FIG 5.13 Myocardial cell biology and human disease Three examples illustrating facets of cell biology, each resulting in human cardiac disease All involve loss of function mutations in which a critical protein is either not made or is nonfunctional For clarity, many details in the disease processes are omitted in the diagrams (A) The structural underpinnings of dystrophin's function, whose total loss results in Duchenne muscular dystrophy, and partial loss results in Becker muscular dystrophy The protein links the actin cytoskeletal components to the membrane and then to the extracellular matrix, forming an integral part of the cardiomyocyte's ability to manage the repeated cycles of mechanical stress (B) The role of LAMP2 in binding and then translocating chaperone-mediated cargo for degradation and recycling in the lysosome via chaperone-mediated autophagy Loss of function of this protein results in Danon disease Arrow 1, The misfolded protein is attached to specific chaperones and targeted to LAMP2 Arrow 2, Unfolding begins as the co-chaperones are released and LAMP2 forms oligomers Arrow 3, In an energy-requiring step powered by guanosine triphosphate (not shown), the protein is translocated to the interior of the lysosome through a 4n oligomer of LAMP2, where it is accessible to lysosomal hydrolases and other proteases for degradation (C) The action of the protein tafazzin, which is critical for correctly remodeling and synthesizing the active forms of the glycoprotein cardiolipin Tafazzin loss of function causes the accumulation of incomplete or mismodeled cardiolipin species that are non- or hypofunctional, resulting in compromised mitochondrial structure, function, and respiration deficits At 2.2 Mb and 79 exons, the dystrophin gene (DMD) is the largest known human gene Missense mutations are rare and most DMD mutations are large deletions (~70%) or duplications (~10%) of one or more exons However, ~20% are smaller mutations, often disrupting a splice site as outlined above (see Fig 5.6) and we now consider these mutations in some detail Interestingly, most deletion mutations are concentrated in exons 45-55 and most duplications in exons 2-10 Those mutations that do not affect the reading frame will allow translation of a slightly longer or shorter central portion of dystrophin, leaving intact the N- and C-terminal domains, regions that are critical for dystrophin to connect the extracellular matrix to actin and hence preserve some protein functionality Most Becker muscular dystrophy–related mutations preserve the reading frame, allowing production of abnormal dystrophin with altered functional qualities and resulting in a less severe phenotype compared to DMD However, many DMD deletion/duplications and most mutations result in a reading frame shift or otherwise generate a premature stop codon (see Fig 5.6), in which case the protein is significantly truncated and cannot stably integrate into the sarcolemma This results in the characteristic absence of dystrophin in patients with DMD.232 The disease course is characterized by progressive skeletal muscle weakness, respiratory insufficiency, and cardiomyopathy resulting in heart failure At the cellular level (see Fig 5.13), lack of dystrophin results in sarcolemma fragility, which, in turn leads to microlesions and eventually altered calcium homeostasis, mitochondrial function, neuronal nitric oxide synthase activity and cell death Contributing to the pathology downstream is altered cell regeneration, inflammation, and replacement fibrosis Corticosteroids, the mainstay of treatment, can ameliorate the downstream inflammation but do not directly address the basic problem of dystrophin deficiency.233,234 DMD and the consequences of therapy affect multiple organ systems: musculoskeletal, pulmonary, cardiovascular, endocrine, and digestive Cognitive dysfunction and behavioral disorders are present in approximately 30% of the patients, which is not surprising since dystrophin is expressed in the brain Because of broad spectrum pathology, multidisciplinary teams are well suited to provide care for these patients and typically involve neurology, cardiology, pulmonology, orthopedics, rehabilitation medicine, endocrinology, gastroenterology/nutrition, behavioral medicine, and palliative care The average life expectancy is typically 18 to 19 years of age However, advances in supportive care, especially noninvasive mechanical ventilation,235,236 have resulted in survival into the fourth decade of life.237 Cardiac involvement in DMD includes cardiomyopathy and/or arrhythmia.238 Histologic examination of myocardium typically shows areas of myocyte hypertrophy and atrophy interspersed with regions of fibrosis While current recommendations are to begin cardiac screening at age 6 with an electrocardiogram and echocardiogram, it is unusual for changes in cardiac function to manifest by echocardiography before age 10 years Nevertheless, these early studies establish a baseline of cardiac function and may be useful in planning for anesthesia as DMD patients may require surgery to treat noncardiac manifestations In addition, the baseline echocardiogram will reveal structural defects such as an atrial septal defect, ventricular septal defect, or patent ductus arteriosus, which also might be detrimental to cardiac function Finally, clinical manifestations of heart failure such as fatigue, weight loss, and intolerance of activities of daily living may not be recognized due to skeletal muscle disease, delaying cardiac-directed treatment It is recommended that DMD patients have these screening tests every 2 years until age 10 years, then annually thereafter as the risk of cardiomyopathy increases with age.230,239 Cardiac magnetic resonance imaging (cMRI) is becoming an increasingly popular modality to assess ventricular function In addition to circumventing the problem of poor echocardiographic windows in older DMD patients cMRI can assess for subepicardial fibrosis manifested by late gadolinium enhancement (LGE), interstitial fibrosis estimated by T1 mapping of extracellular volume, and circumferential strain analysis, which may detect systolic dysfunction before LVEF is measurably decreased.240,241 Female DMD carriers for a dystrophin mutation may be asymptomatic, but due to random X inactivation some may develop cardiac or skeletal muscle pathology similar to males with DMD Approximately 10% of DMD carriers are estimated to have cardiomyopathy, but this could prove to be an underestimate, and the percentage increase as advanced imaging techniques are more widely applied Recently cMRI has been used to assess ventricular function and myocardial fibrosis burden in DMD carriers In two recent small series, 18% to 40% of female carriers had decreased LVEF and ~35% to 70% had subepicardial fibrosis evidenced by LGE The average age of LGE(+) females was greater than LGE(−) females, and the extent of LGE also increased with age In both studies, approximately 50% of LGE+ subjects nevertheless had normal LVEF, indicating occult myocardial disease.242,243 While the effect on cardiomyopathy on the life expectancy of DMD carriers is not known, the American Academy of Pediatrics recommends routine follow-up for DMD carriers and treatment of those with evidence of cardiac involvement.244 The mainstays of pharmacologic therapy for DMD cardiomyopathy are ... Because of broad spectrum pathology, multidisciplinary teams are well suited to provide care for these patients and typically involve neurology, cardiology, pulmonology, orthopedics, rehabilitation medicine, endocrinology, gastroenterology/nutrition, behavioral medicine, and palliative care... occult myocardial disease.242,243 While the effect on cardiomyopathy on the life expectancy of DMD carriers is not known, the American Academy of Pediatrics recommends routine follow-up for DMD carriers and treatment of those with evidence of cardiac involvement.244