Does blood pressure affect macular thickness in healthy individuals? And is this altered by type two diabetes mellitus?

Transcription

1 Does blood pressure affect macular thickness in healthy individuals? And is this altered by type two diabetes mellitus? Type 2 diabetes mellitus (T2DM) is commonly associated with a raised blood pressure. The prevalence of hypertension is higher in the T2DM population than in the general population, with about 60% of people with T2DM having hypertension by the age of 75 year old (1). Blood pressure has previously been shown to be associated with the development of microvascular complications, in a study by UKPDS it was demonstrated that intensive blood pressure management slows the progression of microvascular complication by 37% compared to a less tightly controlled group(1). The retina is one of the microvascular beds that are susceptible to damage and is the site affected by diabetic retinopathy. Diabetic retinopathy (DR) is now one of the leading causes of blindness in working aged adults in westernised countries. Traditionally retinal photography has been used to take photographs of the fundus of the eye. Clinically these photographs are taken to monitor the progression of a disease, diagnosis of a disease or in screening programs (e.g. diabetic retinopathy screening program). However the downside to this tool is that these images are 2 dimensional and as a result cannot detect small changes in the thickness of the retina that have been implicated in the progression of some diseases e.g. diabetic retinopathy. With technological advance a new type of imaging is available, Optical coherence tomography (OCT). This is a type of non-invasive medical imaging which uses low coherence tomography to generate cross-sectional pictures of the retina that collectively create a 3D image, allowing macular thickness to be measured, this can be subdivided into nine subdivisions centred on the fovea. The central subfield (fovea) is the area of most clinical relevance as it has the densest concentration of cones and is responsible for central vision. An increase in the thickness of this area is a preclinical sign of macular oedema, a complication of diabetes. Macular thickness in individuals with diabetic macular oedema (DMO) has been linked to blood pressure parameters both independent and dependently. Acute alterations in fovea thickness have been reported in connection with posture, with the fovea thickness decreasing though the day and increasing in the evening. This diurnal thickness changes have been positively correlated with brachial pulse pressure, both when the fovea thickness was measured at 9am and over a 24-hour period (2, 3). Additional research demonstrated that overnight changes in macular thickness correlated directly with the overnight change in mean arterial blood pressure (4). However there is only a small amount of literature examining whether blood pressure and macular thickness are associated in T2DM patients with no DR. Preliminary work from Exeter looking into blood pressure parameters effects on macular thickness have shown that in individual without diabetes but with varying risk factors of the metabolic syndrome mean arterial blood pressure was positively associated with macular thickness (5). Capillary pressure has also been observed to be positively correlated to fovea thickness in individuals without diabetes(6). Previous research has examined whether fovea or macular thickness is altered in T2DM compared to controls with contrasting results. These studies did not investigate the potential contributing factors like blood pressure. As a result this report will be carrying on from the previous work from Exeter and will look at the relationship between systemic blood pressure and macular thickness initially in control individuals to confirm previous preliminary observations. It will also examine whether the same relationship between blood pressure and macular thickness is observed in patients with T2DM. Thus the aims of this report is to examine whether macular thickness is altered by blood pressure in individuals without diabetes and whether this relationship is affected by T2DM. Abigail Coe 1

