Analysis of the intraocular pressure pulse

This thesis was concerned with investigating methods of improving the IOP pulse’s potential as a measure of clinical utility. There were three principal sections to the work. 1. Optimisation of measurement and analysis of the IOP pulse. A literature review, covering the years 1960 – 2002 and other relevant scientific publications, provided a knowledge base on the IOP pulse. Initial studies investigated suitable instrumentation and measurement techniques. Fourier transformation was identified as a promising method of analysing the IOP pulse and this technique was developed. 2. Investigation of ocular and systemic variables that affect IOP pulse measurements In order to recognise clinically important changes in IOP pulse measurement, studies were performed to identify influencing factors. Fourier analysis was tested against traditional parameters in order to assess its ability to detect differences in IOP pulse. In addition, it had been speculated that the waveform components of the IOP pulse contained vascular characteristic analogous to those components found in arterial pulse waves. Validation studies to test this hypothesis were attempted. 3. The nature of the intraocular pressure pulse in health and disease and its relation to systemic cardiovascular variables. Fourier analysis and traditional parameters were applied to the IOP pulse measurements taken on diseased and healthy eyes. Only the derived parameter, pulsatile ocular blood flow (POBF) detected differences in diseased groups. The use of an ocular pressure-volume relationship may have improved the POBF measure’s variance in comparison to the measurement of the pulse’s amplitude or Fourier components. Finally, the importance of the driving force of pulsatile blood flow, the arterial pressure pulse, is highlighted. A method of combining the measurements of pulsatile blood flow and pulsatile blood pressure to create a measure of ocular vascular impedance is described along with its advantages for future studies.

Physiological and pathological human ocular perfusion characteristics

There were three principle aims to this thesis. Firstly, the acquisition protocols of clinical blood flow apparatus were investigated in order to optimise them for both cross-sectional and longitudinal application. Secondly, the effects of physiological factors including age and systematic circulation on ocular blood flow were investigated. Finally, the ocular perfusion characteristics of patients diagnosed with ocular diseases considered to be of a vascular origin were investigated. The principle findings of this work are:- 1) Optimisation of clinical investigationsPhotodiode sensitivity of the scanning laser Doppler flowmeter should be kept within a range of 70-150 DC when acquiring images of the retina and optic nerve head in order to optimise the reproducibility of capillary blood flow measures. Account of the physiological spatial variation in retinal blood flow measures can be made using standard analysis protocols of the scanning laser Doppler flowmeter combined with a local search strategy. Measurements of pulsatile ocular blood flow using the ocular blood flow analyser are reproducible, however this reproducibility can be improved when consecutive intraocular pressure pulses are used to calculate pulsatile ocular blood flow. Spectral analysis of the intraocular pressure pulse-wave is viable and identifies the first four harmonic components of the waveform. 2) Physiological variation in ocular perfusionAge results in a significant reduction in perfusion of the retinal microcirculation, which is not evident in larger vessel beds such as the choroid. Despite known asymmetry in the systemic vasculature, no evidence of interocular asymmetry in ocular perfusion is apparent. 3) Pathological variation in ocular perfusionIn primary open angle glaucoma, perfusion is reduced in the retinal microcirculation of patients classified as having early to moderate visual field defects. However, ocular pulsatility defects are masked when patients and subjects are matched for systemic variables (pulse rate and mean arterial pressure); differentiation is facilitated by the application of waveform analysis to the continuos intraocular pressure curve even in the early stages of disease. Diabetic patients with adequate glycaemic control, exhibit maintenance of macular blood flow, macular topography and visual function following phacoemulsification.

