The Ultrasound Window Into Vascular Ageing: A Technology Review by the VascAgeNet COST Action.

Non-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker.

Assessing hemodynamics from the photoplethysmogram to gain insights into vascular age: a review from VascAgeNet.

The photoplethysmogram (PPG) signal is widely measured by clinical and consumer devices, and it is emerging as a potential tool for assessing vascular age. The shape and timing of the PPG pulse wave are both influenced by normal vascular aging, changes in arterial stiffness and blood pressure, and atherosclerosis. This review summarizes research into assessing vascular age from the PPG. Three categories of approaches are described: 1) those which use a single PPG signal (based on pulse wave analysis), 2) those which use multiple PPG signals (such as pulse transit time measurement), and 3) those which use PPG and other signals (such as pulse arrival time measurement). Evidence is then presented on the performance, repeatability and reproducibility, and clinical utility of PPG-derived parameters of vascular age. Finally, the review outlines key directions for future research to realize the full potential of photoplethysmography for assessing vascular age.

Regulatory Requirements For Medical Devices And Vascular Ageing: An Overview.

The development and use of medical devices are subject to regulations and approval activities to enter the market. These are mandatory for manufacturers and have important implications for all involved professionals. In fact, the innovation process, starting from a clinical need, includes the identification of a solution and its implementation, and requires taking into account crucial aspects according to regulatory requirements in each phase. These include exemplary validation or risk management. The aim of this work is to provide an overview of some key aspects of regulation and their implementation in medical devices for vascular ageing assessment. In particular, regulatory scenarios in Europe, Australia and the United States of America are described and examples of marketed medical devices for vascular ageing assessment are provided. Strong and active links among industry, research, clinical experts and governments adds value for the community, requiring the ability to communicate between different skills and backgrounds: this multidisciplinary and multi-partner collaboration can speed up the innovation process and can increase the system's efficiency related to both social and ethical impact.

Technical Validation and Usability of a Portable Ultrasound-Based System for Carotid Assessment of Vascular Ageing: A Pilot Study.

OBJECTIVE: The objective of this work was to investigate technical validation and usability of an innovative, technically simple, easy-to-use, and portable integrated system to assess carotid function and structure by ultrasound. METHODS: The studied system integrated a hardware (the Interson SP-L01 embedded ultrasound probe [Interson, Pleasanton, CA, USA]) and a software measuring the instantaneous diameter of the carotid artery in real-time from B-mode ultrasound image sequences (Carotid Studio, by Quipu Srl [Pisa, Italy]). Technical validation was evaluated by intra-operator reproducibility of two measurements acquired by an expert operator, and agreement with state-of-the-art technique (Mylab25 by Esaote SpA [Genova, Italy], Carotid Studio 4.3 by Quipu Srl) was evaluated in laboratory settings in 12 healthy volunteers; usability of the portable integrated system was investigated by administering questionnaires to users and the results were reported with scores based on a five-point scale. RESULTS: Twelve (12) healthy volunteers (five men, mean age 44.5±13.6 years, free of cardiovascular disease or risk factors), were recruited. Agreement with state-of-the-art technique was satisfactory, with no significant bias. Coefficient of variation (intra-operator reproducibility) was 3.2% (2.5% SD) for intima-media thickness, 0.9% (0.7% SD) for diameter, and 2.5% (2.2% SD) for distension. Usability questionnaires showed an overall positive judgement of the integrated system with respect to the traditional one, obtaining an average score greater than 4 (on a five-point scale). CONCLUSIONS: A portable, innovative prototype to easily assess ultrasound carotid parameters of vascular ageing was successfully designed, developed, and demonstrated to be comparable with state-of-the art technique. Usability was also satisfactory.

Cardiometabolic risk and subclinical vascular damage assessment in idiopathic inflammatory myopathies: a challenge for the clinician.