2 Methods Participant information This report uses the baseline participant data from a longitudinal study called SUMMIT. This study is investigating whether macular thickness precedes or parallels the development and/or progression of background retinopathy. At baseline, 455 participants with type-2 diabetes with either no or background retinopathy and 71 controls were recruited. To address the aim of this report a subset of participant s data was used. The exclusion criteria was treatment with an antihypertensive in both populations and presence of any retinopathy in the T2DM group Statistical analysis The data from the right eye was used in all analysis. Univariate analysis was performed using Pearson s or Spearman s correlation depending on the normality, to explore whether macular thickness is associated mean arterial blood pressure (MAP), measure of systemic blood pressure for each group. The primary macular thickness parameter examined was fovea thickness, because of its clinical importance. On the basis of univariate analysis the inner nasal quadrant and outer temporal quadrant were selected to represent thickness in the inner and outer quadrants. These relationships were then further explored, using linear regression adjusting for known confounding variables, age and gender. For groups larger than 39 the potential confounding variable, waist to hip ratio was additionally adjusted for. To determine if there were any influential cases affecting the results Mahalanobis distance was checked against Barnett and Lewis (1978) table of critical values, Cook s distances (less than one) and Leverage values (less than (predictors + 1)/n) were checked. If an influential case/s were found the test was repeated excluding them to check they were not unduly influencing the results. The regression analysis was repeated in both groups using normotensive participants only. Macular thickness measurement All participants underwent bilateral OCT examination using the Cirrus OCT instrument (Carl Zeiss) operated by an experienced team member. This machine measures thickness from the inner limiting membrane (vitreoretinal interface) to the mid-point of the retinal pigment epithelium. The macular cube 512x128 scan protocol was used which performs 128 horizontal lines of 512 A-scans in a 6x6m scanning area. The fovea is defined as the fixation point with a radius of 500um. The fovea is then surrounded by two concentric rings (inner ring diameter 3mm and outer ring 6mm diameter), these concentric circles are then divided into four subfields temporal, superior, nasal and inferior. The software automatically determines the thickness of the 9 sub divisions of the macular. This is a reproducible technique; my mean coefficient of variation for the fovea thickness was 0.88% (range of 0.36% to 1.43%) calculated from 5 separate measurements each for two people. Mean arterial blood pressure Participants were supine when their blood pressure was taken 6 times at the brachial artery (3 times on the left and 3 times on the right) using an automatic blood pressure recorder. The mean of the 6 systolic (SBP) and 6 diastolic (DBP) were then used to calculate MAP (MAP = DBP +1/3(SBP-DBP).) Waist to hip Waist measurement was taken half way between the iliac crest and costal margin, the hip was measured at the widest circumference over the buttocks and below the iliac crest. These measurements were repeated and Abigail Coe 2

3 the mean note. To calculate the waist to hip ratio the following equation was used waist/hip = waist to hip ratio. Results Comparison of participant groups Baseline characteristics of participants are summarised in table 1 and 2. Control group T2DM group Mean (SD) Range Mean (SD) Range Total sample Men n (%) 18 (39.1%) - 52 (65.1%) - Age 64.2 (1.1) (1.1) MAP 96.8 (1.6) (1.2) Waist to hip ratio 0.88 (0.01) (0.01) HBA1C 39 (0.45) (1.63) Fovea thickness (17.89) (25.69) Table 1: Participant characteristic data for the T2DM and control group Control and T2DM groups There was no significant difference between the groups for age and mean arterial blood pressure. There was a difference in distribution of female and males between the groups, with there being a higher proportion of men in the T2DM group. As expected, there was a significant difference between HbA1c (P<0.001) and waist to hip ratio (P<0.001) between the two groups. The difference in HbA1c is expected due to the difference in diabetes status, and in the regression models age and waist to hip ratio are adjusted for. Normotensive groups Participant s characteristics of the normotensive T2DM and control groups are presented in table 2; there was a difference in the distribution of females and males between the groups. There was no significant difference between the groups for age and mean arterial pressure. However there was a significant difference for waist to hip ratio (P<0.001) and HbA1c (P<0.001). The difference in in HBA1C is expected due to the difference in diabetes status, and in the regression models gender and waist to hip have been adjusted for. Control normotensive group Diabetic normotensive group Mean (SD) Range Mean (SD) Range Total sample Men (%) 12 (41.4%) - 27 (67.5%) - Age 62.6 (1.4) (1.7) MAP 90.8 (1.2) (0.9) Waist to hip ratio 0.87 (0.02) (0.01) HBA1C 39 (0.56) (2.57) Fovea thickness (18.92) (23.65) Table 2: Participant characteristics for normotensive control and T2DM groups Abigail Coe 3

4 Main results Fovea thickness and mean arterial blood pressure were significant associated in the control group, with the relationship strengthening when hypertensive participants were excluded (all control participants: R=0.298, p<0.05; Normotensive control participants only: R=0.560, p<0.01, univariate analysis, Table 3). These trends remained when adjusted for age and gender (Standardised Beta=0.386, p<0.01; Standardised Beta=0.534, p<0.01 Table 5). When hip to waist ratio was also adjusted for the relationship between the fovea and mean arterial blood pressure was unchanged (see table 6). However, no association between mean arterial blood pressure and fovea thickness was observed in the T2DM group with either univariate or linear regression analysis. To explore which inner and outer quadrant would be used in the analysis the relationship between all inner and outer quadrants and MAP was explored in the whole cohort (combined T2DM and control group). Collectively there were no significant associations between the inner and outer quadrants and mean arterial blood pressure in the whole cohort. The inner nasal and outer superior quadrants had the strongest correlation coefficient in the inner and outer quadrants when a univariate analysis was performed using data from all participants (Table 4). Thus, these two quadrants were used to further explore the relationship with MAP using linear regression. However, the relationship still remained not significant when adjusting for age and gender (Table7). Correlation coefficient (R) P value All controls All T2DM Control normotensive group T2DM normotensive group Table 3: Association between Fovea thickness and mean arterial blood pressure. Correlation coefficient and P value. Significant results presented in bold. Correlation coefficient ( R ) P value Inner superior Inner nasal Inner inferior Inner temporal Outer superior Outer nasal Outer inferior Outer temporal Table 4: Association between macular thickness and mean arterial blood pressure. Correlation coefficient and p value for all participants Abigail Coe 4

5 Unstandardised beta (standard error) Standardised Beta P values Non diabetic (0.233) Diabetics (0.268) Non diabetic normotensive (0.492) Diabetic normotensive (0.646) Table 5: Association between Fovea thickness and mean arterial blood pressure. Unstandardised and standardised beta values for mean arterial blood pressure for 4 participant groups, generated from the forced entered models adjusting for age and gender. Unstandardised beta (standard error) Standardised Beta P value Non diabetic (0.238) Diabetics (0.271) Table 6: Association between Fovea thickness and mean arterial blood pressure. Unstandardised and standardised beta values for mean arterial blood pressure for the controls and T2DM, generated from the forced entered models adjusting for age, gender and waist to hip ratio. Unstandardised beta (standard error) Standardised Beta P value Non diabetic (0.187) Diabetics (0.198) Non diabetic normotensive (0.453) Diabetic normotensive (0.546) Table 7: Association between semi nasal thickness and mean arterial blood pressure. Unstandardised and standardised beta values for mean arterial blood pressure for 4 participant groups from forced entered models adjusting for age and gender. Discussion This study has shown that MAP and fovea thickness are positively and independently associated in the control group, with the relationship absent in the diabetic group; suggesting that diabetes alters the relationship between the fovea and MAP observed in the controls However MAP was not associated with the inner and outer quadrants thickness in both the diabetic and control groups. Interestingly, the study suggests that the relationship between the fovea and MAP is strengthened when hypertensive participants were excluded from analysis. The vasculature of the eye is one site vulnerable to diabetes complications and is involved in diabetic retinopathy and DMO. The observation that MAP is associated only with the fovea in the controls may be due to the fact the retina has two-blood supplies, the retinal and choroid vessels. The retinal blood supply has four main branches and supplies the neuro retina except the photoreceptor layers and retinal pigment (RPE) layer, which are avascular and rely on the choriocapillaris from the choroid. The choroid receives 80% of the ocular blood and is responsible for the metabolic demands of the fovea (avascular zone in the retina)(7) as well as the photoreceptor and RPE layers. Thus the observed difference in the relationship between MAP with the fovea and the inner and outer quadrants of the macular may reflect the different vascular networks that supply them and their differing regulatory mechanisms. Abigail Coe 5

6 The findings from this report differ from the previous work from Exeter. Previously they found that there was a relationship between the outer quadrants with blood pressure but not for the fovea. A potential reason for the discrepancy is that different OCT technologies were used, the OCT machines in the earlier research used time domain OCT (Stratus, Carl Zeiss), which acquired 6 evenly spaced 6mm radial lines which intersect in the fovea, which have 128 a-scans along each line. Meaning the measurements for the outer quadrants had lower resolution and the scan points were further apart compared to the spectral domain which was used when collecting this data, this methods scans a 6x6mm area of the retina which has 128 horizontal lines with 512 A- scans per line, that is 65,536 sampled points compared to 768. They also measure to different depths; the stratus measured from the Inner limiting membrane to the interface between the outer and inner photoreceptors, meaning the readings are not comparable. The other big difference was the age distribution between the studies, the other study had a wide range of ages from 26 to 78 where as the participants in this report were from an older age bracket 41 to 83 years. Age is a known confounding variable that effects macular thickness and as a result could affect the relationships observed. The limitation to this report the potential confounding variable of the duration of diabetes was not taken into account. In this report it was observed that hypertension reduces the strength of the relationship between MAP and fovea thickness in the control group. This may suggest that hypertension could play a role in altering the normal regulatory mechanisms, which in turn influence the observed association between MAP and fovea thickness. Evidence to support changes in the retina and choroid with hypertension included observations that benign hypertension was associated with changes in the vasculature of the arteries and arterioles of the choroid. Alterations found in postmortem eyes included aneurysmal dilations and focal narrowing that are randomly distributed throughout the vasculature, however this disease process does not seem affect capillaries, veins and the RPE (8).Currently there is minimal literature on the effect of hypertension on the haemodynamics of the choroid. One study found there was no significant change in choroid for all parameters measured, this does not support the previous findings the physiology is altered by increasing blood pressure. But that paper did find the mean velocity was 2.4% greater and the volume and flow was 13.9% and 8% less (9), there are limitations to the conclusions that can be drawn from this study as it only had a sample size of 15, with 12 being on antihypertensive medication so further research is required. Hypertension is associated with an accelerated aging process. If these changes observed have a similar physiological effect as that implicated in the disease process of age related macular degeneration, where choroid blood flow decreases(10) it could in part contribute to the weakening of the relationship, observed when hypertensive participants are included in the group for the non-diabetics. Even though in the study blood flow is an arbitrary unit, blood flow rate can be calculated by the difference between arterial and venous blood pressure divided by resistance, if blood flow decreases in the choroid due to hypertension, either resistance increases or the difference in blood pressure readings decrease. If there is a decrease in the difference in pressure in the choroid then potentially the average capillary pressure is decreased which would reduce fluid filtration in the fovea region altering the strength of the correlation. Alternatively if microvascular rarefaction, a feature of hypertension, were taking place in the choroid resistance could increase affecting the normal function of the choroid. There was no significant difference between the fovea thickness between the diabetic and non-diabetic groups. Fovea thickness was within the healthy normal range for this OCT machine(11) in both groups. In the diabetic groups the relationship between MAP and fovea thickness is lost, suggesting that diabetes per se alters the relationship. As the choroid blood vessels feed the fovea, alteration of the choroid by diabetes could play a role. Diabetes has been seen to alter the structure and physiology of the choroid; this could contribute to the loss of the relationship. In diabetic patients it has been seen that the choroids autoregulation is compromised. For example one study found that using isometric exercises to increase systemic blood pressure in diabetics caused choroid blood flow to increase linearly compared to non-diabetics, however the choroid response to changes in perfusion pressure were largely unaffected. Diabetes is associated with a reduced Abigail Coe 6

