoxicity, and myocarditis to the extent that immunomodulatory medications are part of current GTT protocols for a minimum of 60 days post infusion to mitigate these serious systemic inflammatory effects.

Serum troponin elevations and clinical myocarditis have occurred in multiple viral vector GTT trials to date.⁷ The pathophysiology of myocarditis after gene therapy is incompletely understood, but there are multiple hypotheses⁷:

Viral vector associated myocarditis due to innate immune response triggered by direct infection of myocytes and endothelium via viral receptors with release and activation of inflammatory mediators and potential cytokine storm

Humoral/cellular response to vector (ex. AAV capsid) leading to generalized inflammation with cardiac involvement due to adaptive immune response

Humoral response to transgene product expressed in cardiac tissue

The immunologic responses that may lead to myocarditis or other acute myocardial injury can be seen immediately post-administration and potentially in the following weeks, depending on the mechanism. While the severity of myocardial injury has been variable in reports to date, mortality attributed to cardiac dysfunction has occurred.⁸ Notably, acute serious myocarditis and troponin I elevation are included in the ELEVIDYS Warnings and Precautions.⁵

Acute myocarditis is a potential life-threatening short-term complication following AAV GTT. Longer term cardiovascular sequalae of GTT remains unclear, particularly in this population with progressive cardiomyopathy. Importantly, the potential relative risks of GTT for the nonambulatory DMD population is distinct from the younger ambulatory population and must be considered. As younger patients typically have not yet developed DMD-related cardiac disease, cardiac stressors such as myocarditis and systemic inflammation are typically well tolerated, with potential benefit of maintaining functioning skeletal muscle mass.

In the nonambulatory, older age groups, the risk-benefit ratio may change due to patients having baseline dystrophinopathy-related cardiomyopathy with decreased cardiac reserve. Consequentially, there may be a higher risk for death or significant morbidity with myocarditis or other cardiopulmonary instability. As viral vector drug dosing is weight based, larger patients require higher viral loads which drive the inflammatory response. While no SAE were reported in the 6 nonambulatory study subjects reviewed by the FDA as the basis for their accelerated approval,⁴ this cohort is too small to provide reassurance as to the impact on cardiac outcomes in this population. The current active Sarepta clinical trial ENVISION, which includes nonambulatory subjects without age limit, has LV ejection fraction (EF) < 40% or clinical signs or symptoms of cardiomyopathy as exclusion criteria. Post-marketing trial data is not expected to be available until 2027 or later, making it several years before further data on cardiac efficacy and safety outcomes in this population becomes available.

In addition, to date there have been no DMD GTT studies that included those with symptomatic heart failure or severe cardiomyopathy, yet this population was not excluded from the recent FDA approved ELEVIDYS expanded labelling. This has raised concern among the DMD cardiology community. The purpose 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. While the current label includes a warning regarding potential for myocarditis and recommendations to check troponin-I levels weekly for first month, our consensus opinion is that this plan alone is not sufficient for patients with pre-existing cardiac dysfunction who are potentially at higher risk for cardiac adverse outcomes.

Further data are needed to understand the risk of GTT related cardiac injury across the phenotype, genotype, and gene product spectrum. Standardization of clinical cardiac monitoring will expedite this process.

Methods

Utilizing the successful model of a learning network to accelerate real time knowledge by development and sharing of best practices, the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) formed a committee dedicated to improving cardiac care and outcomes for children with cardiomyopathy due to muscular dystrophy(MD).⁹ The ACTION MD Committee applied their expertise in treating all stages of DMD cardiomyopathy, as well as acute and chronic heart failure in children and young adults, to develop these consensus recommendations for cardiac surveillance of males with DMD receiving viral GTT. The primary goal is to maximize safety via proactive screening for myocardial injury to aid early detection of adverse cardiac events.

