Bart Spronck

Pressure-dependence of arterial stiffness: potential clinical implications.

Background: Arterial stiffness measures such as pulse wave velocity (PWV) have a known dependence on actual blood pressure, requiring consideration in cardiovascular risk assessment and management. Given the impact of ageing on arterial wall structure, the pressure-dependence of PWV may vary with age. Methods: Using a noninvasive model-based approach, combining carotid artery echo-tracking and tonometry waveforms, we obtained pressure-area curves in 23 hypertensive patients at baseline and after 3 months of antihypertensive treatment. We predicted the follow-up PWV decrease using modelled baseline curves and follow-up pressures. In addition, on the basis of these curves, we estimated PWV values for two age groups (mean ages 41 and 64 years) at predefined hypertensive (160/90 mmHg) and normotensive (120/80 mmHg) pressure ranges. Results: Follow-up measurements showed a near 1 m/s decrease in carotid PWV when compared with baseline, which fully agreed with our model-prediction given the roughly 10 mmHg decrease in diastolic pressure. The stiffness-blood pressure-age pattern was in close agreement with corresponding data from the ‘Reference Values for Arterial Stiffness’ study, linking the physical and empirical bases of our findings. Conclusion: Our study demonstrates that the innate pressure-dependence of arterial stiffness may have implications for the clinical use of arterial stiffness measurements, both in risk assessment and in treatment monitoring of individual patients. We propose a number of clinically feasible approaches to account for the blood pressure effect on PWV measurements.

Arterial stiffness index beta and cardio-ankle vascular index inherently depend on blood pressure but can be readily corrected

Objectives: Arterial stiffness index &bgr; and cardio-ankle vascular index (CAVI) are widely accepted to quantify the intrinsic exponent (&bgr;0) of the blood pressure (BP)-diameter relationship. CAVI and &bgr; assume an exponential relationship between pressure (P) and diameter (d). We aim to demonstrate that, under this assumption, &bgr; and CAVI as currently implemented are inherently BP-dependent and to provide corrected, BP-independent forms of CAVI and &bgr;. Methods and results: In P = Prefe&bgr;0[(d/dref)-1], usually reference pressure (Pref) and reference diameter (dref) are substituted with DBP and diastolic diameter to accommodate measurements. Consequently, the resulting exponent is not equal to the pressure-independent &bgr;0. CAVI does not only suffer from this ‘reference pressure’ effect, but also from the linear approximation of (dP/dd). For example, assuming &bgr;0 = 7, an increase of SBP/DBP from 110/70 to 170/120 mmHg increased &bgr; by 8.1% and CAVI by 14.3%. We derived corrected forms of &bgr; and of CAVI (CAVI0) that indeed did not change with BP and represent the pressure-independent &bgr;0. To substantiate the BP effect on CAVI in a typical follow-up study, we realistically simulated patients (n = 161) before and following BP-lowering ‘treatment’ (assuming no follow-up change in intrinsic &bgr;0 and therefore in actual P–d relationship). Lowering BP from 160 ± 14/111 ± 11 to 120 ± 15/79 ± 11 mmHg (p < 0.001) resulted in a significant CAVI decrease (from 8.1 ± 2.0 to 7.7 ± 2.1, p = 0.008); CAVI0 did not change (9.8 ± 2.4 and 9.9 ± 2.6, p = 0.499). Conclusion: &bgr; and CAVI as currently implemented are inherently BP-dependent, potentially leading to erroneous conclusions in arterial stiffness trials. BP-independent forms are presented to readily overcome this problem.

Heart Rate Dependency of Large Artery Stiffness

Carotid-femoral pulse wave velocity (cfPWV) quantifies large artery stiffness, it is used in hemodynamic research and is considered a useful cardiovascular clinical marker. cfPWV is blood pressure (BP) dependent. Intrinsic heart rate (HR) dependency of cfPWV is unknown because increasing HR is commonly accompanied by increasing BP. This study aims to quantify cfPWV dependency on acute, sympathovagal-independent changes in HR, independent of BP. Individuals (n=52, age 40–93 years, 11 female) with in situ cardiac pacemakers or cardioverter defibrillators were paced at 60, 70, 80, 90, and 100 bpm. BP and cfPWV were measured at each HR. Both cfPWV (mean [95% CI], 0.31 [0.26–0.37] m/s per 10 bpm; P<0.001) and central aortic diastolic pressure (3.78 [3.40–4.17] mm Hg/10 bpm; P<0.001) increased with HR. The HR effect on cfPWV was isolated by correcting the BP effects by 3 different methods: (1) statistically, by a linear mixed model; (2) mathematically, using an exponential relationship between BP and cross-sectional lumen area; and (3) using measured BP dependency of cfPWV derived from changes in BP induced by orthostatic changes (seated and supine) in a subset of subjects (n=17). The BP-independent effects of HR on cfPWV were quantified as 0.20 [0.11–0.28] m/s per 10 bpm (P<0.001, method 1), 0.16 [0.11–0.22] m/s per 10 bpm (P<0.001, method 2), and 0.16 [0.11–0.21] m/s per 10 bpm (P<0.001, method 3). With a mean HR dependency in the range of 0.16 to 0.20 m/s per 10 bpm, cfPWV may be considered to have minimal physiologically relevant changes for small changes in HR, but larger differences in HR must be considered as contributing to significant differences in cfPWV.

