Introduction to the Special Issue on Neuromuscular Cardiopulmonary
Medicine in the Age of Emerging Therapies
David J. Birnkrant MD
Division of Pediatric Pulmonology and Sleep Medicine
Department of Pediatrics
MetroHealth Medical Center
Case Western Reserve University School of Medicine
Cleveland, Ohio
dbirnkrant@metrohealth.org
Linda H. Cripe MD
Division of Pediatric Cardiology
Nationwide Children’s Hospital
The Ohio State University College of Medicine
Columbus, Ohio
Linda.Cripe@nationwidechildrens.org
Correspondence to: David J. Birnkrant MD
Department of Pediatrics
2500 MetroHealth Drive
Cleveland, OH 44109
dbirnkrant@metrohealth.org
Financial Disclosures: Dr. Birnkrant is a Clinical Advisor to Advanced
Bio Machines PTE LTD (ABM Respiratory Care) and has a financial interest
in patents licensed to ABM Respiratory Care. Dr. Cripe has no relevant
financial disclosures.
Neuromuscular diseases often affect the respiratory muscles and, as a
result, respiratory complications are a major cause of morbidity.
Respiratory muscle weakness leads to hypoventilation and
sleep-disordered breathing, as well as impaired coughing, which results
in pneumonia, atelectasis, mucus plugging, aspirations and respiratory
failure.1 The therapeutic focus has been on treating
respiratory complications with assisted ventilation and assisted
coughing.2 This approach has been successful in
patients with Duchenne muscular dystrophy (DMD), extending patient
survival into their 30’s and beyond.3
With prolonged survival through anticipatory management of respiratory
impairment, attention has shifted to neuromuscular cardiac
complications. Neuromuscular diseases vary in the nature and severity of
their cardiac involvement, with complications ranging from
cardiomyopathy to conduction disorders and arrhythmias. In individual
patients, the severity of cardiac muscle involvement does not
necessarily correlate with the severity of respiratory (skeletal) muscle
involvement, complicating assessment of baseline natural history and
prognosis.4 DMD provides a good example of the
rationale for the focus on cardiac therapies: when patients are managed
with assisted ventilation, DMD cardiomyopathy becomes the primary cause
of patient death,5 and so effective cardiac management
strategies are needed.
Until recently, pharmacologic therapy for neuromuscular cardiopulmonary
complications were quite limited. In DMD, glucocorticoids can improve
long-term pulmonary function, allowing patients to achieve a higher peak
FVC at a later age. While the therapy typically delays the onset of
significant pulmonary impairment by a few years, it cannot arrest the
progressive decline to very low levels of pulmonary function that typify
the disease.6 With regard to DMD heart function,
studies of glucocorticoid therapy have yielded mixed results, while
certain conventional cardiac medications, such as angiotensin converting
enzyme (ACE) inhibitors and aldosterone receptor antagonists, may slow
short-term decline, with possible long-term benefits.7,8 However, DMD cardiomyopathy is progressive and
while aggressive management of late-stage cardiac disease can be
mitigating, in one study mean survival was only 8 months after the onset
of congestive heart failure (CHF).9 Overall, existing
pharmacologic options are very limited, and better therapies are badly
needed, including cardiac therapies designed specifically for the
particular cardiomyopathy associated with DMD.
Thus, it is a welcome development that neuromuscular medicine is being
revolutionized by new genetic and molecular therapies.10,11 The purpose of this Special Issue is to present
an overview of these new therapies, to examine their cardiopulmonary
effects, and to consider the future of neuromuscular cardiopulmonary
care. The emphasis will be on DMD and, to a lesser extent, spinal
muscular atrophy (SMA), as these are the diseases with the most robust
new drug development and related cardiopulmonary outcome data.
