Pulsatile Function of the Cardiovascular System
Project 1: Nitric oxide and inflammatory markers with pulsatile stretch of arterial endothelial cells in hypertension
Endothelial cells of arteries are subjected to shear stress and cyclical strain. These endothelial cells regulate vascular tone through activation of endothelial nitric oxide synthase and subsequent nitric oxide release. Inflammatory markers have also been shown to alter nitric oxide production. This endothelial function is often down regulated in people with high blood pressure. Preliminary evidence suggests that the extent and frequency of the cyclic stretch applied to the cells may modify endothelial function.
- That pulsatile stretch of arterial endothelial cells alters expression of nitric oxide synthase and inflammation.
- That long term increased blood pressure and pulsatile stretch modifies this expression.
- To quantify the pulsatile stretch of arteries in rats genetically predisposed to high blood pressure, their normotensive strain, and rats predisposed to high blood pressure treated with an antihypertensive therapy.
- To detect any differences in endothelial function associated with endothelial dependent nitric oxide release.
- To isolate and culture arterial endothelial cells from the above groups of animals.
- To quantify markers of nitric oxide synthase and inflammation from the cultured endothelial cells.
- To quantify markers of nitric oxide synthase and inflammation from the culture endothelial cells following forced, ex-vivo cyclic pulsatile stretch applied to the cells.
This project will involve quantification of vascular nitric oxide and nitric oxide synthase through vessel myography, Western Blot techniques, and/or quantitative PCR. The extent of vessel stretch will be modified using both an animal model of hypertension, including antihypertensive treatment as a control arm, and through ex-vivo stretch of cultured endothelial cells. Stretch of cells in the animal models of hypertension will be quantified using ultrasound techniques and stretch of cells in the ex-vivo setting is controlled by a purpose built cell stretching device. The aims of the experiment will be satisfied through a combination of both direct measurement of vascular function (myography) and through nitric oxide and inflammatory marker expression quantification in endothelial cells cultured from the vessels of these animals.
Project 2: Arterial stiffness and blood pressure variability in response to dietary salt intake
Increased salt intake in the diet has long been associated with increased blood pressure, increased arterial stiffness, and increased probability of death. More recent studies have found a strong correlation between variability in blood pressure and cardiovascular events. Pilot study work has uncovered a possible association between the variability in the stiffness of large arteries and dietary salt intake. This study has been designed to further explore these possible associations.
- That increased salt intake increases variability in both blood pressure and large artery stiffness.
- That this association can be observed in a cross-sectional of the population.
- To quantify blood pressure variability and large artery stiffness variability in an animal model of a high sodium diet.
- To quantify any correlation between dietary salt intake and variability in central aortic blood pressure parameters in the general population.
The first part of this project will involve a controlled experiment in rodents implanted with telemetry instruments to measure blood pressure and arterial stiffness. Comparison will be drawn between animals on a high sodium diet and those on a normal diet. Telemetry measurements will give measures of variability in aortic blood pressure and stiffness. The second part of the study will involve a cross sectional study of the cardiovascular event free human population. Dietary sodium will be measured using 24 hour urinary collection and parameters of aortic blood pressure and stiffness will be measured using ambulatory blood pressure monitors that have recently included the technology for non-invasive estimation of such parameters. The project will conclude through a tightly controlled animal study whether there is an association between increased salt intake and cardiovascular variability and in a cross-sectional study whether that finding may be translated to the human population.
Project 3: Blood pressure lowering mechanisms of long-term baroreceptor stimulation
Treatment of high blood pressure is not always successful using pharmacological agents. Recent studies have shown that what was once thought to be a short-term controller of blood pressure (the baroreceptor system), can also be used for long term control. This is done by electrical stimulate of nerves on the carotid artery in the neck. Investigations are underway to elucidate mechanisms responsible for the long term control of blood pressure using this technique and to uncover additional cardiovascular benefits beyond the reduction of blood pressure.
That long term stimulation of the baroreceptor complex results in differential effects in the kidneys, heart, and peripheral vasculature.
