Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training: Outcomes From a Pilot Randomized Clinical Trial.

Introduction: An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow. Methods: We examined 23 participants, randomized into a UPA group (n=12) and an EPA group (n=11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO2peak, mL/kg/min) testing at baseline and following a 26-week intervention. TCCD was used to measure MFV and PI. Participants in the EPA group completed supervised aerobic exercise training for 26 weeks. Kendall's tau b correlation was used to examine relationships between variables. The Wilcoxon Rank Sum tests were used to examine changes between the UPA and EPA groups. Results: There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks; the change between the UPA and EPA groups was also not significant (p=0.603). There was no evidence of an association between change in VO2peak and change in MFV or PI (all p-values >0.05). Participants in the EPA group significantly increased their VO2peak compared to the UPA group (p=0.027). Conclusion: This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.

Stent interventions for pulmonary artery stenosis improve bi-ventricular flow efficiency in a swine model.

BACKGROUND: Branch pulmonary artery (PA) stenosis (PAS) commonly occurs in patients with congenital heart disease (CHD). Prior studies have documented technical success and clinical outcomes of PA stent interventions for PAS but the impact of PA stent interventions on ventricular function is unknown. The objective of this study was to utilize 4D flow cardiovascular magnetic resonance (CMR) to better understand the impact of PAS and PA stenting on ventricular contraction and ventricular flow in a swine model of unilateral branch PA stenosis. METHODS: 18 swine (4 sham, 4 untreated left PAS, 10 PAS stent intervention) underwent right heart catheterization and CMR at 20 weeks age (55 kg). CMR included ventricular strain analysis and 4D flow CMR. RESULTS: 4D flow CMR measured inefficient right ventricular (RV) and left ventricular (LV) flow patterns in the PAS group (RV non-dimensional (n.d.) vorticity: sham 82 ± 47, PAS 120 ± 47; LV n.d. vorticity: sham 57 ± 5, PAS 78 ± 15 p < 0.01) despite the PAS group having normal heart rate, ejection fraction and end-diastolic volume. The intervention group demonstrated increased ejection fraction that resulted in more efficient ventricular flow compared to untreated PAS (RV n.d. vorticity: 59 ± 12 p < 0.01; LV n.d. vorticity: 41 ± 7 p < 0.001). CONCLUSION: These results describe previously unknown consequences of PAS on ventricular function in an animal model of unilateral PA stenosis and show that PA stent interventions improve ventricular flow efficiency. This study also highlights the sensitivity of 4D flow CMR biomarkers to detect earlier ventricular dysfunction assisting in identification of patients who may benefit from PAS interventions.

Pulmonary artery and lung parenchymal growth following early versus delayed stent interventions in a swine pulmonary artery stenosis model.

OBJECTIVES: Compare lung parenchymal and pulmonary artery (PA) growth and hemodynamics following early and delayed PA stent interventions for treatment of unilateral branch PA stenosis (PAS) in swine. BACKGROUND: How the pulmonary circulation remodels in response to different durations of hypoperfusion and how much growth and function can be recovered with catheter directed interventions at differing time periods of lung development is not understood. METHODS: A total of 18 swine were assigned to four groups: Sham (n = 4), untreated left PAS (LPAS) (n = 4), early intervention (EI) (n = 5), and delayed intervention (DI) (n = 5). EI had left pulmonary artery (LPA) stenting at 5 weeks (6 kg) with redilation at 10 weeks. DI had stenting at 10 weeks. All underwent right heart catheterization, computed tomography, magnetic resonance imaging, and histology at 20 weeks (55 kg). RESULTS: EI decreased the extent of histologic changes in the left lung as DI had marked alveolar septal and bronchovascular abnormalities (p = .05 and p < .05 vs. sham) that were less prevalent in EI. EI also increased left lung volumes and alveolar counts compared to DI. EI and DI equally restored LPA pulsatility, R heart pressures, and distal LPA growth. EI and DI improved, but did not normalize LPA stenosis diameter (LPA/DAo ratio: Sham 1.27 ± 0.11 mm/mm, DI 0.88 ± 0.10 mm/mm, EI 1.01 ± 0.09 mm/mm) and pulmonary blood flow distributions (LPA-flow%: Sham 52 ± 5%, LPAS 7 ± 2%, DI 44 ± 3%, EI 40 ± 2%). CONCLUSION: In this surgically created PAS model, EI was associated with improved lung parenchymal development compared to DI. Longer durations of L lung hypoperfusion did not detrimentally affect PA growth and R heart hemodynamics. Functional and anatomical discrepancies persist despite successful stent interventions that warrant additional investigation.