The effect of innate compliance on the performance of a counterpulsation device

Cardiovascular disease (CVD) continues to be one of the top causes of mortality in the world. World Heart Organization (WHO) reported that in 2004, CVD contributed to almost 30% of death from estimated worldwide death figures of 58 million[1]. Heart failure treatment varies from lifestyle adjustment to heart transplantation; its aims are to reduce HF symptoms, prolong patient survival and minimize risk [2]. One alternative available in the market for HF treatment is Left Ventricular Assist Device (LVAD). Chronic Intermittent Mechanical Support (CIMS) device is a novel (LVAD) heart failure treatment using counterpulsation similar to Intra Aortic Balloon Pumps (IABP). However, the implantation site of the CIMS balloon is in the ascending aorta just distal to aortic valve contrasted with IABP in the descending aorta. Counterpulsation coupled with implantation close to the aortic valve enables comparable flow augmentation with reduced balloon volume. Two prototypes of the CIMS balloon were constructed using rapid prototyping: the straight-body model is a cylindrical tube with a silicone membrane lining with zero expansive compliance. The compliant-body model had a bulging structure that allowed the membrane to expand under native systolic pressure increasing the device’s static compliance to 1.5 mL/mmHg. This study examined the effect of device compliance and vascular compliance on counterpulsating flow augmentation. Both prototypes were tested on a two-element Windkessel model human mock circulatory loop (MCL). The devices were placed just distal to aortic valve and left coronary artery. The MCL mimicked HF with cardiac output of 3 L/min, left ventricular pressure of 85/15 mmHg, aortic pressure of 70/50 mmHg and left coronary artery flow rate of 66 mL/min. The mean arterial pressure (MAP) was calculated to be 57 mmHg. Arterial compliance was set to be1.25 mL/mmHg and 2.5 mL/mmHg. Inflation of the balloon was triggered at the dicrotic notch while deflation was at minimum aortic pressure prior to systole. Important haemodynamics parameters such as left ventricular pressure (LVP), aortic pressure (AoP), cardiac output (CO), left coronary artery flowrate (QcorMean), and dP (Peak aortic diastolic augmentation pressure – AoPmax ) were simultaneously recorded for both non-assisted mode and assisted mode. ANOVA was used to analyse the effect of both factors (balloon and arterial compliance) to flow augmentation. The results showed that for cardiac output and left coronary artery flowrate, there were significant difference between balloon and arterial compliance at p < 0.001. Cardiac output recorded maximum output at 18% for compliant body and stiff arterial compliance. Left coronary artery flowrate also recorded around 20% increase due to compliant body and stiffer arterial compliance. Resistance to blood ejection recorded highest difference for combination of straight body and stiffer arterial compliance. From these results it is clear that both balloon and arterial compliance are statistically significant factors for flow augmentation on peripheral artery and reduction of resistance. Although the result for resistance reduction was different from flow augmentation, these results serves as an important aspect which will influence the future design of the CIMS balloon and its control strategy. References: 1. Mathers C, Boerma T, Fat DM. The Global Burden of disease:2004 update. Geneva: World Heatlh Organization; 2008. 2. Jessup M, Brozena S. Heart Failure. N Engl J Med 2003;348:2007-18.

Enhanced diabetes care to patients of south Asian ethnic origin (the United Kingdom Asian Diabetes Study):a cluster randomised controlled trial

Background - Delivery of high-quality, evidence-based health care to deprived sectors of the community is a major goal for society. We investigated the effectiveness of a culturally sensitive, enhanced care package in UK general practices for improvement of cardiovascular risk factors in patients of south Asian origin with type 2 diabetes. Methods - In this cluster randomised controlled trial, 21 inner-city practices in the UK were assigned by simple randomisation to intervention (enhanced care including additional time with practice nurse and support from a link worker and diabetes-specialist nurse [nine practices; n=868]) or control (standard care [12 practices; n=618]) groups. All adult patients of south Asian origin with type 2 diabetes were eligible. Prescribing algorithms with clearly defined targets were provided for all practices. Primary outcomes were changes in blood pressure, total cholesterol, and glycaemic control (haemoglobin A1c) after 2 years. Analysis was by intention to treat. This trial is registered, number ISRCTN 38297969. Findings - We recorded significant differences between treatment groups in diastolic blood pressure (1·91 [95% CI -2·88 to -0·94] mm?Hg, p=0·0001) and mean arterial pressure (1·36 [-2·49 to -0·23] mm?Hg, p=0·0180), after adjustment for confounders and clustering. We noted no significant differences between groups for total cholesterol (0·03 [-0·04 to 0·11] mmol/L), systolic blood pressure (-0·33 [-2·41 to 1·75] mm?Hg), or HbA1c (-0·15% [-0·33 to 0·03]). Economic analysis suggests that the nurse-led intervention was not cost effective (incremental cost-effectiveness ratio £28?933 per QALY gained). Across the whole study population over the 2 years of the trial, systolic blood pressure, diastolic blood pressure, and cholesterol decreased significantly by 4·9 (95% CI 4·0–5·9) mm?Hg, 3·8 (3·2–4·4) mm?Hg, and 0·45 (0·40–0·51) mmol/L, respectively, and we recorded a small and non-significant increase for haemoglobin A1c (0·04% [-0·04 to 0·13]), p=0·290). Interpretation - We recorded additional, although small, benefits from our culturally tailored care package that were greater than the secular changes achieved in the UK in recent years. Stricter targets in general practice and further measures to motivate patients are needed to achieve best possible health-care outcomes in south Asian patients with diabetes. Funding - Pfizer, Sanofi-Aventis, Servier Laboratories UK, Merck Sharp & Dohme/Schering-Plough, Takeda UK, Roche, Merck Pharma, Daiichi-Sankyo UK, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Bristol-Myers Squibb, Solvay Health Care, and Assurance Medical Society UK.

The hypotensive effect of acute and chronic AMP-activated protein kinase activation in normal and hyperlipidemic mice

AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE-/- mice on high fat diet for 6 weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE-/- mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE-/- mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE-/- mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance.