Baroreflex sensitivity is impaired in survivors of mild COVID-19 at 3-6 months of clinical recovery; association with carotid artery stiffness.

The association between the stiffening of barosensitive regions of central arteries and the derangements in baroreflex functions remains unexplored in COVID-19 survivors. Fifty-seven survivors of mild COVID-19 (defined as presence of upper respiratory tract symptoms and/or fever without shortness of breath or hypoxia; SpO2 > 93%), with an age range of 22-66 years (27 females) participated at 3-6 months of recovering from the acute phase of RT-PCR positive COVID-19. Healthy volunteers whose baroreflex sensitivity (BRS) and arterial stiffness data were acquired prior to the onset of the pandemic constituted the control group. BRS was found to be significantly lower in the COVID survivor group for the systolic blood pressure-based sequences (BRSSBP ) [9.78 (7.16-17.74) ms/mmHg vs 16.5 (11.25-23.78) ms/mmHg; p = 0.0253]. The COVID survivor group showed significantly higher carotid ß stiffness index [7.16 (5.75-8.18) vs 5.64 (4.34-6.96); (p = 0.0004)], and pulse wave velocity ß (PWVß ) [5.67 (4.96-6.32) m/s vs 5.12 (4.37-5.41) m/s; p = 0.0002]. BRS quantified by both the sequence and spectral methods showed an inverse correlation with PWVß in the male survivors. Impairment of BRS in the male survivors of mild COVID-19 at 3-6 months of clinical recovery shows association with carotid artery stiffness.

Central and local arterial stiffness in White Europeans compared to age-, sex-, and BMI-matched South Asians.

BACKGROUND: Ethnicity impacts cardiovascular disease (CVD) risk, and South Asians demonstrate a higher risk than White Europeans. Arterial stiffness is known to contribute to CVD, and differences in arterial stiffness between ethnicities could explain the disparity in CVD risk. We compared central and local arterial stiffness between White Europeans and South Asians and investigated which factors are associated with arterial stiffness. METHODS: Data were collected from cohorts of White Europeans (the Netherlands) and South Asians (India). We matched cohorts on individual level using age, sex, and body mass index (BMI). Arterial stiffness was measured with ARTSENS® Plus. Central stiffness was expressed as carotid-femoral pulse wave velocity (cf-PWV, m/s), and local carotid stiffness was quantified using the carotid stiffness index (Beta) and pressure-strain elastic modulus (Epsilon, kPa). We compared arterial stiffness between cohorts and used multivariable linear regression to identify factors related to stiffness. RESULTS: We included n = 121 participants per cohort (age 53±10 years, 55% male, BMI 24 kg/m2). Cf-PWV was lower in White Europeans compared to South Asians (6.8±1.9 vs. 8.2±1.8 m/s, p<0.001), but no differences were found for local stiffness parameters Beta (5.4±2.4 vs. 5.8±2.3, p = 0.17) and Epsilon (72±35 vs. 70±31 kPa, p = 0.56). Age (standardized ß, 95% confidence interval: 0.28, 0.17-0.39), systolic blood pressure (0.32, 0.21-0.43), and South Asian ethnicity (0.46, 0.35-0.57) were associated with cf-PWV; associations were similar between cohorts (p>0.05 for interaction). Systolic blood pressure was associated with carotid stiffness in both cohorts, whereas age was associated to carotid stiffness only in South Asians and BMI only in White Europeans. CONCLUSION: Ethnicity is associated with central but not local arterial stiffness. Conversely, ethnicity seems to modify associations between CVD risk factors and local but not central arterial stiffness. This suggests that ethnicity interacts with arterial stiffness measures and the association of these measures with CVD risk factors.

Evaluation of Pulse Contour Markers using an A-Mode Ultrasound: Association with Carotid Stiffness Markers and Ageing.