7 blood flow in the choroid and early development of vascular lesions compared to healthy individuals. These changes are also accompanied by central choroid thinning in all stages of type 2 diabetics and is thought to be due to possible choriocapillaris atrophy.(12) This decrease in blood flow is similar to the trend found in hypertensive patients, however unlike hypertension the RPE and Bruch s membrane are implicated in the diabetic disease process. The choroid relies on a healthy RPE and Bruch s membrane, the RPE in diabetes can become weakened and is indicated as one of the causative factors in the development of diabetic retinopathy and the Bruch membrane thickens and compromises nutrient delivery. Both of these factors could contribute to the loss of the relationship in diabetics. The OCT device utilised in this research measured net macular thickness from the ILM to the mid-point of the RPE, it provide no information about the individual layers. Thus, an alternative hypothetical contributing factor is that there may be diabetes related changes within the individual layers of the retina that mask the relationship between blood pressure and fovea thickness in the diabetic group. Recent studies have examined whether there are changes in the thickness of layers in the peri foveal area (the area surrounding the fovea, which equates to the inner quadrants on the OCT scan) of the retina. Research has suggested that the following layers thickness alter with diabetes: retinal nerve fibre layer, Ganglion cell layer/inner plexiform layer and outer nuclear layer(13, 14). However studies have inconclusively suggested various layers increase in thickness too. The fovea thickness has contributions from all layers of the retina apart from the retinal nerve fibre layer; if the changes in the peri foveal region also happen in the fovea then it could play a role in the loss of the relationship, as there is limited literature on the foveal region more research is required. It is difficult to form a definitive hypothesis to explain the relationships observed due to the complexity of the regulation and the small amount of literature on this topic. Possible contributing factors have been discussed however further research is required. Possible areas to examine in the future are the effect of hypertension on haemodynamics (with the exclusion criteria of antihypertensive medication) and does diabetes have an effect on the thickness of the different layers in the central quadrant (fovea) on an OCT scan. In summary this report has shown that the only quadrant that is correlated with MAP is the fovea in nondiabetic participants. This relationship weakens when hypertensive participants are included, with potential contributing factors to this weakening are, vascular damage, microvascular refraction and alterations in the haemodynamics. This relationship between MAP and the fovea is lost in the diabetic groups, which suggest diabetes is altering this relationship. Diabetes is known to cause vascular damage; alterations in haemodynamics as well as effecting the RPE and brunch membrane; these observed changed are hypothesised to collectively contribute to the loss of the relationship. However, further research is required to fully understand the observed relationship between MAP and fovea thickness. By understanding this relationship it may provide valuable insight into the development of diabetic and hypertensive retinopathy. I would like to thank the Wellcome trust and the Inspire board at the University of Exeter for awarding me the grant, which has made this research possible. I would also like to thank the Diabetes and Vascular Medicine Research centre at the RD & E and especially Dr Kim Gooding for her guidance and encouragement throughout the process. This experience was hugely enjoyable and has undoubtedly helped with my personal development and confidence. Though each process I have gained transferable skills that will help me throughout my degree e.g. background reading and critical appraisal of previous work, understanding the background knowledge to be able to critically analyse papers methodology and reliability of findings. I found the experience extremely rewarding and it has inspired me to seek other research opportunities during my time at medical school. If the opportunity arose I would also love to continue on from this work looking a whether diabetes causes changes in thickness of the layers in the fovea. Abigail Coe 7