Efforts were made to suggest a cardiac monitoring protocol that will be easily coordinated with current GTT protocols, typically consisting of baseline assessments (blood draw and imaging) followed by serial blood draws and clinic visits with GTT team for post infusion monitoring and anti-inflammatory medication titration. Myocarditis diagnostic criteria and evaluation are concordant with 2021 American Heart Association guidelines for Diagnosis of Myocarditis in Children¹⁰ and 2020 Expert consensus statement for Management of Acute and Chronic Inflammatory Cardiomyopathy.¹¹

Results

Preemptive planning

A guiding principle of these recommendations is partnership of cardiologists with GTT prescribers, who are commonly neuromuscular specialists. A patient's cardiologist should be included as part of the GTT selection process to determine cardiac risk profile (Table 1) and to advise the GTT team on potential patient-specific considerations that might influence risk for adverse cardiac events and alter post infusion monitoring and management plan (Table 2). Similarly, simply prescribing the recommended testing should not be considered equivalent to the active involvement of a pediatric cardiologist. The current recommendations are intended as minimum surveillance. As patients may live a distance away from the infusion medical center, it is reasonable for GTT team to request that High Cardiac Risk patients remain in local vicinity for a period of weeks following infusion to facilitate rapid access to skilled medical care and follow-up as needed. This should be determined by the multidisciplinary team on an individualized basis.

Table 1.

Risk stratification for potential adverse cardiac outcomes to Gene Transfer Therapy (GTT).

Cardiac Risk Category	Ejection Fraction(CMR* or ECHO)	Modifiers
Standard	≥55%
High	<55%	LGE, Arrhythmias
Considerations that might increase risk for adverse cardiac outcomes: Higher viral dosing for heavier weight patients LGE on CMR might represent more extensive cardiac involvement and correspondingly less cardiac reserve when exposed to GTT, even if systolic function is normal Presence of arrhythmias, independent of systolic function Untreated pulmonary insufficiency (example nonadherence with noninvasive ventilation prescription) or pulmonary hypertension

*CMR = Cardiac MRI assessment preferably for accuracy.

LGE = late gadolinium enhancement.

Table 2.

Cardiac surveillance protocol based on cardiac risk profile.

STANDARD Cardiac Risk Profile (EF ≥ 55%)
	Baseline (within 6 mos)	2–3 days	1 week	2 weeks	3 weeks	4 weeks	2 mos	3 mos	6 mos	9 mos	1 year
Cardiology visit	X							O	X		X
NT-proBNP
Troponin I	X	X	X	X	X	X		O	X		X
ECG	X		X			X		O	X		X
Echocardiogram	X		X			X		O	X		X
CMR (unsedated)	O										X
Ambulatory Rhythm monitor	O							O			X
HIGH Cardiac Risk Profile (EF < 55%)
	Baseline (within 3 mos)	2–3 days	1 week	2 weeks	3 weeks	4 weeks	2 mos	3 mos	6 mos	9 mos	1 year
Cardiology visit	X					XX	XX	XX	X	XX	X
NT-proBNP	XX								XX		XX
Troponin I	X	X	X	X	X	X	XX	XX	X	XX	X
ECG	X		X	O	O	X	XX	XX	X	XX	X
Echocardiogram	X		X			X	XX	XX	X	XX	X
CMR (unsedated)	XX										X
Ambulatory Rhythm monitor	XX							O			X

KEY: X = recommended, XX = difference from Standard Risk protocol, O = optional.

Additionally, a cardiologist familiar with cardiac manifestations of neuromuscular disorders and/or a cardiologist familiar with diagnosis and treatment of acute myocarditis should be identified as a point person at each institution to review cardiac labs, cardiac diagnostic testing results, and triage relevant clinical questions in real time related to GTT infusions.

While the risk of serious cardiac complications requiring emergent care is rare, this topic should be included in the pre-GTT discussions with families including the potential for cardiac decompensation and need for temporary mechanical circulatory support. This is essential for patients who have preexisting cardiac dysfunction. Similarly, we encourage communication by cardiology team members with ICU and surgery teams of the potential of DMD GTT recipients to require advanced cardiac therapies and to assess emergent care strategies preemptively. For patients who have had previous central lines, ultrasound assessment for neck vessel patency can be considered.

Risk stratification for potential adverse cardiac outcomes to GTT

Suggested surveillance is focused on early detection of myocarditis which can range from asymptomatic elevation in serum troponin to a rapid fulminant course resulting in cardiogenic shock and death due to acute ventricular dysfunction and or life-threatening arrhythmias.