Vascular ageing is directly associated with the blood vessel wall structural and functional abnormalities. Pulse morphology carries information on these abnormalities, and pulse contour analysis (PCA) identifies key amplitudes and timing information on the pulse waveforms that has a prognostic value towards cardiovascular risk stratification. PCA markers derived from second derivative waveforms represent the accelerative and decelerative phase of an arterial pulse. In this work, second derivative diameter waveforms of central arteries such as carotid artery are obtained using an A-mode ultrasound device. The derived PCA markers (b/a, c/a, d/a, e/a, (b-c-d-e)/a) from diameter waveform is investigated for its association with central stiffness markers and aging. An observational and cross-sectional study on 106 subjects (51 male/55 females) was conducted for this investigation. The highest correlation (r = 0.5, P < 0.001) was observed between c/a and PWV, and the lowest correlation was between c/a and AC. Group average values of PCA markers for each age decade group were correlated strongly (r > 0.9, p < 0.001) with age. A change > 19% was observed between the group average values of PCA markers of the normotensive and hypertensive population. The applicability of aforesaid PCA markers on central pulse waveforms, measured using a noninvasive device in resource-limited field settings, would accelerate such large scale vascular screening that is essential to understanding the cardiovascular risks at a population level. Clinical Relevance- This study provides an investigation into using second derivative diameter waveforms obtained from the carotid artery to find its associations with arterial stiffness and ageing.

Estimation of Characteristic Impedance using Multi-Gaussian Modelled Flow Velocity Waveform: A Virtual Subjects Study.

Characteristic impedance (Zc) of the blood vessel relates the pulsatile pressure to pulsatile blood flow velocity devoid of any wave reflections. Estimation of ZC is useful for indirect evaluation of local pulse wave velocity and crucial for solving wave separation analysis (WSA) which separates the forward-backward pressure and flow velocity waveforms. As opposed to conventional WSA, which requires simultaneous measurement of pressure and flow velocity waveform, simplified WSA relies on modelled flow velocity waveforms, mainly introduced for the aorta. This work uses a multi-Gaussian decomposition (MGD) modelled flow velocity waveform to estimate ZC by employing a frequency domain analysis, which is applicable to other arteries such as carotid. Thus obtained ZC is compared with Zc estimated from true flow velocity waveform for healthy (virtual) subjects taken for the carotid artery. The MGD modelled flow velocity waveform estimated ZC for a range of 4.98 to 34.79 with a group average of 16.43±0.10. The difference between the group average values of both ZC was only 4.72%. A statistically significant and strong correlation (r = 0.708, p < 0.0001) was observed for ZC obtained from MGD modelled flow velocity waveform with ZC obtained from actual flow velocity waveform. The bias for ZC1 between the two methods was 0.74, with confidence intervals (CIs) between 7.44 and -5.96 for the Bland-Altman analysis. Therefore, ZC from MGD modelled flow velocity waveform is a potential surrogate of the flow velocity model for WSA at the carotid artery. Clinical Relevance- This study provides a new method to derive characteristic impedance without the measurement of actual flow velocity waveform. The method requires a single pulse waveform (pressure or diameter).

Time-warping for robust automated arterial wall-recognition and tracking from single-scan-line ultrasound signals.

Current ultrasound methods for recognition and motion-tracking of arterial walls are suited for image-based B-mode or M-mode scans but not adequately robust for single-line image-free scans. We introduce a time-warping-based technique to address this need. Its performance was validated through simulations and in-vivo trials on 21 subjects. The method recognized wall locations with 100 % precision for simulated frames (SNR > 10 dB). Clustering detections for multiple frames achieved sensitivity >98 %, while it was âˆ¼90 % without clustering. The absence of arterial walls was predicted with 100 % specificity. In-vivo results corroborated the performance outcomes yielding a sensitivity ≥94 %, precision ≥98 %, and specificity ≥98 % using the clustering scheme. Further, excellent frame-to-frame tracking accuracy (absolute error <3 %, RMSE <2 µm) was demonstrated. Image-free measurements of peak arterial distension agreed with the image-based ones, within an error of 1.08 ± 3.65 % and RMSE of 38 µm. The method discerned the presence of arterial walls in A-mode frames, robustly localized, and tracked them even when they were proximal to hyperechoic regions or slow-moving tissue structures. Unification of delineation techniques with the proposed methods facilitates a complete image-free framework for measuring arterial dynamics and the development of reliable A-mode devices.

Image-free ultrasound for local and regional vascular stiffness assessment: the ARTSENS Plus.

