A composite measurement concept for monitoring cardiac function in Fabry disease.

Abstract

Background: Fabry disease (FD) is an X-linked, multisystemic, progressive lysosomal disorder caused by GLA variants resulting in alpha-galactosidase A deficiency. Although cardiovascular disease is the leading cause of death in people with FD, the progression of cardiac dysfunction remains poorly understood, mainly due to a lack of clinical measurement tools for predicting cardiac progression risk over relevant timescales. New, accessible tools are needed to measure cardiac functional change and predict event risk over shorter timescales. Digital tools allow at-home, frequent data collection that could help detect elevated cardiac event risk, inform treatment and management, and support novel therapy development. Digital measures are designed, developed, and validated using recognized frameworks. We present a novel composite measurement concept aligned to established guidance that utilizes digital tools to improve the monitoring of cardiac function in FD.

Methods: A targeted literature search, patient advisory board, and clinician advisory board were conducted to identify important FD signs and symptoms and the most suitable cardiac patient-reported outcomes and digital tools for concurrent remote collection of subjective and objective data.

Results: The literature search highlighted a lack of FD-specific cardiac digital monitoring tools. Patient advisory board discussions and survey responses highlighted pain, gastrointestinal issues, and fatigue as important FD symptoms, and participants expressed a desire to understand how cardiac manifestations impacted these symptoms. The clinician advisory board noted a lack of specific diagnostic, monitoring, and prognosis (especially cardiac) tools in FD. The composite measurement concept was developed to capture the signs and symptoms most important to people living with FD, alongside heart-rate variability, electrocardiograms, blood pressure, and quality of life as relevant measures within the cardiac domain that can be staged in a progression model with clear group boundaries.

Conclusions: Based on work completed to date, developing a composite measurement concept that utilizes digital tools to improve the measurement of cardiac function in FD is conceptually possible and aligns with the evidentiary framework for designing and building a monitoring biomarker. This composite measurement concept could be used for future analytical validation, usability, and clinical validation, seeking to capture progressing cardiac dysfunction in people living with FD.