In human medicine, vascular diseases are important and independently linked with mortality. Changes in arterial structure and function contribute to a poorer ‘vascular health’. The latter is mainly assessed by determination of arterial wall stiffness, regionally and locally. Using different techniques it has been demonstrated that age, race and gender have an effect on the arterial wall stiffness. In horses, the most important, often fatal, vascular disorder is arterial rupture. This condition has been associated with breed (e.g. aortic rupture in Friesians), age, exercise, parturition, copulation and α1-agonist treatment. Nevertheless, knowledge of the pathophysiology of arterial rupture and the effect of age and breed remained very limited, since up till now, techniques to measure and assess arterial wall stiffness were not available.
The General introduction of this thesis gives an overview of normal and abnormal structural, biomechanical and functional properties of the arterial wall in humans and the current knowledge in equines. First the normal structure of the arterial wall is described, followed by an explanation of the physiological function of the arterial tree. This includes an overview of blood pressure regulation and different blood pressure measurement techniques, followed by a description of normal blood pressure in horses. Next, an outline of the biomechanical properties of the arterial wall is given, combined with possible ex vivo tests to describe these biomechanical properties. This is followed by a short description of the most used mathematical models that allow studying arterial tree flow dynamics and pressure waves. Measuring techniques for arterial wall stiffness assessment in human patients are described, together with the effect of aging, gender, training and race. Lastly, the most common arterial disorders in horses are described, including exercise-induced arterial rupture, aortocardiac fistulation, aortopulmonary fistulation in Friesians horses and arterial rupture associated with phenylephrine administration or parturition.
The first objective of this dissertation was to predict and understand flow profiles and pressures over the whole arterial tree of the healthy horse (Chapter 3). First, we have detailed the anatomy of the equine arterial tree (diameter, branch length and branching angle of 113 arterial segments). Based on these details, together with literature data, physiological data from ultrasound images and invasive blood pressure measurements, we have developed a mathematical one-dimensional model which mimics the arterial flow in horses. Adapting the model by taking into account gravity improved predicted flow waveform morphology. Outcomes of this model showed plausible predictions of pressures and flow waves throughout the arterial tree. Moreover, simulated flow waveforms showed a similar oscillating pattern as observed in ultrasound Doppler images. Wave power analysis helped to explain the contours of arterial flow profiles. Techniques to reliably measure arterial wall stiffness in horses were developed and applied (Chapter 4). Regional arterial wall stiffness parameters, aortic to external iliac artery pulse wave velocity and carotid to external iliac artery pulse wave velocity calculated using pulsed wave Doppler, showed low coefficients of variation (3-15%). Local arterial wall stiffness parameters including diameter and lumen area change, diameter and lumen area strain, compliance, distensibility and stiffness index of the cranial and caudal common carotid artery, proximal aorta and external iliac artery showed low to high coefficients of variation (10-68%). We concluded that local arterial wall stiffness parameters are, in contrary to regional arterial wall stiffness parameters, not suitable for individual follow-up of patients, but can have an added value for population research.
In Chapter 5, the previously developed techniques were used to assess differences in arterial wall stiffness between Warmblood horses and Friesian horses, as Friesians are known to be predisposed to aortic rupture. Aortic to external iliac artery and carotid to external iliac artery pulse wave velocity were significantly higher in Friesians horses compared to Warmblood horses (6.52±2.51 and 7.06±1.60 m/s vs. 5.95±0.94 and 5.79±1.43 m/s), indicating a stiffer aorta in Friesians. This could be confirmed by lower local arterial wall stiffness parameters in Friesians. Additionally Friesian horses showed a significantly higher systolic (146±18 mmHg), diastolic (97±12 mmHg) and mean arterial blood pressure (115±15 mmHg) and a higher pulse pressure (49±9 mmHg) compared to Warmblood horses (135±14 mmHg, 91±10 mmHg, 106±13 mmHg and 44±9 mmHg, respectively). These findings, in combination with the previously described differences in collagen amount and cross-linking pattern, make it highly probable that the predisposition of Friesian horses to aortic rupture is, at least partially, related to increased arterial wall stiffness.
In Chapter 6, the effect of age on the arterial wall stiffness in horses was assessed using the same techniques. Older horses showed significantly larger arterial diameters compared to young horses, in combination with an increased arterial wall thickness. Aortic to external and carotid to external iliac artery pulse wave velocity were clearly higher in old horses (6.2±1.3 m/s and 6.0±2.2 m/s) compared to young horses (5.3±0.6 m/s and 4.6±0.8 m/s), in combination with lower local aortic and carotid arterial wall stiffness parameters, confirming stiffer arteries in older horses. No difference in blood pressure was found. Arterial compliance was maximal in the aorta and decreased towards the periphery. Results indicate that horses, in accordance with humans, present age-related arterial wall stiffening, in combination with luminal enlargement and arterial wall thickening.
In Chapter 7 we aimed at investigating the structural and biomechanical effects of aging on the equine arterial wall. Histological findings showed a decrease in the amount of elastin from the proximal aorta (34±3%) towards the peripheral arteries (8±5% in the median artery). A significant increase in wall thickness in aged horses was found, in combination with an increased area % of smooth muscle actin. Biomechanical properties were assessed using an inflation-extension test pressurising (15-300 mmHg) proximal aortas, distal aortas, common carotid arteries and external iliac arteries. Rupture occurred in a minority of arteries (8/78) at high pressures (250-300mmHg), and mostly occurred in older horses (7/8). Age significantly affected the pressure-area curve of the distal aorta, common carotid artery and external iliac artery, the pressure-compliance curve of the proximal aorta and the common carotid artery, and the pressure-distensibility curve of the proximal aorta. Larger vascular cross-sectional areas at the same pressure were found in older horses, combined with a lower compliance in older horses at physiological pressures. Results indicate structural and biomechanical arterial wall changes due to aging, which explain the in vivo differences in arterial wall stiffness between young and old horses.
As a general conclusion, by providing new insights in equine arterial physiology, this work contributes to the knowledge of the pathophysiology of arterial rupture in horses. A unique dataset of the equine arterial tree is provided, in combination with an equine specific mathematic model to study and predict the normal blood flow and pressure waves in horses. This model can be a starting point for studying arterial pathophysiology during hypertension, exercise or drug administration in future. A technique to study vascular health in the standing, unsedated horse by measuring local and regional arterial wall stiffness is described. We have demonstrated that age affects the arterial wall stiffness in vivo which corresponds to structural and biomechanical changes observed ex vivo. Furthermore, we have demonstrated that Friesians have a stiffer aorta, which could predispose this breed to aortic rupture. In future it would be useful to assess the effect of breed (other than Friesians), gender and training on the arterial wall stiffness, in order to further unravel the underlying causes of arterial rupture in horses.