Early Detection of Subclinical Cardiac Involvement with Novel Cardiac Imaging Modalities in a Patient with Becker Muscular Dystrophy

INTRODUCTION

Duchenne (DMD) and Becker muscular dystrophy (BMD) are X-linked genetic disorders of the dystrophin gene located at the Xp21.¹ DMD is characterized by the total absence or dysfunction while BMD is characterized by reduced expression of the dystrophin.¹ In BMD, asymptomatic cardiac involvement develops in over 70% of adult cases and cardiac symptoms are generally masked by the relative/preferred immobility.² The onset of symptomatic cardiac involvement in BMD is usually in the third decade of life and the severity or the age of onset shows no correlation to skeletal muscle involvement.²

Novel imaging techniques like cardiovascular magnetic resonance (CMR)³ and myocardial strain imaging⁴ has been shown to detect cardiac involvement by depicting early scar formations and regional wall motion abnormalities that may be under-diagnosed by conventional echocardiography. Recent data advocate early initiation of therapy to limit the deadly cascade of insidious cardiac deterioration in DMD/BMD implicating the importance of early diagnosis.⁵ Herein we report a BMD case with asymptomatic cardiac involvement demonstrated with novel cardiac imaging modalities.

CASE REPORT

A 33-year-old Caucasian male with a previous diagnosis of BMD admitted to our clinic for cardiac evaluation. BMD was diagnosed at the age of 30 with slightly progressive weakness in proximal muscle groups, calf pain on exercise and positive muscle biopsy immunohistochemical staining consistent with BMD (Figure 1). Screening for deletions/duplications in the dystrophin gene failed to detect a pathogenic mutation. His electromyogram showed myopathic changes, consisting of small polyphasic potentials, especially on the proximal upper extremities. He was being screened for cardiac involvement regularly by cardiac examination and transthoracic echocardiography transthoracic echocardiography (TTE) in every 6 months (recent TTEs were all reported to be "unremarkable"). He showed no angina, dyspnea, paroxysmal nocturnal dyspnea, syncope or palpitations. His daily activities were not restricted and his New York Heart Association Class was I. He had no family history of heart disease or myopathy and he was a smoker for the last 16 years (1 pack/day). His blood pressure was 125/75 mmHg and heart rate was regular (92 beats/min). His electrocardiography (ECG) showed sinus rhythm with ST-T wave abnormalities, R:S = 1.1 in V1, left posterior hemiblock, Q waves in V5-V6, with a rate of 95/min. A chest X-ray showed a normal cardiothoracic index (0.40). His laboratory values were in normal limits apart from highly increased creatin kinase (2423 U/L), slightly elevated aspartate and alanine transaminase (56 U/L, 66 U/L respectively) levels. NT-pro brain natriuretic peptide level was 20 pg/ml and troponin T < 0,01 μg/L. TTE was performed and slight regional wall motion abnormalities in basal and mid left ventricular (LV) inferolateral segments on parasternal short-axis views with a lower limit of normal LV ejection fraction (Simpson method 52%) were detected. We aimed to demonstrate myocardial deformation (strain) to confirm our visual findings on TTE so we assessed two-dimensional images with speckle tracking and demonstrated reduced strain values at basal anterior, anterior-septal and inferior wall (Figure 2A). The former two low strain regions were reported to be "normokinetic" on initial TTE. We also used CMR with late gadolinium enhancement (LGE) to accurately diagnose the localization and extent of myocardial involvement. CMR also revealed scar formations with LGE on anterolateral and mainly inferolateral segments with a LVEF of 45% (Figure 2B).

Figure 1.

Muscle biopsy immunohistochemistry for dystrophin showing weak and patchy staining.

Figure 2.

(A) Bull-eye plot of peak systolic longitudinal strain by speckle tracking echocardiography. The center represents apex, the rim represents the basal left ventricular segments. (B) Short-axis contrast cardiac magnetic resonance images of the patient. White arrow indicates subepicardial late gadolinium enhancement suggestive of scarring on mid-inferolateral segments.

We sought to rule out myocarditis, hypertrophic cardiomyopathy (HCM) and myocardial ischemia in a young male smoker with defined ECG and TTE abnormalities. Since genetic screening couldn’t reveal specific deletion/duplications, small deletions, insertions or single-base changes that are difficult to identify by routine assays may be thought of as approximately 15 to 20 percent of DMD/BMD mutations are.¹ In order to rule out major epicardial coronary occlusion or anomaly, we obtained a 64-slice coronary computed tomography angiography and all coronary arteries were patent with normal anatomy. Strikingly, our CMR findings were similar to the subepicardial pattern of patients with biopsy-proven myocarditis which myocardial damage in posterolateral LV wall is a predominant finding.⁶ However, inflammatory markers, cardiotropic viral titers or any history suggestive of myocarditis were absent. TTE ruled out the hypertrophic cardiomyopathy. Patients with clinical phenotypes suggestive of DMD/BMD, but without a clear X-linked pattern of inheritance or negative genetic screening, may have defects in other genes, including those encoding the dystrophin-associated glycoproteins like Limb-girdle muscular dystrophy.

DISCUSSIONS

It is well demonstrated that extensive cardiac fibrosis/scarring is already present even in the hearts of BMD/DMD patients with preserved LV systolic function.^2,4,5 The presence of subtle abnormalities such as sinus tachycardia may indicate early cardiac involvement² leading to symptomatic cardiac involvement with palpitations, dizziness, syncope, dyspnea, leg edema, or coughing.² Early diagnosis of cardiac involvement in patients with BMD may be useful, since an early institution of heart failure medication may lead to beneficial ventricular remodeling with improvement in LV systolic function or at least decelerate progressive dysfunction.⁵ In our case, angiotensin-converting enzyme inhibitor therapy (Ramipril) was initiated and planned to be titrated up to maximally tolerated dose as reported previously.⁷ As a well demonstrated anti-fibrotic approach in dystrophinopathic cardiomyopathy;⁵ mineralocorticoid receptor antagonists might also be a future combination candidate in his therapy.

This patient was failed to find a pathogenic mutation in the dystrophin gene and the diagnosis is made by a muscle biopsy. Therefore, the case is not a typical BMD. It was reported that the causative genetic variant is found in 82% of BMD cases.⁸ Around one-third of mutations are de novo in the affected male proband.⁹ Jones et al. illustrate the challenges in diagnosing males with potential dystrophinopathies due to single nucleotide variants in DMD causing missense substitutions or splicing abnormalities, and the importance of muscle biopsy for accurate diagnosis.¹⁰ Although genetic testing has replaced muscle biopsy analysis for diagnosis of many dystrophinopathies, in a small but important proportion of cases, current analysis methods may not detect clinically significant splice variants, complex rearrangements, or reliably infer likely pathogenicity of missense variants.¹⁰

LEARNING POINTS

Cardiac involvement in BMD may be under-diagnosed with conventional cardiac imaging techniques. Considering that skeletal muscle weakness is not correlated with the progression of cardiomyopathy in BMD patients, detailed and regular cardiac evaluation with novel and more accurate techniques seems to be necessary even in patients with mild proximal weakness.

FUNDING

None.

CONFLICT OF INTEREST

All authors declare no conflict of interest.