Multiscale Computational Analysis of Right Ventricular Mechanoenergetics.

Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

Associations of circulating T-cell subsets in carotid artery stiffness: the Multi-Ethnic Study of Atherosclerosis.

Background: Arterial stiffness measured by total pulse wave velocity (T-PWV) is associated with increased risk of multiple age-related diseases. T-PWV can be described by structural (S-PWV) and load-dependent (LD-PWV) arterial stiffening. T-cells have been associated with arterial remodeling, blood pressure, and arterial stiffness in humans and animals; however, it is unknown whether T-cells are related to S-PWV or LD-PWV. Therefore, we evaluated the cross-sectional associations of peripheral T-cell subpopulations with T-PWV, S-PWV, and LD-PWV stiffness. Methods: Peripheral blood T-cells were characterized using flow cytometry and the carotid artery was measured using B-mode ultrasound to calculate T-PWV at the baseline examination in a subset of the Multi-Ethnic Study of Atherosclerosis (MESA, n=1,984). A participant-specific exponential model was used to calculate S-PWV and LD-PWV based on elastic modulus and blood pressure gradients. The associations between five primary (p-significance<0.01) and twenty-five exploratory (p-significance<0.05) immune cell subpopulations, per 1-SD increment, and arterial stiffness measures were assessed using adjusted, linear regressions. Results: For the primary analysis, higher CD4+CD28-CD57+ T-cells were associated with higher LD-PWV (ß=0.04 m/s, p<0.01) after adjusting for co-variates. For the exploratory analysis, T-cell subpopulations that commonly shift with aging towards memory and differentiated/immunosenescent phenotypes were associated with greater T-PWV, S-PWV, and LD-PWV after adjusting for co-variates. Conclusions: In this cross-sectional study, several T-cell subpopulations commonly associated with aging were related with measures of arterial stiffness. Longitudinal studies that examine changes in T-cell subpopulations and measures of arterial stiffness are warranted.

Simple Models of Complex Mechanics for Improved Hypertension Care: Learning to De-stiffen Arteries.

Arteries can stiffen via different mechanisms due to the distending effects of blood pressure, the extracellular (ECM) and vascular smooth muscle cells (VSMC). This short review discusses how these simple models can be applied to the complex biomechanics of arteries to gain physiological insight into why an individual's arteries are stiff and identify new therapeutic strategies. In the Multi-Ethnic Study of Atherosclerosis, the important question of whether arteries stiffen with aging due to load-dependent or structural stiffening was investigated. Structural stiffening was consistently observed with aging, but load-dependent stiffening was highly variable. Importantly, the high load-dependent stiffness was associated with future cardiovascular disease events, but structural stiffness was not. Clinical studies in older, hypertensive adults surprisingly show that decreasing vascular smooth muscle tone can cause clinically significant increases in arterial stiffness. To understand this paradox, the author developed a model simple enough for clinical data but with biologically relevant extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) stiffness parameters. The effect of VSMC tone on arterial stiffness depends on the ECM-VSMC stiffness ratio. Future research is needed to develop a framework that incorporates both the blood pressure dependence of arterial stiffness and the VSMC-ECM interaction on hemodynamics. This could result in personalized arterial stiffness treatments and improved CVD outcomes. The subtitle of this review is "Learning to De-Stiffen Arteries" because our results have so far only shown that we can acutely make arteries stiffer. We are optimistic though that the findings and the analytic techniques covered here will be one of the many steps along the path of the arterial stiffness research community learning how to de-stiffen arteries.

Biomechanics models predict increasing smooth muscle tone as a novel therapeutic target for central arterial dysfunction in hypertension.

