Imaging and serum biomarkers for cardiomyopathy in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder characterized by profound muscle weakness and cardiomyopathy. DMD arises from mutations that completely ablate dystrophin production, and most commonly, these are large genetic deletions that disrupt the reading frame of the DMD gene. Becker Muscular Dystrophy (BMD) also arises from DMD gene mutations, but in BMD the nature of the gene mutations, typically in-frame genetic deletions, leaves some dystrophin protein production intact. Consequently, BMD patients have symptom onset later than DMD patients. Most DMD boys are diagnosed by age 5 with weakness and elevated serum creatine kinase. Boys with DMD are treated with glucocorticoid steroids to prolong ambulation and improve cardiopulmonary function.¹ Many young DMD boys will improve on motor function tests, especially after initiating steroids.² Despite steroids, most DMD patients lose ambulation in the early second decade, transitioning to full time wheelchair use.

Cardiomyopathy in DMD and BMD is frequent, with current guidelines recommending early institution of angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB), along with guidance on beta blockers and aldosterone antagonism.³ Early institution of guideline-directed medical therapy (GDMT) slows progression of DMD cardiomyopathy.⁴ Medical treatment, including steroids and GDMT, along with noninvasive respiratory support, has shifted the DMD lifespan so that many individuals now survive into the fourth decade. Although lifespan has improved, quality of life remains impaired by muscle weakness limiting activities of daily living.

Approved gene-directed treatments for DMD include exon skipping antisense drugs that produce re-framed dystrophin.⁵ These agents, which produce from 1-8% of dystrophin, require regular intravenous infusions. Viral gene therapy is currently being evaluated in clinical trials, and, to date, more than 150 boys with DMD have received adeno-associated viruses expressing micro-dystrophin. Because of limited viral carrying capacity, micro-dystrophin includes only a fraction of the entire dystrophin gene, specifically lacking many of dystrophin’s internal protein repeats. Micro-dystrophin retains dystrophin’s N- and C-terminus, and so micro-dystrophin is designed to mimic BMD. Since BMD patients also have muscle symptoms and develop cardiomyopathy, micro-dystrophin gene therapy cannot be expected to correct all symptoms.

Cardiomyopathy in both DMD and BMD presents as heart failure with reduced ejection fraction (HFrEF) with intense fibrofatty infiltration seen as delayed enhancement on cardiac magnetic resonance (CMR) imaging. Notably, with accompanying skeletal muscle loss of function and loss of ambulation and upper limb function, heart failure symptoms in DMD are more subtle than in ambulatory HFrEF patients, forcing greater reliance on surrogate measures. In DMD, cardiomyopathy is usually evident after onset of skeletal muscle weakness, but cardiomyopathy progression in DMD and BMD does not perfectly parallel skeletal muscle involvement.

Dystrophin plays an essential role in stabilizing the plasma membrane of cardiomyocytes as it does skeletal myofibers. However, respiratory function, degree of ambulation and physical activity, and stressors that impact cardiac load can affect the heart disproportionately, and these outcomes may not be readily predictable based on the primary dystrophin mutation. Developing biomarkers for cardiomyopathy progression in DMD can help guide the timing and delivery of treatment, which is especially important for the non-ambulatory patient.

A new paper by Soslow et al. now describes CMR and serum biomarker measurements in DMD participants who were enrolled from two prospective observational cohorts who were mostly treated with steroids and some cardiac medications.⁶ The DMD cohort had a median age of 12.9 years (range 7.4 to 27.5 years) at first imaging. At the time of first imaging, 70% of participants were treated with ACEi/ARB, while only 31% were treated with beta adrenergic blocker and only 9% were receiving aldosterone antagonism. During the 7 year study, 15 of 78 participants died (19%), and mortality was from both cardiac and respiratory causes (13/15). All deaths occurred under the age of 20, and over 70% died under age 15.

At the time of first imaging, the average LVEF was 57% (41% LVEF<55%) but 71% already had late gadolinium enhancement (LGE) mainly affecting the base, inferior and lateral LV segments, reflecting fibrofatty infiltration and indicating an active disease process in the myocardium. DMD hearts were also not significantly enlarged, which may reflect the nonambulatory status of the DMD participants. For those participants with repeated imaging, LVEF declined at a rate of 3% in one year and 5% over two years, and LGE also increased as well. LVEF decline correlated with mortality, as did global and mid-LV circumferential strain. Of the serum biomarkers evaluated, NTproBNP, but not BNP or troponin, associated with mortality. This point is clinically relevant since it underscores the importance of using the more sensitive NTproBNP to monitor DMD cardiomyopathy.

Although this was a single center study, the findings corroborate well with other reports and, together, these studies emphasize the rapid time course of DMD cardiomyopathy and the urgency needed to improve its treatment. Menon et al. previously correlated transmural LGE with ventricular tachycardia in a smaller DMD cohort.⁷ In an older DMD and BMD patients, Florian et al. associated LGE and adverse cardiac events.⁸ This study examined 88 DMD/BMD participants (mean age 29), and over the study interval (47±18 months), only two participants died or required transplant, the prespecified primary endpoint. Secondary endpoints of heart failure hospitalization and non-sustained VT were seen in 24% of the cohort, and both secondary endpoints correlated with LVEF and LGE, especially transmural LGE. In the Florian study, the use of ACEi/ARB, beta blocker and aldosterone antagonism was significantly correlated with a reduction in secondary endpoints. The younger cohort examined by Soslow had higher mortality than the older cohort studied by Florian. The higher mortality in the Soslow study might reflect the more severe DMD cohort, the longer study duration, and the underutilization of guideline-directed therapy for heart failure in the cohort, especially beta blockers.

A recent study also used CMR to ascertain trajectory of DMD cardiomyopathy. This study recruited DMD individuals from two sites (n=59 in total, ages 5.3 to 18yrs), and it evaluated change over time, highlighting shifts in circumferential strain as a biomarker for DMD cardiomyopathy progression.⁹ This group also identified a trend toward benefit from ACEi/ARB and found that loss of ambulation trended towards a worsening of peak circumferential strain.

Translating to the clinical care setting, these studies demonstrate that CMR imaging and NTproBNP are important biomarkers to assess cardiomyopathy progression in DMD, and, furthermore, these studies underscore the benefit of GDMT, especially beta blockers. In the clinical trial setting where more agents are undergoing evaluation, there is a pressing need for surrogate biomarkers for DMD cardiomyopathy. Traditional measures of heart failure symptoms are unreliable in patients whose ambulation and activities are compromised by primary neuromuscular weakness, forcing the use of imaging and blood biomarkers to assess patient wellbeing. The drug regulatory process has traditionally favored trial outcome measures such as MACE, 6 minute walk, and Kanas City Cardiomyopathy Questionnaire over biomarkers such as BNP and LVEF. However, because DMD is both rare and has accompanying muscle weakness, these and other biomarkers represent a practical means of assessing efficacy in the clinic and in clinical trials.