While intuitively an adult patient with baseline severely decreased systolic function (ex. EF 30%) may be considered at higher risk than a young child with minimal decreased cardiac function (ex. EF 53%), for algorithm simplicity at this time, surveillance protocol is suggested based on having normal (EF ≥ 55%) versus abnormal (EF <55%) systolic function (Table 1). As evidence supported risk factors for adverse cardiac events become available, this algorithm will be modified. Considerations that might increase risk for adverse cardiac outcomes include:

Higher viral dosing for heavier weight patients

Late gadolinium enhancement (LGE) on CMR might represent more extensive cardiac involvement and correspondingly less cardiac reserve when exposed to GTT, even if systolic function is normal

Presence of arrhythmias, independent of systolic function, might represent more extensive cardiac involvement and correspondingly less cardiac reserve when exposed to GTT

Untreated respiratory insufficiency (example nonadherence with noninvasive ventilation prescription) or evidence of pulmonary hypertension (echocardiographic)

As new information is available these recommendations for cardiac surveillance will be revised accordingly (Table 2).

Justification for proposed DMD GTT Cardiac surveillance plan

Biomarkers

Injury and death of cardiomyocytes results in troponin release to blood. Historically, serum troponin-I can be a sensitive and specific finding in myocarditis, when judged against the gold standard of endomyocardial biopsy.¹² However, troponin-I peak does not correlate well with the clinical course of myocarditis.¹³ Normal values for high sensitivity troponin assays vary by age, gender and manufacturer.¹⁴ In addition, elevated troponin-I is found in patients with dystrophinopathies who are asymptomatic and without infectious or cardiac concerns, making the diagnosis of GTT-associated myocarditis more challenging.^{15, 16} Baseline troponin-I assessment immediately prior to GTT is therefore essential, with serial measurements at pre-specified timepoints prudent for detection of myocarditis (Figure 1).

Figure 1.

Cardiac surveillance summary.

Acute troponin-I elevation in the immediate post-infusion stage as a marker of myocarditis may be distinct from later troponin elevation related to indolent, inflammatory states. Of note, there is no current recommendation for use of standard troponin-I vs high-sensitivity assays, but the same platform should be used for trending in each patient. As cardiac troponin-T is not as specific to cardiac muscle in DMD, its use is not recommended for this purpose.¹⁷

Other biomarkers, such as markers of inflammation (white blood cell counts, platelet counts), and B type natriuretic peptide (BNP) are not specific to myocarditis. BNP is a useful marker of acute heart failure, which may not be present in all cases of myocarditis. Therefore, normal values of these markers may not exclude acute myocardial inflammation, but may be helpful as a baseline in High Cardiac Risk patients. At this time, data regarding correlation of GTT-associated myocarditis with serum markers of inflammation is not available. Thus, only trending of troponin is recommended for GTT myocarditis surveillance at this time. While trending of inflammatory and other biomarkers may be informative, they would be considered exploratory at this time and are therefore not advocated for or against in this document.

Arrhythmia and conduction system surveillance

Electrocardiogram (ECG) abnormalities as well as atrial and ventricular ectopy have been described in patients with DMD across the spectrum of cardiomyopathy. The burden of dysrhythmias generally correlates with the severity of CM, although individual cases of symptomatic arrhythmia including sudden cardiac death have been reported early in the disease process.^18–20

ECG abnormalities, specifically ST segment changes, are the most common finding in cases of acute myocarditis in both children and adults.^{10, 11} T-wave inversion, QRS prolongation, low voltage, atrioventricular heart block, bradycardia, tachycardia, supraventricular and/or ventricular arrhythmias can all be ECG manifestations of acute myocarditis. Therefore, obtaining baseline and serial ECGs for comparisons post DMD GTT infusion has utility for acute myocarditis surveillance. Additional ECGs should be obtained as needed post infusion to correlate with abnormal troponin I values from baseline.

Subacute or chronic myocarditis could also occur following DMD GTT and manifest sub-clinically as increased ectopy and or arrhythmia burden. Ambulatory rhythm monitoring should therefore be considered within the first 3–6 months post-gene therapy and compared with baseline.

Surveillance cardiac imaging

Noninvasive imaging to serially assess cardiac function is an essential part of cardiac care for DMD.^{21, 22} Echo and CMR are both established diagnostic tools for DMD CM as well as myocarditis. Considerations regarding each technique specific to the purpose of screening for GTT-related myocarditis are reviewed.