OBJECTIVES: A high prevalence of cardiovascular disease (CVD), not fully explained by the prevalence of traditional risk factors only, is reported in patients with idiopathic inflammatory myopathies (IIMs). Thus, we investigated if novel markers of CVD risk, like carotid diameter and advanced glycated end products, can better predict increased CVD risk in IIM patients. METHODS: We studied 43 consecutive patients diagnosed with IIM. All the patients underwent a clinical and laboratory evaluation of cardiovascular risk factors and characterisation of myositis disease activity. Non-invasive instrumental examinations performed included the measurement of carotid parameters (intima-media thickness, IMT and mean arterial diameter, mAD) by ultrasonic techniques, advanced glycation end-product accumulation in the skin by autofluorescence (AF) and body composition by bioelectrical impedance analysis. The parameters were compared to those measured in 29 controls, with similar mean age, BMI, blood pressure and smoking habits. RESULTS: IIM patients showed normal carotid IMT and distensibility, but higher carotid mAD (p=0.012), higher skin AF (p<0.001), lower fat free mass (p=0.036) and increased waist circumference compared to controls. A significant correlation was observed among AF and mAD (rho=0.317 p<0.05), carotid distension (rho=0.391 p=0.036) and IMT (rho=0.627 p<0.001). CONCLUSIONS: Abnormalities of the studied parameters suggest a higher risk of CV disease in IIM patients independent of disease activity. In this population, a thorough assessment of CV risk is recommended also in absence of overt CV disease during the clinical evaluation.

Unique device identification and traceability for medical software: A major challenge for manufacturers in an ever-evolving marketplace.

BACKGROUND AND OBJECTIVES: Similarly to what already established and implemented in the United States, the concept of the Unique Device Identification (UDI) system has been introduced with the European Regulations for medical devices MDR (EU) 2017/745 and in-vitro diagnostic medical devices IVDR (EU) 2017/746 and it is on the way to become a worldwide standard. The aim of this work was to provide a possible approach for the implementation of UDI and traceability in Europe for standalone software medical devices according to lifecycle and quality system standards. METHODS: The key points of the UDI regulation were determined and analyzed in order to identify the main issues related to the manufacturing of software medical devices and, in particular, labeling, privacy aspects, UDI assignment criteria, and international standards compliance. RESULTS: An approach for the management of each key point was suggested, resulting in different levels of implementation for UDI and traceability. CONCLUSIONS: Among the various types of medical devices, software is an increasingly large reality with very specific characteristics that must be taken into consideration. All the relevant aspects for the implementation of the UDI should be taken into consideration to combine safety and feasibility in order to effectively pursue the traceability of these medical devices.

Acute Cardiovascular Adaptation to Strenuous Exercise: An Integrative Ultrasound Study.

OBJECTIVES: The aim of this study was to evaluate the acute effects of participation in an Ironman distance triathlon competition on arterial function by ultrasound, in relation to cardiac function and body water content. METHODS: Twenty-eight male triathletes participating in an Ironman distance competition underwent carotid, femoral, and cardiac ultrasound examinations. Moreover, the presence of extravascular lung water was identified by lung echo B-lines (echogenic coherent wedge-shaped signal with a narrow origin from the hyperechoic pleural line) at rest and within 20 minutes of arrival. RESULTS: At the end of the competition, athletes showed an increased heart rate (mean ± SD, from 60.2 ± 13.1 to 82.8 ± 15.6 beats/min; P < .0001) and unchanged mean blood pressure (from 93 ± 14 to 91 ± 10 mm Hg; P > .05) in the presence of negligible dehydration (total body water from 48.0 ± 4.0 to 46.5 ± 3.9 kg; P > .05). Cardiac output increased (from 5.5 ± 1.2 to 6.7 ± 2.4 L/min; P < .05) in the presence of an unchanged stroke volume (from 64 ± 14 to 59 ± 16 mL; P > .05) and unchanged left ventricular elastance (from 1.52 ± 0.48 to 1.39 ± 0.48 mm Hg/mL/m2 ; P > .05). The mean carotid diameter increased (from 7.19 ± 0.65 to 7.61 ± 0.76 mm; P < .05), whereas the mean femoral diameter was unchanged at the end of the competition (from 10.41 ± 0.83 to 10.49 ± 0.82 mm; P > .05). Carotid intima-media thickness was significantly reduced (from 537 ± 70 to 495 ± 70 µm; P < .05), whereas B-lines increased significantly after the competition (from 1 [0-4] to 12 [5-23]; P < .0001). CONCLUSIONS: These data suggest different acute functional adaptation in central arteries with respect to peripheral leg vessels.

Carotid-Ventricular Coupling During Exercise: A Pilot Study.

