Label-Free Multiphoton Microscopy for the Detection and Monitoring of Calcific Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD) is the most common valvular heart disease. CAVD results in a considerable socio-economic burden, especially considering the aging population in Europe and North America. The only treatment standard is surgical valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. Novel diagnostic techniques and biomarkers for early detection and monitoring of CAVD progression are thus a pressing need. Additionally, non-destructive tools are required for longitudinal in vitro and in vivo assessment of CAVD initiation and progression that can be translated into clinical practice in the future. Multiphoton microscopy (MPM) facilitates label-free and non-destructive imaging to obtain quantitative, optical biomarkers that have been shown to correlate with key events during CAVD progression. MPM can also be used to obtain spatiotemporal readouts of metabolic changes that occur in the cells. While cellular metabolism has been extensively explored for various cardiovascular disorders like atherosclerosis, hypertension, and heart failure, and has shown potential in elucidating key pathophysiological processes in heart valve diseases, it has yet to gain traction in the study of CAVD. Furthermore, MPM also provides structural, functional, and metabolic readouts that have the potential to correlate with key pathophysiological events in CAVD progression. This review outlines the applicability of MPM and its derived quantitative metrics for the detection and monitoring of early CAVD progression. The review will further focus on the MPM-detectable metabolic biomarkers that correlate with key biological events during valve pathogenesis and their potential role in assessing CAVD pathophysiology.

Identification of MMP9 as a Novel Biomarker to Mitochondrial Metabolism Disorder and Oxidative Stress in Calcific Aortic Valve Stenosis

“…This includes mitochondrial fragmentation, mitochondrial dysfunction (such as excessive ROS accumulation), reduction of mitochondrial membrane potential, and mitochondrial metabolic disorders, such as the obvious downregulation of glutathione metabolism and the tricarboxylic acid (TCA) cycle. The study of Tandon et al [ 8 ] showed that changes in mitochondrial morphology may lead to the accumulation of collagen matrix in valve interstitial cells (VICs), which can be used as an index to evaluate early CAVS. The study of Morciano et al [ 9 ] showed that mitochondrial dysfunction can promote the synthesis of collagen matrix and alkaline phosphatase of VICs and accelerate the calcification process of CAVS.…”

Prognostic value of tumor necrosis based on the evaluation of frequency in invasive breast cancer

“…Thirdly, sections for MPM imaging could be obtained while H&E staining was routinely performed in the pathology laboratory, so the evaluation of clinical samples using the new method could be completed in the laboratory. Currently, MPM had been widely used in various diagnosis studies including dermatology, oncology, neurology, and cardiovascular disorders, and was expected to become a powerful clinical diagnostic tool [ 26 , 45 - 48 ]. In 2007, König et al reported the first clinical application of two-photon microendoscopy in detecting the extracellular matrix collagen and elastin in the dermis of patients with ulcers [ 49 ].…”

Improved segmentation of collagen second harmonic generation images with a deep learning convolutional neural network

“…Second harmonic generation (SHG) microscopy is a nonlinear optical technique that has been used to analyze collagen organization for a broad range of biomedical research applications including skin biomechanics and aging [1,2], ovarian cancer [3] and cardiovascular disease [4]. One key advantage of SHG microscopy is the ability to nondestructively quantify the three-dimensional (3D) organization of collagen fibers due to its intrinsic depth-sectioning capabilities.…”