Translational paradigms in scientific and clinical imaging of cardiac development

Abstract

Congenital heart defects (CHD) are the most prevalent congenital disease, with 45% of deaths resulting from a congenital defect due to a cardiac malformation. Clinically significant CHD permit survival upon birth, but may become immediately life threatening. Advances in surgical intervention have significantly reduced perinatal mortality, but the outcome for many malformations is bleak. Furthermore, patients living while tolerating a CHD often acquire additional complications due to the long-term systemic blood flow changes caused by even subtle anatomical abnormalities. Accurate diagnosis of defects during fetal development is critical for interventional planning and improving patient outcomes. Advances in quantitative, multidimensional imaging are necessary to uncover the basic scientific and clinically relevant morphogenetic changes and associated hemodynamic consequences influencing normal and abnormal heart development. Ultrasound is the most widely used clinical imaging technology for assessing fetal cardiac development. Ultrasound-based fetal assessment modalities include motion mode (M-mode), two dimensional (2D), and 3D/4D imaging. These datasets can be combined with computational fluid dynamics analysis to yield quantitative, volumetric, and physiological data. Additional imaging modalities, however, are available to study basic mechanisms of cardiogenesis, including optical coherence tomography, microcomputed tomography, and magnetic resonance imaging. Each imaging technology has its advantages and disadvantages regarding resolution, depth of penetration, soft tissue contrast considerations, and cost. In this review, we analyze the current clinical and scientific imaging technologies, research studies utilizing them, and appropriate animal models reflecting clinically relevant cardiogenesis and cardiac malformations. We conclude with discussing the translational impact and future opportunities for cardiovascular development imaging research.

Keywords: MRI; OCT; cardiac development; congenital heart defect; imaging; micro-CT; ultrasound.

Figure 1

Live 3D/4D Clinical Ultrasound Imaging: 3D rendered volume using real time 3D ultrasound of a fetus at 33 weeks displaying the four chamber view (A) and the left ventricular outflow tract with aortic valve (C) (Herberg, Steinweg et al. 2011), Ventricular septal defect (VSD) visualized through 3D ultrasound with live xPlane imaging (B) and live 3D ultrasound imaging of the VSD (D) (Xiong, Liu et al. 2012) LV = left ventricle, RV = right venricle, Ao = aorta, LA = left atrium, RA = right atrium, FO = foramen ovale

Figure 2

Schematic of Spatiotemporal Image Correlation Technology: Based on a simplified number of slices, frames per slice, and cycle duration, the heart is scanned in three consecutive slices over time (A), STIC reconstructs consecutive cycles generating a transient volume representing real time 3D ultrasound (B), multiple slices of the heart are acquired during a single ultrasound scan with STIC (C) (Yagel, Cohen et al. 2007)

Figure 3

Atrioventricular canal visualized with ultrasound biomicroscopy (55MHz) through different stages of cardiac development (C), Doppler ultrasound through the atrioventricular canal during development (Butcher, McQuinn et al. 2007) Scale Marks = 100µm

Figure 4

Cross sections of the ventricle in embryonic chick hearts visualized with OCT where endocardial spikes (arrows) are seen on the endocardial tube that is emptied (A) and filled (B) with blood during the heart beat (Manner et al 2009) Scale bar = 100µm *inner curvature

Figure 5

3D segmentation and quantiative analysis of the chick heart after microCT imaging at Day 4(A), Day 7(B), and Day (C) of development, Mathematical relationships of the myocardial volume compared to the entire embyro volume (D), and the chamber specific myocardial volume as compared to the whole heart volume (E)(Kim, Min et al. 2011) Scale Bar = 1mm, LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle

Figure 6

3D MRI scans (3 hrs) of extracted and fixed embryonic mice with spatial resolution of 19.5µm at E12.5 coronal slice (a), E12.5 transverse slice (b), E18.5 coronal slice (c), E18.5 transverse slice (d) (Petiet, Kaufman et al. 2008). Chick embryos imaged with MRI and 3D reconstructed at day 7 (e,f) and day 10 (g,h). The box represents the area that was reconstructed and the dashed lines show the level of the MRI slice (Hogers, van der Weerd et al. 2009) Scale bars = 1mm

Figure 7

Aortic arch WSS distributions found from CFD simulations for stage 21 chicks for a 2 aortic arch configuration (A) and 4 aortic arch configuration (B) (Kowalski, Dur et al. 2013). Acceleration, peak, and deceleration phases in the cardiac cycle are depicted in the CFD simulation data and the color scale ranges from 0–350 dynes/cm². CFD simulations showing the 3D hemodynamic environment in the atrioventricular region of the embryonic chick at HH17 (top) and HH23 (bottom). Arrows represent locations of vortices in the flow. Color legend in HH17 chicks show velocities ranging from 0–5cm/s and WSS ranging from 0–50 dynmes/cm². Color legend in HH23 chicks show velocities rangring from 0–15cm/s and WSS ranging from 0–80dynes/cm²(Yalcin, Shekhar et al. 2011)