Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy characterized by progressive muscle weakness and atrophy. Though most investigations undoubtedly focus on the muscle, increasing evidence suggests that cardiac malfunction is a relevant cause of morbidity and mortality in patients with DMD. “With advanced DMD management and ventilatory support widely applied from 1990s, there is proportionate increase in cardiac causes of death over those associated with respiratory failure,” Florczyk-Soluch et al explained in a review article published in Cellular and Molecular Life Sciences.
Cardiac involvement in patients with DMD may arise by the age of 6 years due to the absence of dystrophin in cardiomyocytes. Most often, patients develop dilated cardiomyopathy, which can progress to end-stage heart failure along with associated supraventricular and ventricular arrhythmias.
Dilated cardiomyopathy is characterized by progressive myocyte loss that leads to a thinner left ventricular (LV) wall and LV dilatation. “In particular the repetitive mechanical stress leads to apoptosis and fibrotic substitution and scarring that proceeds from the epicardium to the endocardium, starting generally at the region behind the posterior and mitral valve apparatus,” Adorisio et al stated in a review article published in the Journal of Clinical Medicine. The injury extends toward the apex and around the heart, eventually culminating in the development of dilated cardiomyopathy.
Early detection of cardiac malfunction is of utmost importance to provide adequate clinical management and prevent heart failure in patients with DMD. Experts believe that “close monitoring by the cardiologists and early treatment, with adequate heart disease stratification, may be the key to prolong the lives of these patients until more promising therapies are available and can predict DMD prognosis and progression more accurately,” as stated by de Souza et al in Expert Review of Cardiovascular Therapy.
Dilated cardiomyopathy can occur at any age, though it often presents around 14 to 15 years of age and becomes frequent in DMD patients over 18 years old. Therefore, it is advisable to initiate the diagnostic assessment of heart conditions at the age of 6 years or at the time of DMD onset. Re-evaluation should be performed every 2 years until 10 years of age and annually thereafter.
Diagnosing Heart Disease in Patients With DMD
Cardiac imaging screening may detect cardiomyopathy in patients with DMD during the asymptomatic stages and prior to alterations in cardiac injury biomarkers. In fact, the diagnostic and prognostic values of serum markers, such as cardiac troponin I and T, in these patients are still controversial.
Electrocardiography, transthoracic echocardiography (ECHO), and cardiac magnetic resonance imaging (CMRI) are commonly used for assessing heart morphology and function in patients with DMD. Heart abnormalities usually found during cardiac screening include sinus tachycardia, short PR interval, increased R/S ratio in the precordial leads with tall R waves, inferolateral Q waves, right axis deviation, and left atrial abnormality.
ECHO is essential to identify left ventricular myocardial dysfunction, which is defined by a left ventricular ejection fraction (LVEF) <55% and a fractional shortening (FS) <28%. Adorisio et al stated, “FS has been considered the best surrogate of LV systolic function, with respect to LVEF, for its high reproducibility.” The myocardial performance index is another early marker of LV dysfunction that can be used in patients with DMD.
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Patients with DMD also have increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E’ velocities compared to age-matched controls. In addition, nearly half of DMD patients showed abnormal myocardial strain.
However, Florczyk-Soluch et al advised, “the poor acoustic windows in DMD patients related to altered body habitus, with scoliosis and adiposity of chest wall, can affect the reproducibility and diagnostic utility of the ECHO measurement.”
On the other hand, CMRI can detect more subtle alterations and has become the method of choice for the study of ventricular structure and function. Moreover, the pattern and distribution of late gadolinium enhancement (LGE) aids the stratification of LV dysfunction severity. In combination with LGE, CMRI allows for tissue characterization and detection of fibrotic areas, which are associated with early-stage DMD. Adorisio et al explained that “the presence of a transmural LGE pattern, often located at the inferolateral wall, is an independent predictor of adverse cardiac events in DMD patients, also in those with a preserved LVEF.”
