Alterations in Multi‐Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein‐C

Taylor, Erik N.; Hoffman, Matthew P.; Barefield, David; Aninwene, George E.; Abrishamchi, Aurash D.; Lynch, Thomas; Govindan, Serengulam V.; Osińska, Hanna; Robbins, Jeffrey; Sadayappan, Sakthivel

doi:10.1161/jaha.115.002836

Cited by 16 publications

(23 citation statements)

References 69 publications

(134 reference statements)

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“…Results are concordant with previous histological reports of myocyte disorganisation in HCM extending to the anterolateral and posterior LV walls (Maron et al 1992), and with the loss of the midwall circumferential layer (Kuribayashi & Roberts, 1992). Moreover, our results agree with recent work using generalised Q-space imaging applied to three homozygous Mybpc3 mouse models at post-natal weeks 10-12, which also showed varying degrees of global myoarchitectural disarray (Taylor et al 2016) with disruption of overall helical patterns and reduced slope of the HA transmural profile in the homozygous Mybpc3 knock-out mouse.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, our results agree with recent work using generalised Q‐space imaging applied to three homozygous Mybpc3 mouse models at post‐natal weeks 10–12, which also showed varying degrees of global myoarchitectural disarray (Taylor et al. ) with disruption of overall helical patterns and reduced slope of the HA transmural profile in the homozygous Mybpc3 knock‐out mouse.…”

Section: Discussionsupporting

confidence: 92%

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Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

et al. 2019

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Myoarchitectural disarray – the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild‐type, heterozygous and homozygous hearts (n = 56) from a Mybpc3‐targeted knock‐out HCM mouse model and imaged the 3D micro‐structure by high‐resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild‐type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild‐type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild‐type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

et al. 2019

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“…OM results imply that the dephosphorylation of cMyBP-C triggers a cascade whereby decreasing actomyosin interactions, inhibiting thin filament orientation, and decreasing myofilament calcium sensitivity finally lead to cardiac dysfunction, which is hard to reverse using only myosin activators. AAA mice also show an increase in transcript levels of sensitive molecular markers, such as atrial natriuretic factor and b-myosin heavy chain, suggesting that cardiac stress and initial remodeling at the molecular level (26), along with altered sarcomere structure, trigger changes in cardiac myoarchitecture causing ventricular dysfunction (34,71). Consequently, we further investigated this cascade effect by comparing 6-week-old mice with 12-week-old mice.…”

Section: Cmybp-c Dephosphorylation Triggers Cardiac Remodeling Affecting Calcium Cyclingmentioning

confidence: 99%

“…Moreover, decreased phosphorylation (i.e. dephosphorylation) in cMyBP-C alters cardiac sarcomere morphology with myoarchitectural disarray, causing contractile impairment (34) and inhomogeneity in excitation-contraction coupling (35), which can, in turn, inhibit actomyosin interactions and reduce contractile force (36). In addition, in vivo studies of haploinsufficiency (37,38) and knockout (39) mouse models of cMyBP-C show enhanced actomyosin interactions, decreased myofilament calcium sensitivity, and increased rate of force redevelopment (40).…”

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confidence: 99%

Phosphorylation of cardiac myosin–binding protein-C contributes to calcium homeostasis