A lumped parameter model of cerebral blood flow control combining cerebral autoregulation and neurovascular coupling

Cerebral blood flow regulation is based on a variety of different mechanisms, of which the relative regulatory role remains largely unknown. The cerebral regulatory system expresses two regulatory properties: cerebral autoregulation and neurovascular coupling. Since partly the same mechanisms play a role in cerebral autoregulation and neurovascular coupling, this study aimed to develop a physiologically based mathematical model of cerebral blood flow regulation combining these properties. A lumped parameter model of the P2 segment of the posterior cerebral artery and its distal vessels was constructed. Blood flow regulation is exerted at the arteriolar level by vascular smooth muscle and implements myogenic, shear stress based, neurogenic, and metabolic mechanisms. In eight healthy subjects, cerebral autoregulation and neurovascular coupling were challenged by squat-stand maneuvers and visual stimulation using a checkerboard pattern, respectively. Cerebral blood flow velocity was measured using transcranial Doppler, whereas blood pressure was measured by finger volume clamping. In seven subjects, the model proposed fits autoregulation and neurovascular coupling measurement data well. Myogenic regulation is found to dominate the autoregulatory response. Neurogenic regulation, although only implemented as a first-order mechanism, describes neurovascular coupling responses to a great extent. It is concluded that our single, integrated model of cerebral blood flow control may be used to identify the main mechanisms affecting cerebral blood flow regulation in individual subjects.

A method for three-dimensional quantification of vascular smooth muscle orientation: application in viable murine carotid arteries

When studying in vivo arterial mechanical behaviour using constitutive models, smooth muscle cells (SMCs) should be considered, while they play an important role in regulating arterial vessel tone. Current constitutive models assume a strictly circumferential SMC orientation, without any dispersion. We hypothesised that SMC orientation would show considerable dispersion in three dimensions and that helical dispersion would be greater than transversal dispersion. To test these hypotheses, we developed a method to quantify the 3D orientation of arterial SMCs. Fluorescently labelled SMC nuclei of left and right carotid arteries of ten mice were imaged using two-photon laser scanning microscopy. Arteries were imaged at a range of luminal pressures. 3D image processing was used to identify individual nuclei and their orientations. SMCs showed to be arranged in two distinct layers. Orientations were quantified by fitting a Bingham distribution to the observed orientations. As hypothesised, orientation dispersion was much larger helically than transversally. With increasing luminal pressure, transversal dispersion decreased significantly, whereas helical dispersion remained unaltered. Additionally, SMC orientations showed a statistically significant (

Head orientation should be considered in ultrasound studies on carotid artery distensibility.

p < 0.05

Direct means of obtaining CAVI0—a corrected cardio-ankle vascular stiffness index (CAVI)—from conventional CAVI measurements or their underlying variables

p<0.05) mean right-handed helix angle in both left and right arteries and in both layers, which is a relevant finding from a developmental biology perspective. In conclusion, vascular SMC orientation (1) can be quantified in 3D; (2) shows considerable dispersion, predominantly in the helical direction; and (3) has a distinct right-handed helical component in both left and right carotid arteries. The obtained quantitative distribution data are instrumental for constitutive modelling of the artery wall and illustrate the merit of our method.

Patient-specific blood pressure correction technique for arterial stiffness: evaluation in a cohort on anti-angiogenic medication

Vascular assessment is becoming increasingly important in the diagnosis of cardiovascular diseases. In particular, clinical assessment of arterial stiffness, as measured by pulse wave velocity (PWV), is gaining increased interest due to the recognition of PWV as an influential factor on the prognosis of hypertension as well as being an independent predictor of cardiovascular and all-cause mortality. Whilst age and blood pressure are established as the two major determinants of PWV, the influence of heart rate on PWV measurements remains controversial with conflicting results being observed in both acute and epidemiological studies. In a majority of studies investigating the acute effects of heart rate on PWV, results were confounded by concomitant changes in blood pressure. Observations from epidemiological studies have also failed to converge, with approximately just half of such studies reporting a significant blood-pressure-independent association between heart rate and PWV. Further to the lack of consensus on the effects of heart rate on PWV, the possible mechanisms contributing to observed PWV changes with heart rate have yet to be fully elucidated, although many investigators have attributed heart-rate related changes in arterial stiffness to the viscoelasticity of the arterial wall. With elevated heart rate being an independent prognostic factor of cardiovascular disease and its association with hypertension, the interaction between heart rate and PWV continues to be relevant in assessing cardiovascular risk.