INTRODUCTION: Vasodilation can paradoxically increase arterial stiffness in older, hypertensive adults. This study modeled increasing smooth muscle tone as a therapeutic strategy to improve central arterial dysfunction in hypertension using participant-specific simulations. METHODS: Participant-specific models of the carotid artery were parameterized from vascular ultrasound measures of nitroglycerin-induced vasodilation in 18 hypertensive veterans. The acute changes in carotid artery mechanics were simulated for changes of ±2, ±4, and ±6% in smooth muscle tone and ±5, ±10, and ±15 mmHg in mean arterial pressure (MAP). The chronic carotid artery adaptations were simulated based on the hypothesis that the carotid artery will remodel wall-cross sectional area to maintain mechanical homeostasis. RESULTS: A 6% increase in smooth muscle tone acutely decreased carotid pulse wave velocity from 6.89 ±â€Š1.24 m/s to 5.83 ±â€Š1.73 m/s, and a 15 mmHg decrease in MAP decreased carotid pulse wave velocity to 6.17 ±â€Š1.23 m/s. A 6% increase in smooth muscle tone acutely decreased wall stress from 76.2 ±â€Š12.3 to 64.2 ±â€Š10.4 kPa, and a 15 mmHg decrease in MAP decreased wall stress to 60.6 ±â€Š10.7 kPa. A 6% increase in smooth muscle tone chronically decreased wall cross-sectional area from 18.3 ±â€Š5.4 to 15.2 ±â€Š4.9 mm 2, and a 15 mmHg decrease in MAP decreased wall cross-sectional area to 14.3 ±â€Š4.6 mm 2 . CONCLUSION: In participant-specific simulation, increasing smooth muscle tone can have a stronger or equivalent effect on carotid artery mechanics compared with decreasing blood pressure. Increasing central arterial smooth muscle tone may be a novel therapeutic target to improve central arterial dysfunction in older, hypertensive adults and should be a focus of future research.

Methods of arterial stiffness calculation and cardiovascular disease events: the multiethnic study of atherosclerosis.

BACKGROUND: A wide variety of different formulae have been used to calculate local arterial stiffness with little external validation in relationship to cardiovascular events. We compared the associations of several arterial stiffness calculations in a large, multiethnic cohort. METHODS: The multi-ethnic study of atherosclerosis (MESA) is a longitudinal study of 6814 adults without clinical cardiovascular disease (CVD) at enrollment. MESA participants with CVD surveillance through year 2018 and carotid ultrasound ( n  = 5873) or aorta MRI ( n  = 3175) at the baseline exam (2000-2002) were included. We analyzed 21 different calculations of local arterial stiffness. Cross-sectional and longitudinal statistical analyses were performed in addition to Cox hazard modeling for associations with CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, adjudicated angina, and cardiovascular death). RESULTS: Carotid artery stiffness calculations had variable correlations with each other ( r  = 0.56-0.99); aortic stiffness measures were similar ( r  = 0.66-0.99). Nevertheless, for CVD events, the hazard ratio (HR) per standard deviation change were similar for all carotid stiffness calculations with HRs in the range of 1.00-1.10 (equivalence P  < 0.001). For the aorta, aortic distensibility coefficient had a stronger association with CVD events (HR 1.18 [1.02-1.37]) compared to aorta Peterson's elastic modulus (HR 0.98 [0.89-1.07]) and aorta pulse wave velocity (HR 1.00 [0.90-1.11]). HRs between all other aortic stiffness calculations were equivalent ( P  < 0.01). CONCLUSION: Different methods of calculating local arterial stiffness largely gave equivalent results, indicating that the variety of different arterial stiffness calculations in use do not cause inconsistent findings.

Carotid Artery Stiffness Mechanisms Are Associated With End Organ Damage and All-Cause Mortality: MESA (Multi-Ethnic Study of Atherosclerosis).