Echocardiogram is the primary clinical tool to assess cardiac structure and function in a typical office-based cardiology setting. Some challenges with echo for those with DMD are mainly related to limited acoustic windows with age and disease progression. Although DMD echo images are suboptimal compared with CMR, echo is generally adequate for assessment of LV systolic function and major clinical changes, with images generally better at younger ages.²³ As echo has the advantage over CMR of broader availability and typically shorter exam duration without need for sedation, it is the basis for cardiac function surveillance post DMD GTT in these recommendations.

CMR has been utilized to deepen our understanding of DMD CM. Studies suggest that the progression of DMD systolic dysfunction typically begins after the development of late gadolinium enhancement (LGE).²⁴ DMD patients have a classic pattern of LGE that begins in the sub-epicardium of the free wall at the base/mid-LV.^{25, 26} Importantly, this pattern can be indistinguishable to that seen in patients with acute myocarditis. Simply using LGE, it is impossible to determine whether the enhancement pattern is due to progression of DMD cardiomyopathy or acute myocarditis. T2 mapping however can be used to distinguish between the usual progression of DMD CM (minimal T2 elevation) and an acute inflammatory event (typically significant T2 elevation reflecting larger patches or diffuse edema).^{26, 27} Having a baseline CMR significantly improves the clinician's ability to distinguish between progression of disease and acute changes related to GTT. However, there are challenges in obtaining CMR without sedation in young children. Sedation only to obtain a baseline CMR study is not currently recommended. However, a non-sedated baseline CMR with contrast within 6 months prior to GTT is strongly recommended to serve as comparison if concern for myocarditis arises. A follow-up CMR with contrast 1 year after GTT is reasonable as the long-term impact on DMD CM is unknown at this time.

Other clinical findings

Gastrointestinal symptoms such as nausea and vomiting are common immediately post GTT infusion though are also common presenting symptoms of heart failure in children.²⁸ This potential overlap of anticipated GTT symptoms with those of myocarditis is an important point of awareness for GTT infusion provider team. Clinical assessment of any patient with nausea, vomiting, chest pain, palpitations, abdominal pain, severe fatigue, rapid breathing should always be obtained in person by the gene therapy provider team with cardiology consultation as needed for clinical concerns.

Managing abnormal findings

Having a preemptive plan for obtaining real time cardiac consultation is essential for all GTT teams. Cardiology consultation, preferably with patient's primary cardiologist, should be obtained for any abnormal screening tests.

Recommended response to abnormal screening results are as follows:

An abnormal pre infusion troponin-I obtained as a baseline should not be considered a contraindication to GTT. Patient's cardiologist should be included in GTT care plan.

An increased troponin value of > 3 times that of the baseline (or >3 times the upper limit of normal in patients with baseline values in the normal range) warrants further investigation, at a minimum a follow-up troponin and ECG within the following day, and may include physical exam and cardiac imaging. A cardiologist should review the ECG on day of exam.

Troponin elevation > 3 times baseline (or >3 times the upper limit of normal in patients with baseline values in the normal range) paired with ECG changes or significant clinical symptoms (respiratory, GI, and or cardiac) warrants an echo same day and consideration of hospital admission.

Any decrement in systolic function, new pericardial effusion, or new > mild valvar regurgitation on echo warrants hospital admission with telemetry monitoring.

Isolated (asymptomatic) Troponin elevation > 10× baseline (or >10× the upper limit of normal in patients with baseline values in the normal range) warrants echo and consideration of hospital admission with telemetry monitoring.

Presence of arrhythmia on ECG, particularly early post-GTT, should trigger cardiac consultation, and may warrant hospital admission on telemetry for observation

In patients with screening abnormalities not meeting above thresholds, it is reasonable to consider more frequent assessments, including ECG or echo with troponin at 2 weeks and 3 weeks post-infusion, or at other interval at the discretion of the consulting cardiologist.

For High Cardiac Risk patients, closer surveillance to that proposed and lower threshold for imaging, mobile telemetry monitoring, and or hospital admission for observation may be considered and guided by collaboration with primary cardiologist.