OBJECTIVE: The combined assessment of vascular health markers is crucial for identifying the cumulative burden of vascular risk factors early on, as well as the extent of vascular aging for effective prediction of future cardiovascular events. This work addresses the need for a currently nonexistent device or system that facilitates such combined assessment in clinical practice and large-scale screening settings. We report an image-free ultrasound device - ARTSENS Plus - developed for the measurement of local and regional arterial stiffness, central and peripheral blood pressure (BP), and vessel dimensions, all in one examination. METHODS: A preclinical study on 90 asymptomatic individuals verified the device's functionality under ARTERY Society guidelines. The device's accuracy of stiffness measures was validated against the reference measures. RESULTS: The interoperator and intraoperator variability was less than 7%. Carotid artery's lumen diameter and local stiffness indices and carotid-femoral regional pulse wave velocity showed excellent agreement with the references (absolute errors were less than 4.1, 9, and 4.1%, respectively). The carotid SBP was 10.02% lower than that of the brachial artery, as expected. CONCLUSION: The study demonstrated the device's ability to perform an effortless and reliable evaluation of the local and regional vascular stiffness and central BP with an accuracy that meets clinical standards.

Arterial pressure pulse wave separation analysis using a multi-Gaussian decomposition model.

Objective.Methods for separating the forward-backward components from blood pulse waves rely on simultaneously measured pressure and flow velocity from a target artery site. Modelling approaches for flow velocity simplify the wave separation analysis (WSA), providing a methodological and instrumentational advantage over the former; however, current methods are limited to the aortic site. In this work, a multi-Gaussian decomposition (MGD) modelled WSA (MGDWSA) is developed for a non-aortic site such as the carotid artery. While the model is an adaptation of the existing wave separation theory, it does not rely on the information of measured or modelled flow velocity.Approach.The proposed model decomposes the arterial pressure waveform using weighted and shifted multi-Gaussians, which are then uniquely combined to yield the forward (PF(t)) and backward (PB(t)) pressure wave. A study using the database of healthy (virtual) subjects was used to evaluate the performance of MGDWSAat the carotid artery and was compared against reference flow-based WSA methods.Main results.The MGD modelled pressure waveform yielded a root-mean-square error (RMSE) < 0.35 mmHg. Reliable forward-backward components with a group average RMSE <2.5 mmHg forPF(t) andPB(t) were obtained. When compared with the reference counterparts, the pulse pressures (ΔPFand ΔPB), as well as reflection quantification indices, showed a statistically significant strong correlation (r > 0.96,p < 0.0001) and (r > 0.83,p < 0.0001) respectively, with an insignificant (p > 0.05) bias.Significance.This study reports WSA for carotid pressure waveforms without assumptions on flow conditions. The proposed method has the potential to adapt and widen the vascular health assessment techniques incorporating pulse wave dynamics.

Image-Free Fast Ultrasound for Measurement of Local Pulse Wave Velocity: In Vitro Validation and In Vivo Feasibility.

Local pulse wave velocity (PWV), a metric of the target artery's stiffness, has been emerging in its clinical value and adoption. State-of-the-art ultrasound technologies used to evaluate local PWV based on pulse waves' features are sophisticated, non-real-time, and are not amenable for field and resource-constrained settings. In this work, we present an image-free ultrasound system to measure local PWV in real-time by employing a pair of ultrasound transducer elements. An in vitro study was performed on the arterial phantom to: 1) characterize the design aspects of the system and 2) validate its accuracy against beat-by-beat (invasive) local PWV measured by a reference dual-element catheter. Furthermore, a repeatability and reproducibility study on 33 subjects (21-52 years) investigated the in vivo measurement feasibility from the carotid artery. With the experimentally deduced optimal design (frame-rate =500 Hz, RF sampling rate =125 MHz, LPF cutoff =14 Hz, and order =4 ), the system yielded repeatable beat-to-beat measurements (variability =1.9 % and over 15 cycles) and achieved a high accuracy (root-mean-square-error =0.19 m/s and absolute-percentage-error =2.4 %) over a wide range of PWVs (2.7-11.4 m/s) from the phantom. Subsequently, on human subjects, the intra- and inter-operator PWV measurements were highly repeatable (intraclass correlation coefficient ). The system does not impose a demand for special processors with high-computational power while offering real-time feedback on acquisition and measurement quality and provides local PWV online. Future large population and animal studies are required to establish the device's clinical usability.

High-frame-rate A-mode ultrasound for calibration-free cuffless carotid pressure: feasibility study using lower body negative pressure intervention.