Background Arterial stiffness can be separated into 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to remodeling of the vessel wall. The relationship between stiffness mechanisms and end organ damage is unknown. Methods and Results MESA (Multi-Ethnic Study of Atherosclerosis) participants with carotid ultrasound were included in this study (n=6147). Carotid pulse wave velocity (cPWV) was calculated to represent total stiffness. Structural stiffness was calculated by adjusting cPWV to a 120/80 mm Hg blood pressure with participant-specific models. Load-dependent stiffness was the difference of total and structural stiffness. Associations with incident chronic kidney disease (CKD), dementia, and mortality were assessed with adjusted Cox models. During 14.3±4.8 years of follow-up, 773 CKD events, 535 dementia events, and 1529 deaths occurred. Total cPWV was associated with mortality (hazard ratio [HR], per 1 m/s, 1.04 [95% CI, 1.01-1.08], P=0.02) and dementia (HR, 1.06 [95% CI, 1.01-1.12], P=0.03) but not CKD (HR, 1.03 [95% CI, 0.98-1.08], P=0.33). Structural cPWV was significantly associated with mortality (HR, 1.04 [95% CI, 1.00-1.08], P=0.04) but not CKD (HR, 1.00 [95% CI, 0.94-1.05], P=0.86) or dementia (HR, 1.06 [95% CI, 0.99-1.13], P=0.06). Load-dependent cPWV was significantly associated with CKD (HR, 1.38 [95% CI, 1.17-1.63], P<0.001) but not mortality (HR, 1.11 [95% CI, 0.99-1.25], P=0.07) or dementia (HR, 1.14 [95% CI, 0.94-1.38], P=0.19). Conclusions The mechanisms of arterial stiffness were associated with all-cause mortality and CKD. Structural stiffness was associated with all-cause mortality, and load-dependent stiffness was associated with CKD. Total stiffness was associated with dementia but load-dependent and structural stiffness were not.

Exercise increases arterial stiffness independent of blood pressure in older Veterans.

BACKGROUND: Exercise-induced changes in arterial function could contribute to a hypertensive response to exercise (HRE) in older individuals. We performed the present analysis to define the acute arterial stiffness response to exercise in ambulatory older adults. METHODS: Thirty-nine Veterans (>60 years old), without known cardiovascular disease, participated in this study, including 19 Veterans who were hypertensive (70.8 ±â€Š6.8 years, 53% women) and 20 Veterans who were normotensive (72.0 ±â€Š9.3 years, 40% women). Arterial stiffness parameters were measured locally with carotid artery ultrasound and regionally with carotid-femoral pulse wave velocity (cfPWV) before and during the 10 min after participants performed a Balke maximal exercise treadmill stress test. RESULTS: The arterial stiffness response to exercise was similar for control and hypertensive participants. At 6 min postexercise, cfPWV was significantly increased (Δ1.5 ±â€Š1.9 m/s, P  = 0.004) despite mean blood pressure (BP) having returned to its baseline value (Δ1 ±â€Š8 mmHg, P  = 0.79). Arterial mechanics modeling also showed BP-independent increases in arterial stiffness with exercise ( P  < 0.05). Postexercise cfPWV was correlated with postexercise SBP ( r  = 0.50, P  = 0.004) while baseline cfPWV ( r  = 0.13, P  = 1.00), and postexercise total peripheral resistance ( r  = -0.18, P  = 1.00) were not. CONCLUSION: In older Veterans, exercise increases arterial stiffness independently of BP and the arterial stiffness increase with exercise is associated with increased postexercise SBP. BP-independent increases in arterial stiffness with exercise could contribute to a HRE in older adults.

Smooth muscle tone alters arterial stiffness: the importance of the extracellular matrix to vascular smooth muscle stiffness ratio.

BACKGROUND: Recent studies show that vascular smooth muscle (VSM) is more important to elastic artery mechanics than previously believed. It remains unclear whether increased VSM tone increases or decreases arterial stiffness. METHODS AND RESULTS: We developed a novel arterial mechanics model based on pressure-diameter relationships that incorporates the contributions of extracellular matrix (ECM) and VSM to arterial stiffness measures. This model is advantageous because it simple enough to use with limited clinical data but has biologically relevant parameters which include ECM stiffness, VSM stiffness, and VSM tone. The model was used to retrospectively analyze the effects of nitroglycerin-induced vasodilation in four clinical studies. Stiffness parameters were modeled for five arterial regions including both elastic and muscular arteries. The model describes complex experimental data with changing VSM tone and blood pressure. Our analysis found that when ECM is less stiff than VSM, increasing VSM tone increases arterial stiffness. The opposite is seen when ECM is stiffer than VSM, increasing VSM tone decreases stiffness. Our results also suggest that VSM tone is a compensatory mechanism for elevated ECM stiffness in hypertensive individuals. CONCLUSION: Based on retrospective analysis of four clinical studies, we propose a simple hypothesis for the role of VSM tone on arterial stiffness: increased VSM tone increases arterial stiffness when VSM is stiffer than ECM and decreases arterial stiffness when ECM is stiffer than VSM. This hypothesis and the methods used in this study could have important implications for understanding arterial physiology in both hypertension and cardiovascular disease and deserve further exploration.