Diagnosis of GTT related myocarditis

The diagnostic criteria for GTT related myocarditis is similar to myocarditis due to other etiologies, within the context of potential baseline abnormalities associated with DMD as described above. Of the four diagnostic strata presented in the AHA 2020 Scientific Statement on Diagnosis and Management of Myocarditis in Children,¹⁰ it is anticipated that diagnoses of GTT associated myocarditis will fall under diagnostic strata 2 - clinically suspected with CMR confirmation, or strata 3 - clinically suspected without positive biopsy or CMR. Clinical suspicion includes presence of: chest pain, elevated troponin, LV dysfunction, ECG changes and or arrhythmias.

Management of post GTT myocarditis

Acute myocarditis of any etiology has a highly variable course that ranges from minimal symptoms to life threatening arrhythmias, heart failure, and rapid onset cardiogenic shock.²⁹ Anticipatory management is important, with therapies focused on supportive care for cardiac output and treatment for arrhythmias. There is significant variation of clinical care protocols across institutions, though expert consensus documents on diagnosis and management of myocarditis have been recently published for both pediatrics¹⁰ and adults¹¹ and will therefore not be delineated here. We recommend continuing institutional practices for treatment of acute inflammatory myocarditis with some additional considerations specific to AAV GTT as the underlying etiology:

Cardiology consultation should be obtained at time of hospital admission, if not already involved, to review labs, diagnostic testing, and clinical questions.

If patient is hospitalized for observation, continuous heart rhythm monitoring to detect arrhythmias and frequent repeat troponin measurement is appropriate. If troponin is downtrending, cardiac function remains at baseline, no arrhythmias are seen after 48 h of close observation, and patient is able to tolerate enteral medications, it may be reasonable to discharge to outpatient monitoring without further therapies.

CMR with T2 mapping may be helpful to confirm diagnosis of acute myocarditis, though hemodynamic stability, need for sedation, and differentiation from baseline CMR abnormalities related to DMD CM must be considered.

Increased corticosteroid dose, as a pulse or intravenous bolus, above current dose to help attenuate the inflammatory response is a treatment of GTT-associated liver injury and may be helpful for GTT myocarditis.³⁰ Steroid bolus and tapers should be prescribed in collaboration with Neuromuscular/ Gastroenterology/ Hepatology providers.

Intravenous immunoglobulin (IVIg) has been used for treatment of autoimmune myositis, inflammatory disease, and myocarditis, with conflicting evidence on efficacy. There is no current evidence for efficacy of IVIg in GTT associated myocarditis, however a recent publication advising on management of GTT-related adverse events includes consideration of IVIg therapy, in addition to steroid bolus, for myocarditis.³⁰ We are in agreement with this recommendation with caution regarding tolerance of intravenous volume load. Administration of IVIg should be with intensivist supervision for management of heart failure.

Later onset of myocarditis may indicate a humoral response, and discussion with Immunology/Rheumatology colleagues may be helpful for immunomodulation therapies.

Preventing acute decompensation and supporting hemodynamics is the primary goal which may require inotropes and temporary mechanical circulatory support. Anticipatory discussions with patient, family, critical care providers, and ECMO team are essential at the time of myocarditis diagnosis.

Post GTT myocarditis therapy and ongoing cardiac monitoring

Cardiac reverse remodeling oral medication regimen including aldosterone inhibitor, beta blocker, and angiotensin converting enzyme inhibitor, is recommended for people with DMD and LV dilation with or without cardiac dysfunction, as for other types of dilated CM.⁹ Augmentation of baseline CM medication regimen (or initiation) is reasonable in the setting of a diagnosis of GTT-related myocarditis (confirmed or clinically suspected such as significant troponin rise with ECG changes) even without cardiac dysfunction. Recommendations regarding activity restrictions after diagnosis of GTT-related myocarditis would be the same as for acute viral myocarditis¹⁰ with individualized guidance provided by patient's cardiologist. Participation in physical therapy and activities of daily life with avoidance of heavy exertion would be appropriate for most. More frequent cardiology follow-up with serial cardiac imaging (CMR and/or echo) to assess new baseline after GTT myocarditis is recommended, as for patients with other etiologies of myocarditis.

