Citations

Arterial stiffness is recognized as a highly clinically relevant and independent prognostic biomarker of cardiovascular disease. Arterial dispersion ultrasound vibrometry (ADUV) uses acoustic radiation force to generate propagating waves in the arterial wall and measures the wave motion to estimate arterial mechanical properties from fitting phase velocity dispersion curves to a waveguide model. ADUV measurements were made with a Verasonics V1 system with a L7-4 linear array transducer in 63 human subjects (27 male/36 female) from ages 50–88 years old. We made measurements at 10 time points within the cardiac cycle, termed cardiac stages. We estimated the phase velocity (median of cp from 400-600 Hz) and G determined from matching the dispersion curves with those from a waveguide model incorporating the artery diameter and wall thickness. Within the same study visit, we measured the intima-media thickness and diameter changes through the cardiac cycle with a General Electric Logiq E9 or E10 scanner. We also tonometry to determine the carotid-femoral pulse wave velocity. We report here comparisons of median phase velocity, cp, and inverted shear modulus, G, at different stages of the cardiac cycle with clinical metrics of arterial stiffness.

Abstract Objective. Measuring waves induced with acoustic radiation force (ARF) in arteries has been studied over the last decade. To date, it remains a challenge to quantitatively assess the local arterial biomechanical properties. The cylindrical shape and waveguide behavior of waves propagating in the arterial wall pose complexities to determining the mechanical properties of the artery. Approach . In this paper, an artery-mimicking tube in water is examined utilizing three-dimensional measurements. The cross-section of the tube is measured while a transducer is translated over 41 different positions along the length of the tube. Motion in the radial direction is calculated using two components of motion which are measured from the two orthogonal views of the cross-section. This enables more accurate estimation of motion along the circumference of tube. Main results . The results provide more information to categorize the motion in tube wall into two types of responses: a transient response and a steady state response. The transient response is caused by ARF application and the waves travel along the length of the tube for a relatively short period of time. This corresponds to the axial and circumferential propagating waves. The two circumferential waves travel along the circumference of tube in CW (clockwise) and CCW (counter-clockwise) direction and result in a standing wave. By using a directional filter, the two waves were successfully separated, and their propagation was more clearly visualized. As a steady state response, a circumferential mode is generated showing a symmetric motion (i.e. the proximal and distal walls move in the opposite direction) following the transient response. Significance. This study provides a more comprehensive understanding of the waves produced in an artery-mimicking tube with ARF application, which will provide opportunities for improving measurement of arterial mechanical properties.

Abstract Objective . Arterial dispersion ultrasound vibrometry (ADUV) relies on the use of guided waves in arterial geometries for shear wave elastography measurements. Both the generation of waves through the use of acoustic radiation force (ARF) and the techniques employed to infer the speed of the resulting wave motion affect the spectral content and accuracy of the measurement. In particular, the effects of the shape and location of the ARF beam in ADUV have not been widely studied. In this work, we investigated how such variations of the ARF beam affect the induced motion and the measurements in the dispersive modes that are excited. Approach. The study includes an experimental evaluation on an arterial phantom and an in vivo validation of the observed trends, observing the two walls of the waveguide, simultaneously, when subjected to variations in the ARF beam extension ( F / N ) and focus location. Main results. Relying on the theory of guided waves in cylindrical shells, the shape of the beam controls the selection and nature of the induced modes, while the location affects the measured dispersion curves (i.e. variation of phase velocity with frequency or wavenumber, multiple modes) across the waveguide walls. Significance. This investigation is important to understand the spectral content variations in ADUV measurements and to maximize inversion accuracy by tuning the ARF beam settings in clinical applications.

New Findings What is the central question of this study? Do humans with high‐affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near‐infrared spectroscopy‐derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. AbstractRecently, researchers in our laboratory have shown that humans with genetic mutations resulting in high‐affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal‐affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near‐infrared spectroscopy‐derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal‐affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Abstract In the vascular system, an extensive network structure provides convective and diffusive transport of oxygen to tissue. In the microcirculation, parameters describing network structure, blood flow, and oxygen transport are highly heterogeneous. This heterogeneity can strongly affect oxygen supply and organ function, including reduced oxygen uptake in the lung and decreased oxygen delivery to tissue. The causes of heterogeneity can be classified as extrinsic or intrinsic. Extrinsic heterogeneity refers to variations in oxygen demand in the systemic circulation or oxygen supply in the lungs. Intrinsic heterogeneity refers to structural heterogeneity due to stochastic growth of blood vessels and variability in flow pathways due to geometric constraints, and resulting variations in blood flow and hematocrit. Mechanisms have evolved to compensate for heterogeneity and thereby improve oxygen uptake in the lung and delivery to tissue. These mechanisms, which involve long‐term structural adaptation and short‐term flow regulation, depend on upstream responses conducted along vessel walls, and work to redistribute flow and maintain blood and tissue oxygenation. Mathematically, the variance of a functional quantity such as oxygen delivery that depends on two or more heterogeneous variables can be reduced if one of the underlying variables is controlled by an appropriate compensatory mechanism. Ineffective regulatory mechanisms can result in poor oxygen delivery even in the presence of adequate overall tissue perfusion. Restoration of endothelial function, and specifically conducted responses, should be considered when addressing tissue hypoxemia and organ failure in clinical settings.