PURPOSE: Existing technologies to measure central blood pressure (CBP) intrinsically depend on peripheral pressure or calibration models derived from it. Pharmacological or physiological interventions yielding different central and peripheral responses compromise the accuracy of such methods. We present a high-frame-rate ultrasound technology for cuffless and calibration-free evaluation of BP from the carotid artery. The system uses a pair of single-element ultrasound transducers to capture the arterial diameter and local pulse wave velocity (PWV) for the evaluation of beat-by-beat BP employing a novel biomechanical model. MATERIALS AND METHODS: System's functionality assessment was conducted on eight male subjects (26 ± 4 years, normotensive and no history of cardiovascular risks) by perturbing pressure via short-term moderate lower body negative pressure (LBNP) intervention (-40 mmHg for 1 min). The ability of the system to capture dynamic responses of carotid pressure to LBNP was investigated and compared against the responses of peripheral pressure measured using a continuous BP monitor. RESULTS: While the carotid pressure manifested trends similar to finger measurements during LBNP, the system also captured the differential carotid-to-peripheral pressure response, which corroborates the literature. The carotid diastolic and mean pressures agreed with the finger pressures (limits-of-agreement within ±7 mmHg) and exhibited acceptable uncertainty (mean absolute errors were 2.4 ± 3.5 and 2.6 ± 4.0 mmHg, respectively). Concurrent to the literature, the carotid systolic and pulse pressures (PPs) were significantly lower than those of the finger pressures by 11.1 ± 9.4 and 11.3 ± 8.2 mmHg, respectively (p < .0001). CONCLUSIONS: The study demonstrated the method's potential for providing cuffless and calibration-free pressure measurements while reliably capturing the physiological aspects, such as PP amplification and dynamic pressure responses to intervention.

Separation of Forward-Backward Waves in the Arterial System using Multi-Gaussian Approach from Single Pulse Waveform.

The arterial pulse waveform has an immense wealth of information in its morphology yet to be explored and translated to clinical practice. Wave separation analysis involves decomposing a pulse wave (pressure or diameter waveform) into a forward wave and a backward wave. The backward wave accumulates reflections due to arterial stiffness gradient, branching and geometric tapering of blood vessels across the arterial tree. The state-of-the-art wave separation analysis is based on estimating the input impedance of the target artery in the frequency/time domain, which requires simultaneously measured or modelled flow velocity and pressure waveform. We are proposing a new method of wave separation analysis using a multi-gaussian decomposition. The novelty of this approach is that it requires only a single pulse waveform at the target artery. Our method was compared against the triangular waveform-based impedance method. We successfully separated forward and backward waveform from the pressure waveform with maximum RMSE less than 5 mmHg and mean RMSE of 1.31 mmHg when compared against the triangular flow/impedance method. Results demonstrated a statistically significant correlation (r>0.66, p<0.0001) for Reflection Magnitude (RM) and Reflection Index (RI) for the multi-gaussian approach against the triangular flow method for 105 virtual subjects. The range of RM was from 0.35 to 0.97 (RI: 27.53% to 49.29%). This method proves to be a technique for evaluating reflection parameters if only a single pulse measurement is available from any artery.Clinical Relevance- This simulation study supplements the evidence for wave reflections. It provides a new method to study wave reflections using only a single pulse waveform without the need for any measured or modelled flow.

Evaluation of Nonlinear Wave Separation Method to Assess Reflection Transit Time: A Virtual Patient Study.

Conventional methods to calculate reflection transit time (RTT) is based on pulse counter analysis. An alternative to this approach is separating forward and backward components from a pulse waveform to calculate the RTT. State-of-the-art in wave separation requires simultaneously measured pressure and flow velocity waveforms. Practically, getting a simultaneous measurement from a single arterial site has its limitations, and this has made the translation of wave separation methods to clinical practice difficult. We propose a new method of wave separation analysis that requires only a single pulse waveform measurement using a multi-Gaussian decomposition approach. The novelty of the method is that it does not require any measured or modelled flow velocity waveform. In this method, the pulse waveform is decomposed into the sum of Gaussians and reconstructed based on model criteria. RTT is calculated as the time difference between normalized forward and backward waveform. The method's feasibility in using RTT as a potential surrogate is demonstrated on 105 diverse selections of virtual subjects. The results were statistically significant and had a strong correlation (r>79, p<0.0001) against clinically approved artery stiffness markers such as Peterson's elastic modulus (Ep), pulse wave velocity (PWV), specific stiffness index (ß), and arterial compliance (AC). Out of all the elasticity markers, a better correlation was found against AC.Clinical Relevance-This simulation study supplements the evidence for the dependence of pulse wave reflections on arterial stiffness. It provides a new method to study wave reflections using only a single pulse waveform.