This Special Issue contains articles on a number of relevant topics,
including an overview of new genetic and molecular therapies for DMD,
examining the currently available cardiopulmonary outcome data; and a
critical examination of pulmonary outcome measures, assessing which
outcomes should be used in treatment studies. We will provide an
overview of cardiopulmonary phenotypic variability and discordance and
their implications for assessing patient prognosis and response to
therapies, and present a new perspective on neuromuscular-induced
sleep-disordered breathing, viewed in the context of new and emerging
therapies. Finally, we will consider which cardiac imaging modalities
should be used as outcome measures in studies assessing DMD heart
function, and take a look at novel therapeutic approaches to DMD heart
disease, including management of rhythm disorders and heart failure, and
the use of left ventricular assist devices.
Our goal with this Special Issue is to explore topics at the interface
of the new therapies, cardiopulmonary function, and patient survival. If
we succeed, then this collection will raise more questions than it
answers. For example, will the new therapies demonstrate long-term
cardiopulmonary efficacy? What are the most clinically meaningful
cardiopulmonary outcome measures, and what is the most valid methodology
to assess them? What ethical issues will arise from the new therapies?
For example, are the emerging therapies already viewed by clinicians,
patients, families and other stakeholders as potential cures? If so, how
has this perceptual shift transformed risk/benefit decisions regarding
participation in new therapies and invasive treatments like intubation,
implantable cardiac devices, and critical care? These issues affect all
stakeholders: patients, their families, clinicians, patient advocates,
and pharmaceutical and device developers. These issues also impact
societal support of therapeutic advances, including the payors who fund
patient care. This is the beginning of a new era in neuromuscular
cardiopulmonary medicine, as it enters the age of translational
medicine, and we hope that this Special Issue will introduce you to some
of the key topics in this rapidly evolving field of medicine.
References
1. Birnkrant DJ, Bushby K, Bann CM et al. Diagnosis and management of
Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health,
and orthopaedic management. Lancet Neurol 2018; 17(4): 347-361.
2. Sheehan DW, Birnkrant DJ, Benditt JO, et al. Respiratory management
of the patient with Duchenne muscular dystrophy. Pediatrics 2018;
142(Suppl 2): S62-S71.
3. Landfeldt E, Thompson R, Sejersen T, et al. Life expectancy at birth
in Duchenne muscular dystrophy: a systematic review and meta-analysis.Eur J Epidemiol 2020; 35(7): 643-653.
4. Jin JB, Carter JC, Sheehan DW, Birnkrant DJ. Cardiopulmonary
phenotypic discordance is common in Duchenne muscular dystrophy.Pediatr Pulmonol 2019; 54(2): 186-193.
5. Birnkrant DJ, Ararat E, Mhanna MJ. Cardiac phenotype determines
survival in Duchenne muscular dystrophy. Pediatr Pulmonol 2016;
51(1): 70-76.
6. McDonald CM, Gordish-Dressman H, Henricson EK et al. Longitudinal
pulmonary function testing outcome measures in Duchenne muscular
dystrophy: Long-term natural history with and without glucocorticoids.Neuromuscul Disord 2018; 28(11): 897-909.
7. Raman SV, Hor KN, Woiciech M, Cardona A, et al. Stabilization of
early Duchenne cardiomyopathy with aldosterone inhibition: results of
the multicenter AIDMD trial. J Am Heart Assoc 2019; 8(19)
doi.org/10.1161/JAHA.119.013501
8. Duboc D, Meune C, Lerebours G, et al. Effect of perindopril on the
onset and progression of left ventricular dysfunction in Duchenne
muscular dystrophy. J Am Coll Cardiol 2005; 45(6): 855-857.
9. Wang M, Birnkrant DJ, Super DM, Jacobs IB, Baher RC. Progressive left
ventricular dysfunction and long-term outcomes in in patients with
Duchenne muscular dystrophy receiving cardiopulmonary therapies.Open Heart 2018; 5(1):e000783. doi: 10.1136/openhrt-2018-000783.
10. Abreu NJ, Waldrop MA. Overview of gene therapy in spinal muscular
atrophy and Duchenne muscular dystrophy. Pediatr Pulmonol 2020.
doi.org/10.1002/ppul.25055
11. Maruyama R, Yokota T. Molecular diagnosis and novel therapies for
neuromuscular diseases. J Pers Med 2020; 10(3): E129. doi:
10.3390/jpm10030129.