Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy that occurs in 1 in 3500 live-born male infants. DMD results from a mutation in chromosome Xp21.1, leading to a deficiency in the cytoskeletal protein dystrophin. Dystrophin is critical for sarcolemmal membrane stability, and its absence results in membrane disruption, altered intracellular calcium metabolism, and eventual myocyte necrosis and fibrosis. Clinically, this results in a myopathy, most notably of skeletal and cardiac muscle.

Cardiac symptoms have historically been noted late in the disease course in patients with DMD. The hallmark cardiovascular disease in DMD is dilated cardiomyopathy, with mortality of ≥30% reported in patients with DMD secondary to heart failure. Early recognition of myocardial dysfunction in patients with DMD is of significant clinical importance. Recent studies have shown the potential for reverse remodeling of detrimental changes in left ventricular (LV) structure and performance in patients with DMD, with improved longevity and clinical outcomes in these patients.

The identification of cardiovascular disease in patients with DMD has been the focus of considerable clinical interest for decades. Electrocardiographic abnormalities are common in patients with DMD. Sinus tachycardia is a frequent finding on 12-lead electrocardiography, as are conduction abnormalities including QT prolongation and right bundle branch block. An anterior QRS pattern is a classic finding and likely reflects the presence of myocardial fibrosis in the posterobasal LV wall. Although electrocardiographic abnormalities often suggest the presence of cardiac disease, serial noninvasive surveillance for evidence of myocardial dysfunction has traditionally relied on the evaluation of LV shortening fraction and ejection fraction. Similar to other diseases affecting LV performance, decreases in LV shortening fraction and ejection fraction in patients with DMD are often late findings and are not well suited to identify subclinical abnormalities of myocardial performance.

Diastolic filling abnormalities have been reported in patients with DMD. Diastole is an active myocardial process that is influenced by alterations in cytosolic calcium concentration and flux. The lack of dystrophin in patients with DMD disrupts sarcolemmal membrane integrity, resulting in altered intracellular calcium homeostasis and impaired ventricular relaxation. Adverse myocardial remodeling then follows, culminating in myocyte hypertrophy and fibrosis with decreased ventricular compliance. These changes in diastolic function often precede other more readily characterized changes in systolic performance, even in very young patients with DMD. Diastolic dysfunction is often present in the absence of significant symptoms or identifiable abnormalities of systolic function. In a recent study evaluating young asymptomatic patients with DMD, marked abnormalities of both ventricular relaxation and compliance were documented in this young cohort. Parameters of ventricular relaxation, including mitral inflow Doppler, mitral annular tissue Doppler (E′), and flow propagation velocity (Vp), were all shown to be adversely affected in patients with DMD, preceding detrimental changes in LV systolic performance. Noninvasive parameters of ventricular compliance, including mitral deceleration time, pulmonary venous atrial reversal duration, and surrogate ratios of LV filling pressure including mitral E/E′ and E/Vp, also were significantly affected early in the course of DMD. These abnormalities of diastolic function were highly predictive of the development of dilated cardiomyopathy with overt heart failure.

Subclinical abnormalities in LV systolic function have recently been reported in patients with DMD using tissue Doppler and strain rate imaging. Young asymptomatic patients with DMD ranging in age from 3 to 12 years were shown to have significantly decreased radial and longitudinal LV peak systolic strain and strain rate as well as systolic and diastolic tissue Doppler velocities compared with controls. These detrimental changes, however, were noted only in the LV inferolateral and anterolateral walls, while no significant changes were noted within the ventricular septum or right ventricular free wall. Early evidence of regional myocardial dysfunction in these myocardial segments may be attributed to increased wall stress as a result of the lack of dystrophin, a hypothesis supported by the presence of increased myocyte damage and myocardial fibrosis reported in other studies in these particular LV wall segments with ultrasound backscatter imaging and direct histologic inspection. Evidence of ventricular dyssynchrony in the inferolateral LV wall also supports the presence of regional contraction and conduction abnormalities in these particular regions in patients with DMD.

Similar cardiac involvement has been reported in female carriers of the X-linked dystrophinopathies, including both DMD and Becker muscular dystrophy (BMD). In these “carriers,” cardiac involvement predominates, with little or no skeletal muscle involvement clinically evident in the majority of patients. However, the incidence of cardiac disease varies significantly between reported series in this cohort of patients, primarily because of patient age at evaluation and the noninvasive methodologies used to characterize their cardiovascular status. Politano et al. published their 10-year serial follow-up data of 197 female carriers of DMD or BMD aged 5 to 60 years. Using 12-lead electrocardiography and M-mode echocardiography, 84% of women had clinically evident preclinical or overt cardiac disease identified during the study period. A clear age predilection was demonstrated in this cohort, with progression from normal cardiac status in the majority of girls aged 5 to 15 years to preclinical or overt heart disease in the older patients. Endomyocardial biopsies in seven carriers with clinically evident cardiac disease demonstrated characteristic changes at the sarcolemmal membrane level, the hallmark abnormality of dystrophinopathy.