Automated measurement of compression-decompression in arterial diameter and wall thickness by image-free ultrasound.

BACKGROUND AND OBJECTIVE: The manual measurement of arterial diameter and wall thickness using imaging modalities demand expertise, and the state-of-art automated or semi-automated measurement features are seldom available in the entry-level systems. The advanced ultrasound modalities are expensive, non-scalable, and less favorable for field and resource-constrained settings. In this work, we present a novel method to measure arterial diameter (D), surrogate intima-media thickness (sIMT), and with them their intra-cardiac cycle changes by employing an affordable image-free ultrasound technology. METHODS: The functionality of the method was systematically validated on a simulation testbed, phantoms and, 40 human subjects. The accuracy, agreement, inter-beat, and inter-operator variabilities were quantified. The in-vivo measurement performance of the method was compared against two reference B-mode tools - Carotid Studio and CAROLAB. RESULTS: Simulations revealed that for the A-mode frames with SNR > 10 dB, the proposed method identifies the desired arterial wall interfaces with an RMSE < 20 µm. The RMSE for the diameter and wall thickness measurements from the static phantom were 111 µm and 14 µm, and for the dynamic phantom were 117 µm and 18 µm, respectively. Strong agreement was seen between the in-vivo measurements of the proposed method and the two reference tools. The mean absolute errors against the two references and the inter-beat variability were smaller than 0.18 mm for D and smaller than 36 µm for sIMT measurements. Likewise, the respective inter-observer variabilities were 0.16 ± 0.23 mm and 43 ± 25 µm. CONCLUSION: Acceptable accuracy and repeatability were observed during the validation, that were on a par with the recently reported B-mode techniques in the literature. The technology being real-time, automated, and relatively inexpensive, is promising for field and low-resource settings.

Local Evaluation of Variation in Pulse Wave Velocity over the Cardiac Cycle using Single-Element Ultrasound Transducer.

A method and system for single-site measurement of local pulse wave velocity (PWV) and its variation over the cardiac cycle are presented. The proposed system employs a single-element ultrasound transducer and associated custom technology to record arterial diameter and wall thickness waveforms in real-time. Simultaneously acquired blood pressure, diameter and wall thickness parameters were used to evaluate diastolic local PWV (CD) and systolic local PWV (Cs) from an arterial site of interest. The developed prototype system was validated on a cohort of 15 subjects (age $=43\pm 12$ years) that includes normotensives and hypertensives. Cs and CD measurements were obtained from the left carotid artery. A significant difference between carotid Cs and CD $(\Delta \mathrm{C})$ was observed in all recruited subjects (group average $\Delta \mathrm{C} = 0.92\pm 0.76\mathrm{m}/\mathrm{s})$, illustrating the arterial pressure dependency of local PWV. The absolute values of Cs and CD were within a range of 3.39 m/s to 7.5 m/s and 3.12 m/s to 5.82 m/s respectively. Normotensive versus hypertensive group-wise analysis was performed to investigate the degree of variation in the carotid local PWV over a cardiac cycle among different BP categories. Study results demonstrated that the proposed approach has a potential to provide valuable surrogate markers for cardiovascular risk assessment.

An In-Vivo Study on Intra-Day Variations in Vascular Stiffness using ARTSENS Pen.

This work presents investigations on intraday variations in arterial stiffness. For this purpose, an in-vivo study was conducted on five subjects over a duration of five consecutive days. Five stiffness index ($\beta $) measurements were obtained per day for each individual. Our clinically validated ARTSENS device was used to perform fully automated reliable stiffness measurements on the carotid artery. For each measurement, two trials were performed and averaged. These trials were observed to be repeatable with the coefficient of variation $< 0.72$%. For each day, one measurement that was performed immediately after the lunch was subject to intervention due to the consumed food, which significantly $( \mathrm {p}< 0.001)$ deviated from the mean baseline $\beta $ of the day. Such significant deviations were not observed for the rest measurements that were performed in the absence of an intervention. Two subjects who consumed caffeinated beverages during the lunch exhibited an increment in $\beta $ measurement (taken immediately after lunch) as compared to mean baseline $\beta $ of the day. Further, there was no significant (p $=$ 0.97) difference between the mean baseline $\beta $ measured over a day and the mean baseline $\beta $ measured over the entire course of the study. Results obtained from the present study demonstrated that the arterial stiffness does not vary significantly over a short period but varies progressively. However, significant temporary variations in stiffness could be observed due to dietary interventions.