The ability of the lung to take up oxygen can be characterized by its effective diffusing capacity, which is determined by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow. At rest, the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, but under conditions of physiological stress such as exercise, oxygen uptake may be inadequate to satisfy tissue demand if flow is very heterogeneous. We previously used a mathematical model of pulmonary oxygen uptake to examine the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity. In the model, flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a normal level of heterogeneity (CV = 1.66), we simulate flow regulation over a range of oxygen consumption from rest to maximal exercise by adjusting pulmonary flow resistance in each vessel in accordance with an HPV response curve obtained from previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each pulmonary capillary; its maximal sensitivity occurs at a stimulus oxygen tension of approximately 30 torr. The purpose of the present study was to determine whether altering the shape of the HPV response curve would result in an improvement in CV reduction. Altering the HPV by shifting the sigmoidal curve to the right by 10 or 20 torr worsened CV, extraction and total pulmonary vascular resistance (PVR). Similar detrimental results were obtained when the range of oxygen tensions over which HPV varied was expanded by a factor of two, increasing the oxygen tension at which the sensitivity of HPV to oxygen tension was maximal. On the other hand, shrinking the range of variation of the HPV curve by a factor of two neither improved nor significantly worsened the CV or extraction, and resulted in a PVR distribution similar to the case of the normal HPV curve. These results demonstrate that the observed shape of the HPV response tends to minimize heterogeneity of pulmonary flow under conditions of exercise.

Background Humans with high O 2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O 2 at which 50% of hemoglobin is saturated (P 50 ) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P 50 . Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P 50 . Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P 50. Methods Nine humans with a HAH mutation (6 female, Age: 40±12yrs, P 50 : 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P 50 : 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O 2 pressure to ~50 mmHg (Avg. F i O 2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz). Results Arterial oxygen (P a O 2 ) and carbon dioxide (P a CO 2 ) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [P a O 2 : (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; P a CO 2 : (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009). Conclusion The findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.

A theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model shows that observed levels of hypoxic vasoconstriction in terminal vessels cannot account for the elevation of PVR associated with hypoxic pulmonary vasoconstriction (HPV). Upstream signaling by conducted responses to engage constriction of arterioles, therefore, plays an essential role in the elevation of PVR during HPV.

Pulmonary oxygen uptake is affected by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow, both of which can limit the lung's capacity for oxygen transport as characterized by its effective diffusing capacity. In previous work, we showed that while under resting conditions the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, under conditions of exercise such flow heterogeneity can preclude the high levels of oxygen uptake necessary to meet tissue demand. The goal of the present study is to test the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity and enable adequate oxygen transport levels in the lung to meet tissue needs under conditions of exercise. A mathematical model of pulmonary oxygen uptake is used, in which flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a high degree of heterogeneity, we simulate flow regulation in the cases of rest and exercise by adjusting pulmonary flow resistance in each vessel in accordance with previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each capillary. The results show a reduction in the effective CV from a baseline of 2.73 to 1.83 under resting conditions and to 0.66 in the case of exercise. The stronger reduction in heterogeneity under conditions of exercise corresponds to the need for greater flow regulation to minimize heterogeneity under conditions of physiologic stress. The predicted level of heterogeneity in exercise is in general agreement with our previous prediction of the upper limit of CV consistent with the levels of oxygen uptake in literature data for exercising humans. The results demonstrate the essential role of HPV to regulate flow and minimize heterogeneity under conditions of exercise and highlight the need for a functional pulmonary flow regulation mechanism under stressful or pathophysiological conditions. Support or Funding Information Supported by NIH U01 HL133362. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Microvascular blood flow regulation has important implications for optimization of metabolism‐perfusion matching in physiological and pathophysiological conditions such as exercise and sepsis. The purpose of this theoretical study is to assess the impact of various regulatory factors on metabolism‐perfusion matching. A microvascular network model including myogenic, shear, and metabolic flow regulation was developed and utilized to obtain estimates of oxygen extraction under control conditions as compared to a 20% global increase in blood flow accompanied by a 50% increase in oxygen consumption. The exercise state was simulated with preserved flow regulation and sepsis was simulated with impaired metabolic flow regulation. For the values of parameters used, overall oxygen extraction was found to be 28% higher in exercise compared to control values as opposed to only 23% higher in sepsis. This study demonstrates the impact of impaired flow regulation on oxygen delivery and highlights microvascular perfusion abnormalities as a putative mechanism for organ failure in critically ill patients.