• ultrasound
• portable system
• carotid distension
• carotid IMT

The overall burden of cardiovascular disease (CVD) is increasing worldwide and the capability of identifying high-risk individuals using reliable and feasible tools is a primary step in tackling the global healthcare challenge of CVD prevention.
Most of the recommended CVD risk prediction scores are solely dependent upon conventional risk factors (such as smoking, obesity, hypercholesterolemia, and hypertension) but it is widely accepted by the scientific community that the description of the cardiovascular status of a person, based only on classic risk factors, is not enough in terms of clinical effectiveness nor in terms of cost to the National Health System.
The ability to identify a "vulnerable" subject, through an effective screening model, can be increased by the introduction of innovative biomarkers, such as those measurable on biomedical signals and images, which are able to detect the presence of vascular damage at the sub-clinical and asymptomatic stage long before the onset of disease.
A leading cause for CVD is atherosclerosis. In the presence of an unopposed and excessive amount of fatty streak formation, the artery undergoes progressive atherosclerotic changes starting from endothelial dysfunction, and gradually remodelling the artery with wall thickening and arterial stiffening, up to vessel wall damage resulting in complicated stenotic lesion. Some of these changes, asymptomatic in the initial stages of atherosclerosis, can be non-invasively estimated by imaging as early biomarkers of atherosclerosis.
In the last years, significant effort has been made to develop reliable and non-invasive systems with the aim of establishing preventative strategies, methods of detection and risk-stratification, and therapeutic interventions by using image-based biomarkers. Researchers and clinicians rely heavily on the use of imaging modalities to quantify the burden of atherosclerosis in arteries including the aorta, carotid arteries, coronary arteries, peripheral vasculature, and microvasculature. Atherosclerosis imaging techniques include modalities with advantages such as high resolution and real time, but which conversely are invasive, time-consuming, and expensive, and expose the patients to ionizing radiations, such as angiography and computed tomography. Ultrasound imaging represents an accessible, safe, and low-cost technique that can be used for atherosclerosis imaging and assessment of the cardiovascular risk.
Recently, robust automated tools were developed, using various engineering methods, for quantification of wall thickness and carotid plaque measurements, the so-called image phenotypes, from B-mode carotid ultrasound.
Among carotid biomarkers of vascular aging, the most extensively studied were carotid Intima-Media Thickness (IMT) and arterial elasticity. Carotid IMT has been considered for a long time a surrogate marker for atherosclerosis and predictor of future vascular events that can be estimated by ultrasound imaging. Similarly, arterial stiffness represents an alteration in vascular function and structure, it is evident from the earliest stages of vascular aging and it has been included in the guidelines for the management of hypertension by the European Society of Hypertension and Cardiology as an important component for the overall cardiovascular risk assessment. The increase of arterial stiffness is measurable in different parts of the arterial tree and great attention has been placed on the local estimation at the carotid site by ultrasound imaging.
Unfortunately, the currently available approach for measuring these biomarkers, besides highly qualified and experienced operators, requires an awkward and bulky system. For the assessment of IMT, carotid diameter (D) and its distension (ΔD), three devices are often required: a standard ultrasound equipment for images acquisition, an automatic software able to provide the biomarkers estimation installed on a laptop, and a video converter connecting the two.
Hence, the general objective of this project is to make carotid biomarkers of atherosclerosis more easily accessible. In order to obtain a reliable and useful stratification of the cardiovascular risk, it is necessary to spread these innovative tools from the research setting to clinical practice and to provide a system configuration to be used also in out-of-office settings.
This research project consists in the development and validation of a device, based on an ultrasound data processing, for non-invasive assessment of carotid IMT and elasticity, which is portable, easy-to-use, low-cost, and reliable, able to provide a concrete technological solution for the implementation of a new screening model encouraged by the scientific community but still too far from reality.
This project intends to implement an approach, aimed at the early prevention of cardiovascular disease among the population, based on the evaluation of ultrasound carotid biomarkers for detecting the presence of pre-clinic atherosclerotic disease and monitor vascular changes due to disease/treatment. Specifically, a non-invasive, easy-to-use, and portable ultrasound system that can be used in screening campaigns in non-hospital facilities such as outpatient clinics, out-of-office settings, squares, etc. for the measurement of carotid IMT and stiffness has been designed and developed. This innovative system consists of an embedded ultrasound imaging system and a stand-alone software for the evaluation of the biomarkers, aiming to obtain an innovative, technically simpler, easier-to-use, and portable system to assess cardiovascular risk in a non-hospital facility.
The new generation of USB ultrasound probe has been deeply analysed for designing, developing, and then validating an innovative system for carotid biomarkers assessment. The innovative system, which is made up only by a light ultrasound probe connected via USB to a laptop running the software for the images analysis, overcomes the limitations of bulkiness, awkwardness and high cost that instead characterize the commonly used equipment. With this new configuration, the probe is directly attached to the computer, and it is no more necessary to use a video converter for retrieving the images coming from the ultrasound machine to be sent to the software for the processing because.