8 Appendix Controls Diabetics Normotensive controls Normotensive diabetics Mean (SD) Mean (SD) Mean (SD) Mean (SD) Fovea (17.89) (25.69) (18.91) (23.65) Inner superior (12.15) (16.17) (13.21) (17.50) Inner nasal (13.05) (17.81) (14.46) (19.06) Inner inferior (13.06) (16.91) (13.85) (18.12) Inner temporal (13.95) (17.82) (13.82) (19.75) Superior (10.23) (14.19) (9.79) (14.98) Nasal (11.02) (14.24) (11.98) (13.84) Inferior (11.68) (13.62) (9.71) (13.60) Temporal (11.21) (14.78) (9.07) (14.82) Table 8: The mean and standard deviations for the 9 quadrants of the scans for each group. Correlation coefficient ( R ) P value Non diabetic Diabetics Non diabetic normotensive Diabetic normotensive Table 9: Association between Inner nasal quadrant thickness and Mean arterial blood pressure. Correlation coefficient and P value Correlation coefficient ( R ) P value Non diabetic Diabetics Non diabetic normotensive Diabetic normotensive Table 10: Association between Outer superior quadrant thickness and mean arterial blood pressure Correlation coefficient and P value Unstandardised beta (standard error) Standardised Beta P value Non diabetic (0.192) Diabetics (0.200) Table 11: Association between semi nasal thickness and mean arterial blood pressure. Unstandardized and standardized beta values for mean arterial blood pressure for the non diabetics and diabetics from forced entered models adjusting for age, gender and waist to hip ratio. Unstandardised beta (standard error) Standardised Beta P value Non diabetic (0.149) Diabetics (0.173) Non diabetic normotensive (0.276) Diabetic normotensive (0.459) Table 12: Association between superior thickness and mean arterial blood pressure Unstandardized and standardized beta values for mean arterial blood pressure for 4 participant groups from forced entered models adjusting for age and gender. Abigail Coe 8

9 Unstandardised beta (standard error) Standardised Beta P value Non diabetic (0.152) Diabetics (0.175) Table 13: Association between superior thickness and mean arterial blood pressure. Unstandardized and standardized beta values for mean arterial blood pressure for the non diabetics and diabetics from forced entered models adjusting for age, gender and waist to hip ratio Reference 1. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Bmj. 1998;317(7160): Polito A, Del Borrello M, Polini G, Furlan F, Isola M, Bandello F. Diurnal variation in clinically significant diabetic macular edema measured by the Stratus OCT. Retina. 2006;26(1): Dupas B, Feldman-Billard S, Bui Quoc E, Erginay A, Guillausseau PJ, Massin P. Influence of pulse pressure and spontaneous variations of macular thickness in patients with diabetic macular oedema. Acta Ophthalmol. 2014;92(5):e Larsen M, Wang M, Sander B. Overnight thickness variation in diabetic macular edema. Invest Ophthalmol Vis Sci. 2005;46(7): Gooding K, Shore A, Lany HV, Ling R, Mitra M, Ball C, et al. Are features of the Metabolic Syndrome Associated with Macular Thickness in Individuals without Diabetes Mellitus? Clinical & Experimental Opthalmology 2012;3(242). 6. Gooding KM, Tooke JE, Lany HV, Mitra M, Ling R, Ball CI, et al. Capillary pressure may predict pre clinical changes in the eye Diabetologia. 2010;53(9): Zion IB, Harris A, Siesky B, Shulman S, McCranor L, Garzozi HJ. Pulsatile ocular blood flow: relationship with flow velocities in vessels supplying the retina and choroid. British journal of ophthalmology. 2007;91(7): Friedman E, Smith T, Kuwabara T, Beyer C. Choroidal vascular patterns in hypertension. Arch Opthalmol. 1964;71: Niknam RM, Schocket LS, Metelitsina T, DuPont JC, Grunwald JE. Effect of hypertension on foveal choroidal haemodynamics Br J Ophthalmol. 2004;88: Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. Effect of systemic hypertension on foveolar choroidal blood flow in age related macular degeneration. Br J Ophthalmol. 2006;90(3): Wolf-Schnurrbusch U, Ceklic L, Brinkmann C, Iliev M, Frey M, Rothenbuehler S, et al. Macular Thickness Measurements in Healthy Eyes Using Six Different Optical Coherence Tomography Instruments. 2009;50(7): Esmaeelpour M, Považay B, Hermann B, Hofer B, Kajic V, Hale S, et al. Mapping choroidal and retinal thickness variation in type 2 diabetes using three-dimensional 1060-nm optical coherence tomography. Invest Opthalmol vis sci. 2011;52(8): vujosevic s, midena e. Retinal Layers Changes in Human Preclinical and Early Clinical Diabetic Retinopathy Support Early Retinal Neuronal and Müller Cells Alterations. Journal of Diabetes Research. 2013;2013: van Dijk HW, Verbraak FD, Kok PH, Stehouwer M, Garvin MK, Sonka M, et al. Early neurodegeneration in the retina of type 2 diabetic patients. Invest Ophthalmol Vis Sci. 2012;53(6): Abigail Coe 9