For those not experiencing cardiac adverse events related to GTT, a return to pre GTT cardiac surveillance for DMD CM, annual cardiac imaging and ECG, is reasonable after completing the year of increased surveillance outlined in Table 2. This should be adjusted per cardiologist's discretion if cardiac adverse events occurred and or patient not at pre GTT baseline.

Summary recommendations for post GTT infusion surveillance

The following are minimal recommendations for DMD GTT recipients WITHOUT acute cardiac concerns following GTT infusion (Table 2):

Labs

For all: Troponin-I to be drawn as close to infusion day as possible. Track troponin-I post infusion within 2–3 days and then weekly for first month. Longer term followup post infusion with troponin-I at 6 months, then yearly. Additional labs to be drawn prn symptoms and to trend abnormal values.

For patients with any preexisting cardiac dysfunction (High Cardiac Risk) add assessment of NT-proBNP/BNP at baseline, 6 months, and yearly. Additionally, increase serial troponin-I monitoring to serve as biomarker of myocyte damage: obtain additional troponin I levels monthly for first 3 months, then every 3 months for first year. Note that high sensitivity troponin-I level, even in asymptomatic normal males, fluctuates by assay used.¹⁴ Troponin-I can be transiently elevated at baseline in DMD males, therefore trends most useful.^{16, 17} Encourage consistency of location of serial blood draws to decrease variability in troponin-I assay type and normal value range.

Procedures

Cardiology provider visit for history and physical exam (rather than testing only) should be coordinated for all prior to infusion to assign cardiac risk category and to review cardiac monitoring plan. Patient specific cardiovascular considerations should be discussed with multidisciplinary GTT team.

Preemptive planning for acute hemodynamic decompensation including potential need for mechanical circulatory support should be performed prior to infusion for all High Cardiac Risk patients. Advanced directives should be documented for all over age 18 years.

Baseline cardiologist visit and cardiac diagnostic studies, ECG and echocardiogram or cardiac MRI (preferable for accuracy) should be obtained within 6 months prior to infusion for Standard Cardiac Risk patients, and within 3 months prior to infusion for High Cardiac Risk patients.

Post infusion surveillance with ECG and Echocardiogram at 1 week, 1 month, 6 months and then annually for all. After 1^st month post infusion, High Cardiac Risk patients should receive additional screening ECG and echocardiogram monthly for first 3 months, then every 3 months to complete 1^st year.

Cardiac MRI (CMR) with T2 mapping for baseline EF and presence of late gadolinium enhancement (LGE) should be strongly considered in all for baseline and at 1 year following infusion. Sedation only for baseline CMR is not currently recommended.

Ambulatory rhythm monitoring to be obtained for baseline, considered at 3 months post infusion, followed by annually. Consider Mobile Cardiac Outpatient Telemetry with ability to transmit real time notification of events in patients with baseline significant dysfunction and or preexisting cardiac dysrhythmias for immediate post infusion monitoring.

Conclusion and future directions

This guidance for cardiac assessment post GTTs is based on initial, limited data and expert consensus. We anticipate multiple versions of this guidance as data evolves, and additional therapies are developed. Ideally, knowledge regarding potential cardiac effects post GTT for DMD over short and long term can be accelerated by consistent surveillance practices across centers.

Footnotes

Acknowledgments

Members of the ACTION Muscular Dystrophy Committee, Nikita Orwick, Katie Flaspholer

ORCID iDs

Beth D. Kaufman

Aravindhan Veerapandiyan

Carol Wittlieb-Weber

Paul Esteso

Renata Shih

Neha Bansal

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

No conflicts of interest of the authors related to this consensus expert opinion document. Other disclosures below:

AV : Has received compensation for ad-hoc advisory boards/consulting activity with Biogen, Novartis, AveXis, Sarepta therapeutics, PTC therapeutics, Scholar Rock, Fibrogen, AMO pharma, Pfizer, Catalyst, Lupin, Entrada therapeutics, MyTomorrows, Percheron, and Italfarmaco outside of the submitted work. CWW: consultant for Pfizer

JS: consultant for WCG Imaging, Immunoforge, Dyne, Sarepta, Pfizer, Fibrogen

CV: consultant for Capricor, Pfizer, Sarepta, Solid bioscience

DN: consultant for Capricor, Lumanity

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during this study.

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