Carotid Artery Stiffness Mechanisms in Hypertension and Their Association with Echolucency and Texture Features: The Multi-ethnic Study of Atherosclerosis (MESA).

Arterial stiffness, echolucency and texture features are altered with hypertension and associated with increased cardiovascular disease risk. The relationship between these markers and structural and load-dependent artery wall changes in hypertension are poorly understood. The Multi-ethnic Study of Atherosclerosis (MESA) is a longitudinal study of 6814 adults from six communities across the United States designed to study subclinical cardiovascular disease. From B-mode imaging of the right common carotid artery at the baseline MESA examination, we calculated carotid artery Young's elastic modulus (YEM, n = 5894) and carotid artery gray-scale texture features (n = 1403). The standard YEM calculation represented total arterial stiffness. Structural stiffness was calculated by adjusting YEM to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. We found that load-dependent YEM was elevated in hypertensive individuals compared with normotensive individuals (35.7 ± 105.5 vs. -62.0 ± 112.4 kPa, p < 0.001) but that structural YEM was similar (425.3 ± 274.8 vs. 428.4 ± 293.0 kPa, p = 0.60). Gray-scale measures of heterogeneity in carotid artery wall texture (gray-level difference statistic contrast) had small but statistically signification correlations with carotid artery stiffness mechanisms. This association was positive for structural YEM (0.107, p < 0.001), while for load-dependent YEM, the association was negative (-0.064, p = 0.02). In conclusion, increased arterial stiffness in hypertension was owing solely to the non-linear mechanics of having higher blood pressure, not structural changes in the artery wall, and high load-dependent stiffness was associated with a more homogenous carotid artery wall texture. This is potentially related to arterial remodeling associated with subclinical atherosclerosis and future cardiovascular disease development. These results also indicate that gray-scale texture features from ultrasound imaging had a small but statistically significant association with load-dependent arterial stiffness and that gray-scale texture features may be partially load dependent.

Carotid Artery Stiffness Mechanisms Associated With Cardiovascular Disease Events and Incident Hypertension: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. It is unknown how these different mechanisms contribute to incident cardiovascular disease (CVD) events. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6814 men and women without CVD at enrollment, from 6 communities in the United States. MESA participants with B-mode carotid ultrasound and brachial blood pressure at baseline Exam in (2000-2002) and CVD surveillance (mean follow-up 14.3 years through 2018) were included (n=5873). Peterson's elastic modulus was calculated to represent total arterial stiffness. Structural stiffness was calculated by adjusting Peterson's elastic modulus to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. RESULTS: In Cox models adjusted for traditional risk factors, load-dependent stiffness was significantly associated with higher incidence of CVD events (hazard ratio/100 mm Hg, 1.21 [95% CI, 1.09-1.34] P<0.001) events while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99-1.07] P=0.10). Analysis of participants who were normotensive (blood pressure <130/80, no antihypertensives) at baseline exam (n=2122) found higher load-dependent stiffness was also associated with significantly higher incidence of hypertension (hazard ratio, 1.53 [95% CI, 1.35-1.75] P<0.001) while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99-1.07] P=0.16). CONCLUSIONS: These results provide valuable new insights into mechanisms underlying the association between arterial stiffness and CVD. Load-dependent stiffness was significantly associated with CVD events but structural stiffness was not.

Effects of nitroglycerin-induced vasodilation on elastic and muscular artery stiffness in older Veterans.

