Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophicmdxmouse hearts

Abstract

<jats:p>Cardiac dysfunction is a primary cause of patient mortality in Duchenne muscular dystrophy, potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between calcium mishandling and myocardial fiber/sheet function as a manifestation of dystrophin-deficient ( mdx) cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx ( N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate calcium concentrations. Optical mapping of calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular calcium reuptake, reflected by a 25% increase of decay times ( T<jats:sub>50</jats:sub>) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with calcium mishandling, ultimately culminating in increased fibrosis. The preservation of relatively normal calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic calcium, points to the significance of regional mechanical factors in the progression of the disease.</jats:p>

Diffusion tensor imaging and histology of developing hearts

“…The directional DTI parameters shown in Figs. and are consistent with previous cardiac DTI studies . Compared with D120, the HA distribution in the LV of 5 m significantly shifted toward circumferential orientation (17% increase) at the expense of significant reduction of LHF (by 44%) (Table ), while the HA slope decreased by 28% only in the RV (Table ).…”

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

“…Potentially, the increased dilation of ttubules on the order of ∼150 nm could lead to structural remodelling of the cellular cytoskeleton, leading to the displacement of LTTC and RyR in cardiac junctions on the order of 10-20 nm required to disrupt Ca 2+ release. Consistent with this proposal, the MDX mouse that has no dystrophin has disrupted cellular cytoskeleton (Viola et al 2014) and disrupted calcium release (Cheng et al 2012). In addition, the vinculin-talin-integrin system could likely have a role in t-tubule remodelling, given its linkage to the actin cytoskeleton (Ziegler et al 2008) and the promiscuity of integrin (depending on the receptor sub-type) to bind to different ECM components, including laminin, fibronectin and collagens, including types I, III, IV and VI (Ross and Borg 2001;Tulla et al 2001), which have all been shown to be within the t-tubules (Kostin et al 1998;Crossman et al 2017).…”

Heart structural remodeling in a mouse model of Duchenne cardiomyopathy revealed using optical polarization tractography [Invited]

“…Therefore the significantly different slope in fiber orientation changes over the depth cannot be caused by any differences in the wall thickness. It is important to note that this study only measured the helix angle of the 3D myocardial fiber located within the plane perpendicular to the incident light [2,8]. Therefore, any orientation changes in planes that are parallel to the incident light were not detected.…”

“…An iterative Jones calculus based algorithm was applied to extract the depth-resolved optic axis for mapping the fiber orientation [13]. The fiber orientation measured is between [-90°, 90°] and represents the projected orientations within the plane perpendicular to the incident light [8,14], which is analog to the "helix" angle measured in DTI [2,7]. The system has a 12.4 µm lateral resolution at the focus and a 5.9 µm axial resolution in tissue.…”

“…Mdx4cv mice develop a progressive cardiomyopathy that shares many features with the human disease [1]. Although mdx4cv mice have been studied extensively, the heart structural remodeling in this model has not been investigated in detail [2]. The heart is a highly adaptive organ and its structure may change in response to progressive deterioration of cardiac function.…”