The design and development of this innovative system, which consists of the SP-L01 Linear Array Probe by Interson and the software Carotid Studio by Quipu Srl, included, in a first step, the integration between the hardware and the software.
Regarding the hardware component, an in-depth research to determine which devices were available on the market has been carried out, and among them, a comparison analysis in terms of technical specifications, integration, available source code, ultrasound image quality, usable probes, cost, and regulatory requirements (for example FDA approval and/or CE mark) was performed.
Regarding the software, Carotid Studio is a software for the estimation of vascular parameters by ultrasound imaging based on a well validated contour tracking algorithm.
This software medical device has achieved the CE mark according to the European Directive 93/42/EEC and subsequent amendments and supplements for medical devices. The software measures the diameter and the intima-media thickness in B-mode ultrasound image sequences of the longitudinal section of the carotid artery. The measurement is obtained automatically and in real-time, thanks to a well validated method that is based on a special contour tracking algorithm. The performance of the measurements, when performed with this kind of algorithm, depends not only on the robustness of the adopted algorithm, but also on the quality of the analysed scan, which is affected by device settings [11,12]. Therefore, within this work it was investigated how different image settings may affect carotid biomarkers estimation performed by the Carotid Studio. In fact, standardization of image settings for semi-automatic measure¬ments is required and it is particularly important especially when the measured parameters are widely used for the calculation of risk, the establishment of reference values and for the prediction of an outcome.
After having identified the software and the best device for the system (i.e., the hardware), the integration between the ultrasound probe and the software has been developed. This task has required the design and implementation of two software modules: a video interface module that should retrieve the images from the ultrasound system and send them to the software video player, and a control module that should accept commands from the user interface for controlling and adjusting the parameters of the ultrasound system (for example image depth, gain, focus depth, etc.). Both software modules were developed in C++ language by integrating the Software Development Kit (SDK) with the Qt platform (https://www.qt.io/). The Application Programming Interface (API) was integrated and used to communicate with the probe and to control and adjust the probe itself. The software modules were finally compiled for Windows operating system environment.
Then, the integrated system has been technically validated in terms of reproducibility of the measurement by an intra-operator inter-session study, with reproducibility expressed as coefficient of variation, and data were compared with the previously published papers regarding Carotid Studio performance. The system was also validated by in lab agreement with the reference technique, in which measurements obtained with the new system have been compared with those based on standard ultrasound equipment, and the agreement between the two approaches was evaluated by Bland-Altman plots.
Measurements of carotid D, IMT e ΔD were successfully analysed from all the sequences of images acquired with both the standard solution and the portable approach in twelve healthy volunteers, revealing good reproducibility of the measurements and agreement with state-of-the-art technique, with reference to values reported in the literature.
The integrated system was last validated in terms of usability, according to IEC 62336 “Medical devices — Part 1: Application of usability engineering to medical devices”, by collecting usability information thanks to questionnaires distributed to physicians testing the system, to ensure safety and confirm the improvement of the new approach.
The usability results evidenced that the new approach is overall very satisfying as regard to its general quality, its easiness for the users that performed all the representative tasks, and its potential usage in clinical practice even though the need for reducing the time required to complete the configuration and for improving the suitability of the graphical user interface emerged.
The design and development of the integrated system has been managed also taking into consideration the regulatory framework of the medical devices. In particular, the new European Regulation (EU) 2017/745 on Medical Devices was published in May 2017 and took effect from 26 May 2021. It has introduced some aspects on how medical devices are investigated, approved, and monitored and affect their daily clinical practice of healthcare professionals in Europe. Medical devices definition includes software, and the new Regulation, for the first time, provides an entirely dedicated article to the rules for its classification (Par. 6.3, Rule 11). In this work, two class IIa medical devices have been assembled and they have been validated both from a technical and usability points of view. The risk management process has been considered during all the phases of the design and development according to the reference standards (i.e., ISO 14971 and IEC 62304) for this field of application. In addition, during this research period, some key points arising from the regulatory context, such as the traceability of the medical device and the quality management system of the manufacturer, have been examined in depth.
These preliminary results pave the way for a faster, simple evaluation of relevant carotid parameters, describing comprehensively different aspects of the vascular aging process and allowing multiparametric, accurate, assessment of individual CV risk. Furthermore, the new smart system will make it simpler to track the effect of targeted non-pharmacological and pharmacological treatments through repeated measures, thus accelerating the clinical development of new cardiovascular drugs.
In addition, the presented system is specifically designed to allow an easy assessment of carotid biomarkers in the largest possible population, including those considered at low or intermediate cardiovascular risk. The latter is the subset in which the measure of vascular aging has the highest predictive value when added to conventional risk scores. Early reclassification of patients as high risk based on vascular aging assessment is a crucial preliminary step to implement simple actions such as change in lifestyle, who could have a significant impact on mitigating the risk of developing overt disease. In order to reach this population at low-to-intermediate risk, preventive campaigns must take place outside the hospital, such as in pharmacies, squares, shopping mall or wellness centre. This approach is aimed of increasing in the general population the awareness of their vascular age and cardiovascular risk, thus promoting a healthier lifestyle and appropriate treatments.