Vascular smooth muscle tone may play an important role in the physiology of increased arterial stiffness that occurs with aging. This study evaluated the impact of smooth muscle tone on arterial stiffness in older individuals following nitroglycerin-induced vasodilation in elastic and muscular arteries. Forty older Veterans (≥60 years old) without known cardiovascular disease were included in this study. Twenty Veterans were included as hypertensive participants (70.8 ± 6.6 years, 10 females), and 20 were included as normotensive controls (72.0 ± 9.3 years, 8 females). Nitroglycerin (NTG)-induced changes in arterial stiffness were measured locally with vascular ultrasound in the carotid and brachial arteries and regionally by carotid-femoral pulse wave velocity (cfPWV) with tonometry. With NTG treatment, both hypertensive participants and normotensive controls Veterans showed increased carotid PWV (6.4 ± 1.3 m/s to 7.2 ± 1.4 m/s, Δ 0.8 ± 1.1 m/s, p = 0.007) and cfPWV (8.6 ± 1.9 m/s to 9.5 ± 2.4 m/s, Δ 0.9 ± 2.3 m/s, p = 0.020) but did not show changes in brachial PWV (11.2 ± 2.4 m/s to 11.1 ± 2.2 m/s, Δ -0.2 ± 2.5 m/s, p = 0.72). The carotid artery was dilated more in control participants than hypertensive Veterans (Δ 0.54 ± 0.19 mm vs. 0.42 ± 0.12 mm, p = 0.022). Brachial artery dilation was similar between the two groups (Δ 0.55 ± 0.26 mm vs. 0.51 ± 0.20 mm, p = 0.46). In older Veterans without known cardiovascular disease, NTG-induced vasodilation increased elastic artery stiffness but did not change muscular artery stiffness. Increased central arterial stiffness and a decrease in the arterial stiffness gradient could offset some of the benefits of lowering blood pressure in older patients who are prescribed vasodilators as an antihypertensive therapy. Elastic artery stiffening with vasodilation warrants further investigation, as it may be important for antihypertensive medication selection and influence CVD development.

Carotid Artery Stiffening With Aging: Structural Versus Load-Dependent Mechanisms in MESA (the Multi-Ethnic Study of Atherosclerosis).

Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. Differentiating these closely coupled mechanisms is important to understanding vascular aging. MESA (Multi-Ethnic Study of Atherosclerosis) participants with B-mode carotid ultrasound and brachial blood pressure at exam 1 and exam 5 (year 10) were included in this study (n=2604). Peterson and Young elastic moduli were calculated to represent total stiffness. Structural stiffness was calculated by adjusting Peterson and Young elastic moduli to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Changes in carotid artery stiffness mechanisms over 10 years were compared by age groups with ANCOVA models adjusted for baseline cardiovascular disease risk factors. The 75- to 84-year age group had the greatest change in total, structural, and load-dependent stiffening compared with younger groups (P<0.05). Only age and cessation of antihypertensive medication were predictive of structural stiffening, whereas age, race/ethnicity, education, blood pressure, cholesterol, and antihypertensive medication were predictive of increased load-dependent stiffening. On average, structural stiffening accounted for the vast majority of total stiffening, but 37% of participants had more load-dependent than structural stiffening. Rates of structural and load-dependent carotid artery stiffening increased with age. Structural stiffening was consistently observed, and load-dependent stiffening was highly variable. Heterogeneity in arterial stiffening mechanisms with aging may influence cardiovascular disease development.

A distributed lumped parameter model of blood flow with fluid-structure interaction.

A distributed lumped parameter (DLP) model of blood flow was recently developed that can be simulated in minutes while still incorporating complex sources of energy dissipation in blood vessels. The aim of this work was to extend the previous DLP modeling framework to include fluid-structure interactions (DLP-FSI). This was done by using a simple compliance term to calculate pressure that does not increase the simulation complexity of the original DLP models. Verification and validation studies found DLP-FSI simulations had good agreement compared to analytical solutions of the wave equations, experimental measurements of pulsatile flow in elastic tubes, and in vivo MRI measurements of thoracic aortic flow. This new development of DLP-FSI allows for significantly improved computational efficiency of FSI simulations compared to FSI approaches that solve the full 3D conservation of mass and momentum equations while also including the complex sources of energy dissipation occurring in cardiovascular flows that other simplified models neglect.

Accelerated Estimation of Pulmonary Artery Stenosis Pressure Gradients with Distributed Lumped Parameter Modeling vs. 3D CFD with Instantaneous Adaptive Mesh Refinement: Experimental Validation in Swine.