Kumar

Haghighi

Kranias

et al. 2020

Journal of Biological Chemistry

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Cardiac myosin–binding protein-C (cMyBP-C) is highly phosphorylated under basal conditions. However, its phosphorylation level is decreased in individuals with heart failure. The necessity of cMyBP-C phosphorylation for proper contractile function is well established, but the physiological and pathological consequences of decreased cMyBP-C phosphorylation in the heart are not clear. Herein, using intact adult cardiomyocytes from mouse models expressing phospho-ablated (AAA) and phospho-mimetic (DDD) cMyBP-C as well as controls, we found that cMyBP-C dephosphorylation is sufficient to reduce contractile parameters and calcium kinetics associated with prolonged decay time of the calcium transient and increased diastolic calcium levels. Isoproterenol stimulation reversed the depressive contractile and Ca2+-kinetic parameters. Moreover, caffeine-induced calcium release yielded no difference between AAA/DDD and controls in calcium content of the sarcoplasmic reticulum. On the other hand, sodium–calcium exchanger function and phosphorylation levels of calcium-handling proteins were significantly decreased in AAA hearts compared with controls. Stress conditions caused increases in both spontaneous aftercontractions in AAA cardiomyocytes and the incidence of arrhythmias in vivo compared with the controls. Treatment with omecamtiv mecarbil, a positive cardiac inotropic drug, rescued the contractile deficit in AAA cardiomyocytes, but not the calcium-handling abnormalities. These findings indicate a cascade effect whereby cMyBP-C dephosphorylation causes contractile defects, which then lead to calcium-cycling abnormalities, resulting in aftercontractions and increased incidence of cardiac arrhythmias under stress conditions. We conclude that improvement of contractile deficits alone without improving calcium handling may be insufficient for effective management of heart failure.

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“…Reduced degree of helix angle at LV were reported in studying of the cardiac myosin binding protein-C using transgenic mice (Taylor et al 2016). However, few work previously reported on imaging the myofiber architecture change in the dystrophin-deficient hearts except for a DTI study of sheet angle difference in hearts (Cheng et al 2012).…”

Section: Introductionmentioning

confidence: 98%

Imaging 3D tissue fiber organization using optical polarization tractography

Wang¹

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Optical polarization tractography (OPT) is a new imaging technology developed based on an advanced Jones matrix implementation of polarization-sensitive optical coherence tomography (PSOCT). OPT can acquire high-resolution, three-dimensional (3D), depth-resolved images of fiber organization in tissue. To validate OPT's accuracy in measuring fiber orientation, a comprehensive histology comparison study was conducted using heart tissues which are known to have a depth-dependent fiber orientation change. A systematic image processing procedure was developed to register histology images with OPT images so that the pixel-wise difference between the two measurements can be compared in details. The validation results indicated that OPT can reveal the tissue fiber tractography with histology-like resolution. OPT was then applied to image freshly excised heart samples of the mdx mouse model of Duchene muscular dystrophies (DMD). A rotational imaging platform was developed to obtain OPT images of the excised whole mouse heart. The imaging light was repetitively scanned along the long axis of the heart while the heart was rotated continuously on the imaging platform. The acquired 3D image data were then transformed to construct the 3D whole heart image. The "cross-helical" laminar architecture of the myocardial fibers can be clearly visualized. More importantly, the OPT results revealed significant global and microscopic structural remodeling in the heart of the mdx mouse. OPT can also be applied to image fiber organization in other fibrous tissue samples. For example, OPT revealed focal fiber disorganization in the tibialis anterior (TA) muscle of the mdx mouse, which was confirmed in histology as muscle damage. The 3D OPT images of the TA muscle can be quantified by analyzing the randomness of the fiber orientation distribution. A "fiber disarray" index can be computed to automatically identify and visualize all damaged tissues in the 3D TA muscle. Since the OPT only images the projected fiber orientation within a plane perpendicular to the light propagation, a dual-angle imaging procedure was developed to obtain the absolute 3D fiber orientation. The two 3D OPT images of the same tissue acquired at two different view angles were registered to reconstruct the image of the absolute 3D fiber orientation. This new method was validated by imaging a mouse extensor digitorum longus (EDL) muscle placed at various known positions. The capability of this dual-angle OPT method was demonstrated by visualizing the absolute 3D muscle fiber structure in mouse TA muscles and the unique arcade collagen fiber architecture in a piece of articular cartilage. In summary, the results presented in this dissertation study indicated that the newly developed OPT technology can obtain high-resolution 3D image of tissue fiber organization. OPT may provide a practical tool for studying disease related fiber structural changes in many fibrous tissues.

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Alterations in Multi‐Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein‐C

Cited by 16 publications

References 69 publications

Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

Phosphorylation of cardiac myosin–binding protein-C contributes to calcium homeostasis

Imaging 3D tissue fiber organization using optical polarization tractography

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