Treating Heart Disease in Patients With DMD
Clinicians are still lacking effective treatment options for DMD. Hence, current therapeutic approaches aim to either delay the onset of cardiac problems or manage the associated symptoms.
DMD patients with normal or ≥50% LVEF can be treated to delay the onset of cardiac dysfunction, usually with angiotensin-converting enzyme (ACE) inhibitors. For instance, early treatment with perindopril, an ACE inhibitor, hinders LV dysfunction and extends the survival of patients with DMD.
Few studies exist concerning the treatment of DMD patients with midrange systolic LV dysfunction, but ACE inhibitors, such as lisinopril and losartan, seem to help preserve ventricular function. The combination with other drugs is also promising. For instance, Adorisio et al indicated, “When the [dilated cardiomyopathy] is detectable even in case of mild reduction of ejection fraction (>45% LVEF), fosinopril or losartan with the combination of mineralocorticoid receptor antagonists (ie, eplerenone) might improve ventricular function.”
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Some studies have also suggested a beneficial effect of beta-adrenergic blocking agents (beta-blockers) in treating DMD patients with dilated cardiomyopathy, while others found no effect. Some studies concluded that combined therapy with ACE inhibitors and beta-blockers had greater effects in improving LV function and preventing major cardiac events (including death, heart failure exacerbation, and severe arrhythmias) than standalone treatment with ACE inhibitors.
Evidence also suggests that glucocorticoids (prednisone or deflazacort) are likely to have a cardioprotective effect, but the underlying mechanisms are not fully understood. Steroid-treated patients showed delayed development of ventricular dysfunction, improved LVEF and FS measurements, and reduced mortality.
In addition, loop diuretics, such as furosemide, might be useful to reduce systemic and pulmonary congestion in advanced stages of the disease. Patients that do not respond to loop diuretic agents alone may benefit from the addition of metolazone.
In advanced stages, cardiac transplantation and left ventricular assist devices are often needed. However, these options must be preceded by a solid evaluation and selection of the patients. Aspects such as kyphoscoliosis,
respiratory muscle weakness, and recovery and rehabilitation after surgery should be considered.
Cellular reprogramming is not only a promising investigational tool but also a novel therapeutic strategy for DMD. For instance, DMD-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed a similar cardiac phenotype to that found in patients with DMD, including increased levels of cytosolic Ca2+, mitochondrial damage, and cell apoptosis. However, some differences have also been reported. As highlighted by Florczyk-Soluch, “the reduced [automaticity] (low spontaneous firing rate) revealed in DMD iPSC-CMs is not characteristic for DMD patients, who usually present enhanced heart rate attributed to elevated sympathetic tone.”
On the other hand, they believe that “[iPSC-CMs] (with restored dystrophin expression and/or modification of secondary pathophysiological pathways) may constitute new options for DMD treatment by autologous transplantation.”
Accordingly, somatic genome editing experiments restored the expression of reframed dystrophin in myoblasts, improved cardiomyocyte calcium metabolism, and arrhythmogenic susceptibility, and rescued myogenic differentiation. Moreover, CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9-mediated deletion of specific exons in the dystrophin gene resulted in the production of functional dystrophin.
Florczyk-Soluch U, Polak K, Dulak J. The multifaceted view of heart problem in Duchenne muscular dystrophy. Cell Mol Life Sci. 2021;78(14):5447-5468. doi:10.1007/s00018-021-03862-2
Adorisio R, Mencarelli E, Cantarutti N, et al. Duchenne dilated cardiomyopathy: cardiac management from prevention to advanced cardiovascular therapies. J Clin Med. 2020;9(10):3186. doi:10.3390/jcm9103186
de Souza F, Bittar Braune C, Dos Santos Nucera APC. Duchenne muscular dystrophy: an overview to the cardiologist. Expert Rev Cardiovasc Ther. 2020;18(12):867-872. doi:10.1080/14779072.2020.1828065