Branch pulmonary artery stenosis (PAS) commonly occurs in congenital heart disease and the pressure gradient over a stenotic PA lesion is an important marker for re-intervention. Image based computational fluid dynamics (CFD) has shown promise for non-invasively estimating pressure gradients but one limitation of CFD is long simulation times. The goal of this study was to compare accelerated predictions of PAS pressure gradients from 3D CFD with instantaneous adaptive mesh refinement (AMR) versus a recently developed 0D distributed lumped parameter CFD model. Predictions were then experimentally validated using a swine PAS model (n = 13). 3D CFD simulations with AMR improved efficiency by 5 times compared to fixed grid CFD simulations. 0D simulations further improved efficiency by 6 times compared to the 3D simulations with AMR. Both 0D and 3D simulations underestimated the pressure gradients measured by catheterization (- 1.87 ± 4.20 and - 1.78 ± 3.70 mmHg respectively). This was partially due to simulations neglecting the effects of a catheter in the stenosis. There was good agreement between 0D and 3D simulations (ICC 0.88 [0.66-0.96]) but only moderate agreement between simulations and experimental measurements (0D ICC 0.60 [0.11-0.86] and 3D ICC 0.66 [0.21-0.88]). Uncertainty assessment indicates that this was likely due to limited medical imaging resolution causing uncertainty in the segmented stenosis diameter in addition to uncertainty in the outlet resistances. This study showed that 0D lumped parameter models and 3D CFD with instantaneous AMR both improve the efficiency of hemodynamic modeling, but uncertainty from medical imaging resolution will limit the accuracy of pressure gradient estimations.

Longitudinal Evolution of Pulmonary Artery Wall Shear Stress in a Swine Model of Pulmonary Artery Stenosis and Stent Interventions.

Branch pulmonary artery stenosis (PAS) commonly occurs in congenital heart disease and it has previously been hypothesized that in branch PAS the pulmonary arteries (PAs) remodel their lumen diameter to maintain constant wall shear stress (WSS). We quantified the longitudinal progression of PA WSS in a swine model of unilateral PAS and two different intervention time courses to test this hypothesis. To quantify WSS in the entire pulmonary tree we used 4D Flow MRI for the large-proximal PAs and a structured tree model for the small-distal PAs. Our results only partially supported the hypothesis that in branch PAS the PAs remodel their lumen diameter to maintain WSS homeostasis. Proximal PA WSS was similar between groups at the final study time-point but WSS of mid-sized (5 mm to 500 µm) PA segments was found to be different between the sham and LPAS groups. This suggests that WSS homeostasis may only be achieved for the large-proximal PAs. Additionally, our results do not show WSS homeostasis being achieved over shorter periods of time suggesting that any potential WSS dependent changes in PA lumen diameter were a long-term remodeling response rather than a short-term vasodilation response. Future studies should confirm if these findings hold true in humans and investigate the impacts of WSS at different levels of the pulmonary tree on growth.

Non-invasive MRI Derived Hemodynamic Simulation to Predict Successful vs. Unsuccessful Catheter Interventions for Branch Pulmonary Artery Stenosis: Proof-of-Concept and Experimental Validation in Swine.

OBJECTIVE: This study assessed the ability of hemodynamic simulations to predict the success of catheter interventions in a swine model of branch pulmonary artery stenosis (bPAS). BACKGROUND: bPAS commonly occurs in congenital heart disease and is often managed with catheter based interventions. However, despite technical success, bPAS interventions do not lead to improved distal pulmonary blood flow (PBF) distribution in approximately 1/3rd of patients. New tools are needed to better identify which patients with bPAS would most benefit from catheter interventions. METHODS: For 13 catheter intervention cases in swine with surgically created left PAS (LPAS), PA pressures from right heart catheterization (RHC) and PBF distributions from MRI were measured before and after catheter interventions. Hemodynamic simulations with a reduced order computational fluid dynamics (CFD) model were performed using non-invasive PBF measurements derived from MRI, and then correlated with changes in invasive measures of hemodynamics and PBF distributions before and after catheter intervention to relieve bPAS. RESULTS: Compared to experimentally measured changes in left PBF distribution, simulations had a small bias (3.4 ± 11.1%), moderate agreement (ICC = 0.69 [0.24-0.90], 0.71 [0.23-0.91]), and good diagnostic capability to predict successful interventions (> 20% PBF increase) (AUC 0.83 [0.59-1.0]). Simulations had poorer prediction of changes in stenotic pressure gradient (ICC = 0.28 [- 0.33 to 0.73], r = 0.57 [- 0.04 to 0.87]) and MPA systolic pressure (ICC = 0.00 [- 0.52 to 0.53], r = 0.29 [- 0.32 to 0.72]). CONCLUSION: While there was only weak to moderate agreement between predicted and measured changes in PA pressures and pulmonary blood flow distributions, hemodynamic simulations did show good diagnostic value for predicting successful versus unsuccessful catheter based interventions to relieve bPAS. The results of this proof of concept study are promising and should encourage future development for using hemodynamic models in planning interventions for patients with bPAS.