Abstract:
Desmoplakin Cardiomyopathy (DSP-CM) is a genetic condition resulting from abnormal variants of the desmoplakin protein – a primary component of the complex linking sarcomeres across cell-cell junctions. DSP-CM leads to the progressive deterioration of cardiac muscle, developing subepicardial fibrosis that spreads around the heart. While the genetics of DSP-CM are known, the cause of this phenotype, disease progression, and how progression can be mitigated are not well known. However, adverse myocardial mechanics, forming elevated stresses manifesting into progressive cell damage and fibrotic remodeling presents a potential explanation to this observed pathophysiological phenomena.
To examine this theory, we look to understand the biomechanics of the heart, which relies on a hierarchical anisotropic nonlinear passive response to effectively promote filling and contraction of heart chambers and deliver blood flow throughout the body. This mechanical function exhibits fractional viscoelasticity, showing a power-law distribution of relaxation and rate dependent effects. Utilizing this understanding, we examine (N=29) patient-specific DSP-CM models at varying stages in the time course of their disease. Patient images were used to create patient-specific models and study the passive and active stresses, with specific emphasis on the subepicardium. Diseased myocardium was also studied in baseline and genetically modified induced pluripotent stem cell (iPSC) cardiomyocytes, formed into tissues and stressed for 48hrs.
Both scales highlight the potential importance of cardiomyocyte power to the progressive deterioration of heart muscle in DSP-CM. At the whole-organ level, image analysis and universal ventricular coordinates highlight the common patterns of disease, which are examined for mechanical variables, highlighting the importance of stress and strain-rate in these areas. At the tissue scale, physiologically induced stress drives deterioration of DSP genetic variants, further accentuating the impact of power as a driving mechanism of cardiomyocyte damage. However, new results add a wrinkle to the story – accentuating the importance of viscoelastic biomechanics and mechanobiology to the mechanics of the heart.
Our results highlight the potential of cardiac biomechanics to elucidate the unique mechanics of the heart in disease – and the critical importance of understanding the mechanobiology of the heart. We demonstrate that DSP-CM shows progressive fibrosis that mirrors mechanics, providing potential clues to underlying drivers of damage and progressive fibrotic remodeling.
Keywords:
Cardiac Biomechanics; Fractional Viscoelasticity; Cardiomyopathy; Patient-Specific Modeling; Engineered Heart Tissues
Bio:
David Nordsletten is a Professor of Biomedical Engineering and Cardiac Surgery at the University of Michigan, Ann Arbor. He graduated with an BS degree in Biomedical Engineering and a Minor in Mathematics from the University of Minnesota, received a Whitaker fellowship to pursue a DPhil degree in Computer Science from Oxford University, and was a postdoctoral researcher at Massachusetts Institute of Technology and Oxford University. Dr Nordsletten was the recipient of a Healthcare Technology Challenge Award fellowship from the EPSRC. He also serves as editor-in-chief for the Springer-Nature Journal, Biomechanics and Modeling in Mechanobiology. His research team focuses on the development of heart and cardiovascular models and modeling techniques, with particular emphasis on integrating imaging and biomechanics / fluid mechanics principles.