OBJECTIVES: To evaluate carotid elasticity and left ventricular elastance during a graded bicycle semisupine exercise test in patients with known or suspected coronary artery disease and compare them with a control group of healthy young volunteers. METHODS: Thirty-six elderly patients and 18 young healthy volunteers were recruited. The right carotid diameter was estimated by an automatic system applied to B-mode sonographic sequences, central mean blood and pulse pressures by radial artery tonometry, and cardiac volumes by 2-dimensional transthoracic echocardiography; from these direct measurements, the carotid cross-sectional distensibility coefficient and left ventricular elastance index were obtained. Analyses were performed at rest, at peak stress, and during the recovery phase. RESULTS: The elderly patients included 20 men (mean age ± SD, 61 ± 8 years); the volunteers included 9 men (mean age, 34 ± 3 years). The mean blood pressure (at rest: patients, 97 ± 7 mm Hg; controls, 93 ± 9 mm Hg; not significant) increased similarly in both groups during exercise and decreased during the recovery phase. The diameter was higher in patients than controls (7.5 ± 1.1 versus 6.2 ± 0.5 mm) and increased significantly with exercise only in the latter group (at peak: 6.5 ± 0.6 mm; P < .05). The distensibility coefficient and elastance index were lower in patients than controls during the test phases [at rest: 24.5 ± 10.2 versus 60.8 ± 21.3 × 10(-3)/kPa and 3.6 ± 1.4 versus 1.6 ± 0.8 mm Hg/(mL/m(2))] and mostly changed in the controls, showing a decreased distensibility coefficient (peak: 40.6 ± 15.1 × 10(-3)/kPa) and an increased elastance index [peak: 5.9 ± 2.8 mm Hg/(mL/m(2))]. CONCLUSIONS: In older patients with multiple cardiovascular risk factors or established coronary artery disease, an abnormal carotid-ventricular adaptation to exercise was observed when compared to young healthy individuals.

Intima media thickness, pulse wave velocity, and flow mediated dilation.

The identification of vascular alterations at the sub-clinical, asymptomatic stages are potentially useful for screening, prevention and improvement of cardiovascular risk stratification beyond classical risk factors.Increased intima-media thickness of the common carotid artery is a well-known marker of early atherosclerosis, which significantly correlates with the development of cardiovascular diseases. More recently, other vascular parameters evaluating both structural and functional arterial proprieties of peripheral arteries have been introduced, for cardiovascular risk stratification and as surrogate endpoints in clinical trials. Increased arterial stiffness, which can be detected by applanation tonometry as carotid-femoral pulse wave velocity, has been shown to predict future cardiovascular events and to significantly improve risk stratification.Finally, earlier vascular abnormalities such as endothelial dysfunction in the peripheral arteries, detected as reduced flow-mediated dilation of the brachial artery, are useful in the research setting and as surrogate endpoints in clinical trials and have also been suggested for their possible clinical use in the future.This manuscript will briefly review clinical evidence supporting the use of these different vascular markers for cardiovascular risk stratification, focusing on the correct methodology, which is a crucial issue to address in order to promote their use in future for routine clinical practice.

Non-invasive assessment of carotid PWV via accelerometric sensors: validation of a new device and comparison with established techniques.

PURPOSE: Carotid pulse wave velocity (PWV) is considered as a surrogate marker for carotid stiffness and its assessment is increasingly being used in clinical practice. However, at the moment, its estimation needs specific equipment and a moderate level of technical expertise; moreover, it is based on a mathematical model. The aim of this study was to validate a new system for non-invasive and model-free carotid PWV assessment based on accelerometric sensors by comparison with currently used techniques. METHODS: Accelerometric PWV (accPWV) values were obtained in 97 volunteers free of cardiovascular disease (age 24-85 years) and compared with standard ultrasound-based carotid stiffness parameters, such as carotid PWV (cPWV), relative distension (relD) and distensibility coefficient (DC). Moreover, the comparison between accPWV measurements and carotid-femoral PWV (cfPWV) was performed. RESULTS: Accelerometric PWV evaluations showed a significant correlation with cPWV measurements (R = 0.67), relD values (R = 0.66) and DC assessments (R = 0.64). These values were also significantly correlated with cfPWV evaluations (R = 0.46). In addition, the first attempt success rate was equal to 76.8 %. CONCLUSIONS: The accelerometric system allows a simple and quick local carotid stiffness evaluation and the values obtained with this system are significantly correlated with known carotid stiffness biomarkers. Therefore, the presented device could provide a concrete opportunity for an easy carotid stiffness evaluation even in clinical practice.

