Cardiac Manifestation and Clinical Management Strategies in Patients with Fabry Disease and Muscular Dystrophy
Creators: Kashyap, Niharika
Publisher: name: University of Alberta Library
Year: 2023

<p>Background<br>
Fabry disease (FD) and Muscular dystrophy (MD) are hereditary disorders with a high burden of heart disease recognized as a common cause of morbidity and mortality. The routine clinical care management of rare genetic diseases is complicated by extensive multisystem involvement, lack of clinical trials and established guidelines, and limited understanding of underlying characteristics that can predict patient prognosis. Our studies explore the utility of standard cardiac monitoring tools, including 12-lead electrocardiogram (ECG), transthoracic echocardiogram (TTE), and cardiovascular magnetic resonance (CMR) imaging), for phenotypic characterization and disease stratification of FD and muscular dystrophy.<br>
Methods and Results<br>
In Chapter 3, we collected clinical profiles and performed baseline CMR imaging in FD (n=95) patients. We identified clinical factors predictive of increased risk of major adverse cardiac events (MACE) in patients with FD targeted to improve clinical outcomes. Patients were followed over a median of 6.3 years (interquartile range [IQR], 4.5-7.0 years). Twenty-six patients reached the composite endpoint with a high prevalence of heart failure and cerebrovascular events, and zero occurrences of cardiac-related deaths. Patients with MACE had worse health-related quality of life scores. We performed multivariable Cox regression analysis and adjusted for age, and diagnoses dyslipidemia or hypertension. Hypertrophy and presence of myocardial fibrosis increase risk of MACE by 4 to 5 times, and dyslipidemia increases risk of MACE by three times. Early Fabry-specific treatment and close monitoring of comorbidities reduce cardiac complications and mortality. These findings highlight the importance of comprehensive multidisciplinary management to help improve outcomes in FD patients. <br>
In Chapter 4, this study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive Emery-Dreifuss muscular dystrophy (XLR-EDMD). Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations using a 12-lead electrocardiogram, 24-hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers. Conduction disease, requiring a permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period of five years, the cardiac status was shown to have stabilized in all the patients. We demonstrate the presence of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with XLR-EDMD. <br>
In Chapter 5, we prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle MD (LGMD), and myotonic dystrophy (DM1) over 7.7-years in addition to an age-and-sex-matched healthy control cohort (n=50). CMR markers, including 3D strain and fibrosis, were assessed for their respective associations with MACE. The dystrophinopathies and LGMD cohorts experienced reduced left ventricular ejection fraction (LVEF) and high burden of replacement fibrosis. In contrast, DM1 cohort experienced impaired systolic function particularly in patients with left bundle branch block and low ventricular mass. Markers of contractile performance were reduced in all MD groups compared to healthy controls. We followed patients over a median follow-up period of 5.2 years, in which 80 MACE occurred. While LVEF was independently predictive of MACE (adjusted hazard ratio [aHR]: 2.96), peak 3D strain amplitude offers greater predictive value (minimum principal [aHR: 5.48], maximum principal [aHR: 3.25], circumferential [aHR: 3.44], longitudinal [aHR: 3.39], and radial strain amplitude [aHR: 2.96]). The minimum principal strain Cox model was the strongest independent predictor and provided incremental value to LVEF to predict MACE in MD patients.<br>
Conclusions<br>
Cardiac dysfunction is observed across FD and MD subtypes and may benefit from therapeutic strategies centred around managing comorbidities and frequent monitoring with 12-lead ECG, TTE and CMR. CMR imaging was practical to distinguish the unique phenotypic profiles and predict the risk of MACE, particularly, LVH and LGE presence in FD patients, and reduced LVEF and 3D strain amplitudes in MD patients. </p>