Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

Optical coherence elastography (OCE), a functional extension of optical coherence tomography (OCT), visualizes tissue strain to deduce the tissue’s biomechanical properties. In this study, we demonstrate intravascular OCE using a 1.1 mm motorized catheter and a 1.6 MHz Fourier domain mode-locked OCT system. We induced an intraluminal pressure change by varying the infusion rate from the proximal end of the catheter. We analysed the pixel-matched phase change between two different frames to yield the radial strain. Imaging experiments were carried out in a phantom and in human coronary arteries in vitro. At an imaging speed of 3019 frames/s, we were able to capture the dynamic strain. Stiff inclusions in the phantom and calcification in atherosclerotic plaques are associated with low strain values and can be distinguished from the surrounding soft material, which exhibits elevated strain. For the first time, circumferential intravascular OCE images are provided side by side with conventional OCT images, simultaneously mapping both the tissue structure and stiffness.

Photoacoustic (PA) imaging can be used to monitor flowing blood inside the microvascular and capillary bed. Ultrasound speckle decorrelation based velocimetry imaging was previously shown to accurately estimate blood flow velocity in mouse brain (micro-)vasculature. Translating this method to photoacoustic imaging will allow simultaneous imaging of flow velocity and extracting functional parameters like blood oxygenation. In this study, we use a pulsed laser diode and a quantitative method based on normalized first order field autocorrelation function of PA field fluctuations to estimate flow velocities in an ink tube phantom and in the microvasculature of the chorioallantoic membrane of a chicken embryo. We demonstrate how the decorrelation time of signals acquired over frames are related to the flow speed and show that the PA flow analysis based on this approach is an angle independent flow velocity imaging method.

Atherosclerosis is a lipid-driven and an inflammatory disease of the artery walls. The composition of atherosclerotic plaque stratifies the risk of a specific plaque to cause a cardiovascular event. In an optical resolution photoacoustic microscopy setup, of 45 μm resolution, we extracted plaque lipid photoacoustic (PA) spectral signatures of human endarterectomy samples in the range of 1150–1240 nm, using matrix assisted laser desorption ionization mass spectrometry imaging as a reference. We found plaque PA signals to correlate best with sphingomyelins and cholesteryl esters. PA signal spectral variations within the plaque area were compared to reference molecular patterns and absorption spectra of lipid laboratory standards. Variability in the lipid spectroscopic features extracted by principal component analysis of all samples revealed three distinct components with peaks at: 1164, 1188, 1196 and 1210 nm. This result will guide the development of PA-based atherosclerosis disease staging capitalizing on lipidomics of atherosclerotic tissue.

Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term 'vulnerable plaque' was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of 'vulnerability' of a specific lesion to the more comprehensive goal of identifying patient 'cardiovascular vulnerability'. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and 'local' diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of 'high-risk' plaques occurring in 'vulnerable' patients.

Imaging guidance is paramount to procedural success in minimally invasive interventions. Catheter-based therapies are the standard of care in the treatment of many cardiac disorders, including coronary artery disease, structural heart disease and electrophysiological conditions. Many of these diseases are caused by, or effect, a change in vasculature or cardiac tissue composition, which can potentially be detected by photoacoustic imaging. This review summarizes the state of the art in photoacoustic imaging approaches that have been proposed for intervention guidance in cardiovascular care. All of these techniques are currently in the preclinical phase. We will conclude with an outlook towards clinical applications.

Prospective identification of lipid-rich vulnerable plaque has remained an elusive goal. Intravascular photoacoustics, a hybrid optical and ultrasonic technology, was developed as a tool for lipid-rich plaque imaging. Here, we present the first in vivo images of lipid-rich coronary atherosclerosis acquired with this new technology in a large animal model, and relate them to independent catheter-based imaging and histology.

Intravascular photoacoustic/ultrasound imaging (IVPA/US) can image the structure and composition of atherosclerotic lesions identifying lipid-rich plaques ex vivo and in vivo. In the literature, multiple IVPA/US catheter designs were presented and validated both in ex-vivo models and preclinical in-vivo situations. Since the catheter is a critical component of the imaging system, we discuss here a catheter design oriented to imaging plaque in a realistic and translatable setting. We present a catheter optimized for light delivery, manageable flush parameters and robustness with reduced mechanical damage risks at the laser/catheter joint interface. We also show capability of imaging within sheath and in water medium.

Atrial fibrillation is a cardiac arrhythmia stemming from abnormal electrical conduction/impulse formation in the atria. To restore cardiac rhythm an RF ablation (RFA) procedure, interrupting aberrant electrical patterns, is commonly performed. One way of improving the procedure (current success rate 60%) is to enable visual feedback on lesion progression, thereby reducing complications linked to over-ablation and mitigating recurrent conductivity due to under-ablation. To visualize the ablation process, we propose photoacoustic (PA) imaging using an ablation catheter for light delivery and an ICE (Intracardiac Echo) catheter for signal reception In this work, we demonstrate two PA-enabled ablation catheters which provide sufficient optical intensity to image fresh and ablated porcine tissue ex vivo.