- To advance the method of long term baroreceptor stimulation in a rodent model of hypertension.
- To measure the impact of long term baroreceptor stimulation on the cardiovascular system.
This project will entail placement of implantable stimulation devices in a rodent that is genetically susceptible to hypertension. Measurement of the response of the cardiovascular system to baroreceptor stimulation will be through a combination of telemetry, high fidelity measurement of large artery and left ventricular pressure and flow, vessel myography, and measurements of kidney function. The project also offers the possibility for collaboration to investigate the impact of baroreceptor stimulation in humans on central aortic blood pressure parameters, as assessed non-invasively using ambulatory blood pressure measurement devices.
Project 4: Non-invasive estimation of intracrannial pressure
The current method of measurement of intracranial pressure is by placing a pressure catheter into the intracranial area through a window made in the skull. This method of measurement does carry some risk of infection and also means that intracranial pressure measurements are only used in the most severe of scenarios. A non-invasive measure of intracranial pressure would open the method to a vast array of exploratory and clinical uses where intracranial pressure cannot currently be measured. Previous work by investigators in the group have shown that non-invasive measures such as intra-ocular pressure, transcranial Doppler measurement of arterial blood flow, and the aortic pressure waveform shape, estimated non-invasively, carry information that may be useful in estimation of intracranial pressure.
That intracranial pressure can be estimated using non-invasively acquired cardiovascular signals.
To develop a multi-regression approach for non-invasive estimation of intracranial pressure.
This project will draw upon a database of existing clinical recordings and be supplemented by non-invasive measures of aortic pressure, intra-ocular pressure, and cerebral vascular blood flow. The study will centre on processing of cardiovascular waveforms including regression and Fourier techniques with the aim to arrive at a robust method for estimation of intracranial pressure.
Project 5: Effect of early anti-hypertensive treatment on development of dementia and associated disorders: haemodynamic investigations in rodent models
There is evidence that cardiovascular risk factors related to pulsatile haemodynamics are associated with development of dementia, manifest as progressive cognitive impairment and Alzheimer’s disease. In human populations, hypertension in midlife has been shown to be a significant marker for development of cerebral dysfunction associated with dementia at older age. However, the underlying mechanisms involved in the relationship between pulsatile haemodynamics and cerebral disorders (impaired cognitive function, accumulation of amyloid plaques as a hallmark of Alzheimer’s disease) are not yet clearly established. In spontaneously hypertensive rats (SHR), it has been shown that early treatment with angiotensin converting enzyme inhibition (ACEi) for a defined period results in the SHR not developing high blood pressure, even when the ACEi treatment has been withdraw. This model will be used to investigate the effect of early antihypertensive treatment on pulsatile haemodynamics and associated cerebral structure and function.
That early treatment of high blood pressure will result in reduced cognitive dysfunction and reduced accumulation of amyloid plaques in the brain.
- To quantify pulsatile haemodynamics, cognitive function and cerebral amyloid load in normotensive rats as a function of time during development to mature age.
- To quantify pulsatile haemodynamics, cognitive function and cerebral amyloid load in SHR as a function of time with development of high blood pressure to mature age
- To quantify pulsatile haemodynamics, cognitive function and cerebral amyloid load in SHR rats treated early with ACEi as a function of time during development to mature age.
- To measure retinal vessel pulsatility in all groups at each time point
The above aims will be investigated in cohorts of normotensive rats (Wistar-Kyoto, WKY), SHR and SHR with early treatment with ACEi. Pulsatile haemodynamics will be quantified in terms of relationships of blood pressure and flow (vascular impedance), wave propagation (pulse wave velocity, wave reflection indices), arterial stiffness (material elastic modulus), endothelial function (vascular myography). Retinal pulsatility will be measured by a specialised retinal camera (Dynamic Vessel Analyser). Cognitive function will be assessed by standard maze tests developed for rodents. Spatial cortical amyloid load will be quantified from stained brain sections. Data analysis will involve comparisons of pulsatile haemodynamic parameters with parameters of cognitive function and cerebral structure at defines time points in all groups.