Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

Abstract

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.

Multiscale cardiac imaging to capture the whole heart and its internal cellular architecture, with applications to congenital heart disease

“…The heart ultrastructural organization is needed for efficient heart pumping and is linked to the cell metabolism 23–25 . Structural malformations in the chambers, valves or vessels of the heart, together with disruptions to the organization or number of cardiac cells, and/or their ultrastructure, can compromise the heart’s ability to pump blood efficiently 8,10,13,26,27 . Anomalous structural and ultrastructural architectures can be detrimental to the heart’s capacity to adapt to new conditions imposed by corrective surgeries or other therapies intended to repair structural congenital heart defects.…”

“…While the structural (morphological or “geometrical”) characteristics of heart malformations have been extensively studied, it is largely unknown whether cardiac cells from malformed hearts are normal or to what extent they are compromised. Recent studies reveal an abnormal orientation of myocardial cells (the heart muscle cells) within CHD hearts 8–10 . Myocardial cells are elongated, cylindrical-like cells, that contract along their long axis.…”

“…In addition to changes in the myocardial organization, the sub-cellular contraction machinery of myocardial cells (e.g the myofibrils that contract the cell; and the mitochondria that provide energy for contraction) may also be compromised in CHD, affecting heart function. The extent to which the cells of malformed hearts exhibit deficiencies is unknown 8,10,13 . This is in part due to limitations of existing technologies that have not achieved precise multiscale mapping to decipher the association between structural and cellular deficiencies in the heart and beyond.…”

High-Resolution Episcopic Microscopy (HREM): Looking Back on 13 Years of Successful Generation of Digital Volume Data of Organic Material for 3D Visualisation and 3D Display

“…DMDD independent stand-alone studies researching genetic regulation of mouse development include the analysis of: normal and abnormal cardiovascular development [49][50][51][52][53][54][55][56][57][58][59][60][61]; the development of the limbs, cloaca and pancreas [42,[62][63][64]; ciliopathies [65]; and the characterisation of cardiac defects in Down syndrome mouse models [66,67]. Despite its value for analysing such processes in embryos between embryonic day E8.5 and E14.5, when organogenesis is already finished, HREM also proved its value for analysing developmental processes in very early embryos immediately after implantation [68].…”

Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

“…However, the mechanisms that lead to an anomalous cardiac architecture in CHD and the clinical consequences of it are unknown. Recent studies have revealed an abnormal orientation of myocardial cells (the heart muscle cells) within CHD hearts ( Garcia-Canadilla et al, 2019 ; Stephenson et al, 2018 ; Garcia-Canadilla et al, 2018 ). Myocardial cells are elongated, cylindrical-like cells, that contract along their long axis.…”