In interventional cardiology catheters are routinely used to access and treat defects and diseases in the heart. Image guidance using forward-looking (FL)ultrasound transducers at the tip of the catheter could give the physician visual feedback during complex procedures such as valve replacement or transseptal puncture. In this work, we investigate FL 3D imaging by integrating a 7 MHz single-element ultrasound transducer at the tip of a novel multi-steerable intracardiac catheter together with an optical shape sensing fiber (OSS). We tested the imaging capability of the integrated device on an ex-vivo pig heart. By acquiring ultrasound A-lines at different locations while steering the catheter tip, a sparse 3D image is obtained. To reconstruct a volumetric image from the sparse data we implemented an adaptive Normalized Convolution (NC)algorithm were the dimension, orientation and angle of the 3D anisotropic kernel changes dynamically according to the scanning path. We acquired ultrasound A-lines of the tricuspid valve and we computed the 3D image using NC with both an isotropic kernel and an anisotropic kernel. We successfully interpolated the sparse data obtaining 3D volumes of the heart. By using an anisotropic kernel better 3D reconstruction is achieved with higher detail information compared to the reconstruction obtained using an isotropic kernel. This pilot experiment demonstrates the potential of FL image guidance during intracardiac procedures using a single-element transducer integrated in a steerable catheter with an OSS fiber.

The absorption of nanosecond laser pulses induces rapid thermo-elastic deformation in tissue. A sub-micrometer scale displacement occurs within a few microseconds after the pulse arrival. In this Letter, we investigate the laser-induced thermo-elastic deformation using a 1.5 MHz phase-sensitive optical coherence tomography (OCT) system. A displacement image can be reconstructed, which enables a new modality of phase-sensitive OCT, called thermo-elastic OCT. An analysis of the results shows that the optical absorption is a dominating factor for the displacement. Thermo-elastic OCT is capable of visualizing inclusions that do not appear on the structural OCT image, providing additional tissue type information.

The information in an ultrasound image depends on the frequency that is used. In a clinical examination it may therefore be beneficial to generate ultrasound images acquired at multiple frequencies, which is difficult to achieve with conventional transducers. Capacitive micromachined ultrasonic transducers (CMUTs) offer a frequency response that is tunable by the bias voltage. In this study we investigate this frequency tunability for ultrasonic imaging. We characterized a CMUT array operated at bias voltages up to three times higher than the collapse-voltage. All elements of the array were connected to a single transmit and receive channel through a bias circuit. We quantified the transmit-receive and transmit sensitivity as a function of frequency for a range of bias voltages. Impulse response measurements show that the center frequency is modifiable between 8.7 MHz and 15.3 MHz with an applied bias voltage of −50 V to −170 V. The maximum transmit sensitivity is 52 kPa/V at a center frequency of 9.0 MHz with an applied bias voltage of −105 V. The −3 dB transmit range in center frequency accessible with the variable bias voltage is 6.7–15.5 MHz. This study shows that a collapse-mode CMUT can operate efficiently at multiple center frequencies when the driving pulse and the bias voltage are optimized. We demonstrate the usefulness of frequency tuning by comparing images at different optimal combinations of driving frequency and bias voltage, acquired by linearly moving the transducer across a tissue mimicking phantom.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice, with increasing incidence globally. RF ablation is a common treatment for AF, attempting to interrupt aberrant electrical patterns. The success rate of this procedure is suboptimal (∼60%), with a substantial amount of patients needing reintervention [1]. Providing the surgeon with real time feedback on lesion formation could increase the efficacy of this procedure [2]. We consider visible contrast in the lesion and routine intracardiac echography (ICE) guidance, to put forward photoacoustic/ultrasound imaging (PAUS) as a means to visualize the lesion. The objective of this study is to identify the optimum illumination wavelengths for lesion contrast and imaging depth [3].

Photoacoustic (PA) imaging offers several attractive features as a biomedical imaging modality, including excellent spatial resolution and functional information such as tissue oxygenation. A key limitation, however, is the contrast to noise ratio that can be obtained from tissue depths greater than 1-2 mm. Microbubbles coated with an optically absorbing shell have been proposed as a possible contrast agent for PA imaging, offering greater signal amplification and improved biocompatibility compared to metallic nanoparticles. A theoretical description of the dynamics of a coated microbubble subject to laser irradiation has been developed previously. The aim of this study was to test the predictions of the model. Two different types of oil-coated microbubbles were fabricated and then exposed to both pulsed and continuous wave (CW) laser irradiation. Their response was characterized using ultra high-speed imaging. Although there was considerable variability across the population, good agreement was found between the experimental results and theoretical predictions in terms of the frequency and amplitude of microbubble oscillation following pulsed excitation. Under CW irradiation, highly nonlinear behavior was observed which may be of considerable interest for developing different PA imaging techniques with greatly improved contrast enhancement.

Microbubbles are used to enhance the contrast in ultrasound imaging. When coated with an optically absorbing material, these bubbles can also provide contrast in photoacoustic imaging. This multimodal aspect is of pronounced interest to the field of medical imaging. The aim of this paper is to provide a theoretical framework to describe the physical phenomena underlying the photoacoustic response. This article presents a model for a spherical gas microbubble suspended in an aqueous environment and coated with an oil layer containing an optically absorbing dye. The model includes heat transfer between the gas core and the surrounding liquids. This framework is suitable for the investigation of both continuous wave and pulsed laser excitation. This work utilizes a combination of finite difference simulations and numerical integration to determine the dependancy on the physical properties, including composition and thickness of the oil layer on the microbubble response. A normalization scheme for a linearized version of the model was derived to facilitate comparison with experimental measurements. The results show that viscosity and thickness of the oil layer determine whether or not microbubble resonance can be excited. This work also examines the use of non-sinusoidal excitation to promote harmonic imaging techniques to further improve the imaging sensitivity.