Medical device regulation in vascular ageing assessment: a VascAgeNet survey exploring knowledge and perception.

BACKGROUND: Regulation has a key role for medical devices throughout their lifecycle aiming to guarantee effectiveness and safety for users. Requirements of Regulation (EU) 2017/745 (MDR) have an impact on novel and previously approved systems. Identification of key stakeholders' needs can support effective implementation of MDR improving the translation to clinical practice of vascular ageing assessment. The aim of this work is to explore knowledge and perception of medical device regulatory framework in vascular ageing field. RESEARCH DESIGN AND METHODS: A survey was developed within VascAgeNet and distributed in the community by means of the EUSurvey platform. RESULTS: Results were derived from 94 participants (27% clinicians, 62% researchers, 11% companies) and evidenced mostly a fair knowledge of MDR (despite self-judged as poor by 51%). Safety (83%), validation (56%), risk management (50%) were considered relevant and associated with the regulatory process. Structured support and regulatory procedures connected with medical devices in daily practice at the institutional level are lacking (only 33% report availability of a regulatory department). CONCLUSIONS: Regulation was recognized relevant by the VascAgeNet community and specific support and training in medical device regulatory science was considered important. A direct link with the regulatory sector is not yet easily available.

Unified Language for Knowledge Dissemination: The Vascular Ageing Glossary, an Initiative by VascAgeNet.

Objectives: In general, a terminology shared and agreed by different stakeholders is important to facilitate communication and cooperation. This holds true in the field of vascular ageing for the benefit of global cardiovascular health. The need to promote a common language and understanding across this area was recognised by VascAgeNet, a collaborative network with relevant and diverse expertise in the vascular ageing field, supported by the European Cooperation in Science and Technology. To contribute to the spread of unified terms in the vascular ageing field, a glossary was created by VascAgeNet and this paper describes the systematic process used for its development. Methods: An initial list of terms and preliminary definitions were collated from the network. A dedicated team was created to design the glossary development process, to facilitate its implementation and to maximise outreach and dissemination. The key steps of the process were to determine: (1) the target audience; (2) a list of priority terms; (3) a template structure for definitions; (4) methods for collecting feedback and (5) the dissemination plan. Results: An implementation strategy was provided for each key step and shared within the network; main decisions were agreed by all members of the glossary team. Small groups of definitions were released on a regular basis within a pilot phase including 19 terms (status: 05.09.2023) that were published openly at https://vascagenet.eu/official-glossary. Conclusions: The strategy for creating the first Vascular Ageing Glossary has been successfully designed and developed within VascAgeNet. A pilot phase covering the first publicly available terms was completed. The glossary is a living document, available to the scientific community, which aims to unify the vascular ageing language. Supplementary Information: The online version contains supplementary material available at 10.1007/s44200-023-00041-5.

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices.

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension.

Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Magnetic Resonance Imaging and Computed Tomography for the Noninvasive Assessment of Arterial Aging: A Review by the VascAgeNet COST Action.

Magnetic resonance imaging and computed tomography allow the characterization of arterial state and function with high confidence and thus play a key role in the understanding of arterial aging and its translation into the clinic. Decades of research into the development of innovative imaging sequences and image analysis techniques have led to the identification of a large number of potential biomarkers, some bringing improvement in basic science, others in clinical practice. Nonetheless, the complexity of some of these biomarkers and the image analysis techniques required for their computation hamper their widespread use. In this narrative review, current biomarkers related to aging of the aorta, their founding principles, the sequence, and postprocessing required, and their predictive values for cardiovascular events are summarized. For each biomarker a summary of reference values and reproducibility studies and limitations is provided. The present review, developed in the COST Action VascAgeNet, aims to guide clinicians and technical researchers in the critical understanding of the possibilities offered by these advanced imaging modalities for studying the state and function of the aorta, and their possible clinically relevant relationships with aging.

Relationship between measures of adiposity, blood pressure and arterial stiffness in adolescents. The MACISTE study.