A more recent report of a younger cohort of girls, aged 6 to 16 years, failed to demonstrate significant functional cardiac abnormalities. These 23 female carriers of DMD and BMD were evaluated with a 12-lead electrocardiography and M-mode echocardiography, with no reported abnormalities in their clinical status or noninvasive results. Importantly, the echocardiographic evaluation was limited to the assessment of LV wall thickness, chamber dimension, and fractional shortening and was performed in a significantly younger population.

In the current issue of the Journal of the American Society of Echocardiography , Weiss et al. present their institutional experience in the evaluation of female “carriers” of DMD and BMD using conventional two-dimensional and exercise stress echocardiography. The aim of their study was to ascertain the prevalence of cardiac contractile abnormalities in these female disease carriers. Twenty-four patients were evaluated with two-dimensional echocardiography at rest and during the performance of a standard exercise Bruce protocol. Compared with age-matched and gender-matched controls, female carriers of DMD and BMD exhibited lower LV ejection fractions at rest (0.56 ± 0.10 vs 0.62 ± 0.07, P = .02) and had significantly abnormal cardiovascular responses to exercise, including the development of an exercise-induced wall motion abnormality or a decrease in exercise LV ejection fraction (0.53 ± 0.14 vs 0.73 ± 0.07 in controls, P < .001). In all, 21 of the 24 patients had abnormal LV ejection fractions at rest or with exercise, with or without the presence of a regional wall motion abnormalities with exercise. Interestingly, wall motion abnormalities were more generalized in this cohort and did not localize to the inferolateral or anterolateral segments, as one would suspect from previously reported data in male patients with DMD or BMD. The authors conclude that significant LV systolic dysfunction is present in the majority of female “carriers” of X-linked dystrophinopathies and that these abnormalities can be unmasked by exercise.

This study emphasizes the potential clinical value of exercise echocardiography to identify subclinical abnormalities of global and regional myocardial function in asymptomatic “carriers” of X-linked dystrophinopathies. Although the present study cohort is substantially older than previously reported series and likely represents a more pronounced course of the disease, it underscores several important observations: (1) The term “carrier” should not be misinterpreted as “unaffected” in this disease process. Indeed, most asymptomatic women in this study had lower global LV ejection fractions at rest and subsequently demonstrated abnormal decreases in ejection fraction with exercise. The presence of regional wall motion abnormalities with exercise underscores the lack of myocardial reserve in these diseased myocardial wall segments. (2) Similarly, “asymptomatic” does not always mean “unaffected.” Male patients with DMD, because of their concomitant skeletal myopathy and decreased basal levels of activity, often do not present with clinical symptoms until very late in the disease course, when heart failure secondary to dilated cardiomyopathy predominates. Female “carriers” of DMD or BMD mutations most often do not have associated skeletal myopathies, and one would suspect that symptoms related to underlying cardiac disease may present earlier. However, many of these patients likely acclimate in their daily lives to their gradual decrease in systolic or diastolic performance, and only with provocative measures such as exercise stress do symptoms become clinically apparent. (3) Periodic evaluation in female “carriers” of X-linked dystrophinopathies is clinically important. Although often not as dramatic as in male patients with DMD, functional abnormalities of LV performance are present in many female carriers, who may benefit from early medical intervention strategies. Exercise stress testing appears to be an ideal modality to identify and serially follow regional and global LV dysfunction in these patients.

Although this report by Weiss et al. provides novel insights into the presence and severity of functional myocardial abnormalities in asymptomatic carriers of DMD and BMD mutations, this line of investigation could be strengthened in several ways: (1) The addition of noninvasive diastolic parameters to the evaluation of these patients both at rest and with exercise would be very enlightening. Previous studies in male patients with DMD have demonstrated significant abnormalities of LV relaxation and compliance that preceded abnormalities of LV systolic function. Although routine Doppler evaluation was performed in a small subset of patients at rest in the current study, a more comprehensive prospective approach is needed to identify and characterize important detrimental changes in diastolic function in this cohort. (2) Do “carriers” of these X-linked mutations exhibit similar regional changes in strain and strain rate imaging compared with male patients with DMD? Is exercise echocardiography not robust enough to detect these more characteristic regional myocardial abnormalities identified in patients with DMD in the inferolateral and anterolateral walls, or does this older “carrier” cohort manifest a more generalized myocardial distribution? The addition of more sensitive deformational techniques to the noninvasive evaluation of this patient population seems intriguing and clinically important. (3) Finally, at what stage should medical management be instituted to treat these abnormalities of ventricular performance? Is the left ventricle capable of reverse remodeling, similar to studies in younger male patients with DMD? Although a large multicenter study will likely be needed to address these and many other relevant questions, the present study sheds new light on the presence and extent of systolic dysfunction in this patient cohort and supports the recommendation that “carriers” of X-linked dystrophinopathies warrant close serial follow-up.