OBJECTIVE: Children and adolescents with adiposity excess are at increased risk of future cardiovascular (CV) disease. Fat accumulation promotes the development of elevated blood pressure (BP) and arterial stiffness, two main determinants of CV risk which are strongly inter-related. We aimed at investigating whether the association between overweight and arterial stiffness, taken at different arterial segments, is mediated by increased BP or is BP-independent. METHODS: Three hundred and twenty-two Italian healthy adolescents (mean age 16.9±1.4 years, 12% with overweight) attending the "G. Donatelli" High School in Terni, Italy, underwent measurement of arterial stiffness by arterial tonometry (aortic stiffness) and semiautomatical detection of pressure-volume ratio of the common carotid (carotid stiffness). The mediator effect of BP was tested for each anthropometric or biochemical measure of fat excess related to arterial stiffness. RESULTS: Both carotid and aortic stiffness showed positive correlations with body mass index, waist, hip, and neck circumferences (NC). Only carotid stiffness, but not aortic stiffness, was associated with serum markers of fat accumulation and metabolic impairment such as insulin, homeostatic model of insulin resistance (HOMA-IR), serum gamma-glutamyl transferase (sGGT) and uric acid. The association with NC was stronger for carotid than for aortic stiffness (Fisher z -to- R 2.07, P  = 0.04), and independent from BP. CONCLUSIONS: In healthy adolescents, fat accumulation is associated with arterial stiffness. The degree of this association differs by arterial segments, since carotid stiffness is more strongly associated to adipose tissue excess than aortic stiffness and shows a BP-independent association with NC whereas aortic stiffness does not.

Vascular ageing: moving from bench towards bedside.

Prevention of cardiovascular disease (CVD) remains one of the largest public health challenges of our time. Identifying individuals at increased cardiovascular risk at an asymptomatic, sub-clinical stage is of paramount importance for minimizing disease progression as well as the substantial health and economic burden associated with overt CVD. Vascular ageing (VA) involves the deterioration in vascular structure and function over time and ultimately leads to damage in the heart, brain, kidney, and other organs. Vascular ageing encompasses the cumulative effect of all cardiovascular risk factors on the arterial wall over the life course and thus may help identify those at elevated cardiovascular risk, early in disease development. Although the concept of VA is gaining interest clinically, it is seldom measured in routine clinical practice due to lack of consensus on how to characterize VA as physiological vs. pathological and various practical issues. In this state-of-the-art review and as a network of scientists, clinicians, engineers, and industry partners with expertise in VA, we address six questions related to VA in an attempt to increase knowledge among the broader medical community and move the routine measurement of VA a little closer from bench towards bedside.

[Endothelial dysfunction. An integrated overview of the physiopatologic and diagnostic aspects]. / Disfunzione endoteliale: verso una visione integrata degli aspetti fisiopatologici e diagnostici.

Endothelial dysfunction is an early alteration in the atherosclerotic process. Cardiovascular risk factors induce endothelial dysfunction, characterized by impaired endothelium-dependent vasodilatation and by new proatherogenic, proinflammatory and prothrombotic properties. It is evident as the study of the endothelium could play a key role in the cardiovascular research and can be an useful tool for risk stratification in primary prevention of cardiovascular disease. An ideal approach for the comprehensive evaluation on endothelial physiopathology would take into account and integrate informations about endothelial biology (activation, injury and regenerative capacity) and endothelial function, so to be correlated with clinical data.

Medical Device Regulation: Should We Care About It?

Medical devices are subject to strict regulatory and approval processes to enter the market and to be used by operators and patients. These are needed to guarantee the users' safety. The different activities of these processes have important implications for all involved stakeholders and for the whole lifecycle of a medical device. The aim of this work is to provide an overview of some key aspects of the new EU Medical Device Regulation and to show why researchers, innovators and clinicians should care about it. Awareness of regulatory requirements can improve the innovation process and its efficiency in terms of both social and ethical impact, but this awareness needs to be raised in the upcoming months and years. One can shortly say "yes, one needs to take care" of the new EU Medical Device Regulation. First and foremost, it is crucial for the sake of the users' safety, which is the regulation's intrinsic goal. Second, it should not just be seen as an obstacle for new innovations in the medical domain, but as a chance as it can provide new opportunities.