Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-014-2614-6
RETINAL DISORDERS
Improvement of mild retinopathy in type 2 diabetic patients correlates with narrowing of retinal arterioles. A prospective observational study Line Pedersen & Peter Jeppesen & Søren Tang Knudsen & Per Løgstrup Poulsen & Toke Bek
Received: 26 November 2013 / Revised: 27 February 2014 / Accepted: 5 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies. Methods Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were reexamined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened. Results At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal The authors had full control of the primary data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. L. Pedersen (*) : P. Jeppesen : T. Bek Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark e-mail: [email protected] S. T. Knudsen : P. L. Poulsen Department of Endocrinology, Aarhus University Hospital, 8000 Aarhus C, Denmark
arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy. Conclusions The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy. Keywords Retinal autoregulation . Type 2 diabetes . Retinal vessel diameter . Longitudinal study
Introduction Diabetic retinopathy is one of the leading causes of blindness in the Western world [1, 2], and the increasing incidence of type 2 diabetes mellitus can be expected to increase the incidence of vision-threatening diabetic retinopathy further [3, 4]. The prevention of this outcome might be facilitated by a more detailed knowledge about the pathophysiology of the disease. Diabetic retinopathy is characterized by morphological lesions in the retina such as microaneurysms, hemorrhages, exudates, capillary occlusion, and neovascularization signifying disturbances in retinal blood flow [5–7]. Although evidence suggests that disturbances in retinal autoregulation may be part of the disease pathogenesis [8], it is unknown whether the changes in blood flow precede or follow the development of retinal lesions. Longitudinal studies with sufficient follow-up time for studying the development of retinal vascular pathology are required for describing the order of occurrence of pathological changes in diabetic retinopathy. Therefore, a prospective study of changes in diabetic retinopathy and retinal vascular function as assessed by the diameter and autoregulation of larger retinal vessels was initiated. Sixty-two patients with type 2 diabetes mellitus and mild diabetic retinopathy entered a prospective observational study including fundus photography and video recordings of
Graefes Arch Clin Exp Ophthalmol
the retina using the Dynamic Vessel Analyzer (DVA). The present article reports 5 years of follow-up of changes in retinopathy and vascular function in this patient cohort.
Methods Design A prospective observational study with 5 years of follow-up. The study was approved by the local ethical committee for medical sciences and fulfilled the Declaration of Helsinki.
front of the camera and was asked to fixate at a bar inside its viewing system. The image of the retinal fundus was displayed on the computer monitor real-time, which allowed the examiner to define a vessel segment to be analyzed (Fig. 1). During the subsequent recording, the software calculated the diameter of the vessel segment 25 times per second based on the contrast between the vessel and the surrounding retina. The DVA computer software automatically adjusted the retinal image to compensate for saccadic eye movements, and interrupted the data sampling during larger eye movements or blinking. Diameter measurements
Patients From 2003-2005, 66 patients (42 males and 23 females) with type 2 diabetes mellitus patients were enrolled in a prospective study of the relation between changes in diabetic retinopathy and retinal autoregulation. The participants were below the age of 65 years and had no other known ocular diseases than mild non-proliferative diabetic retinopathy defined as the presence of 1–4 microaneurysms. The patients were recruited successively among patients attending the screening clinic for diabetic retinopathy at the Department of Ophthalmology, Aarhus University Hospital, and both oral and written consent was obtained before inclusion in the study. Type 2 diabetes mellitus was defined as onset of diabetes over 30 years of age and no insulin treatment within the first year of the disease. The mean age at inclusion was 57.5±5.7 years (mean ± SD) and duration of diabetes 10.0±6.5 years (mean ± SD).
The examination was performed in one eye from each patient, and if retinopathy changes were present in both eyes, the left eye was chosen. The diameter measurements were performed on the longest arteriolar segment located between two bifurcations, which was within three disk diameters from the optic disk and clearly separated from other vessels. An examination consisted of three periods each lasting 180 s. During the first period, the arteriolar diameter was recorded at rest. During the second (exercise) period, the patient lifted a hand weight of 2 kg using the right arm in order to increase the arterial blood pressure, and during the third (restitution) period the patient rested in order for the blood pressure to return to normal (Fig. 2). The blood pressure was measured by an oscillometric technique with a cuff placed on the left arm (705IT, Omron Healthcare, Kyoto, Japan) 30 s after the beginning of the resting period and 120 s after the beginning of the following two periods.
Baseline examination Retinal thickness Ophthalmological examination The patients underwent a standard ophthalmological examination including the measurement of best-corrected visual acuity (BCVA) using Snellen charts, intraocular pressure (Nidek, Tonoref II, Japan), and slit-lamp examination. Dilatation of the pupils was induced with phenylephrine 10 % (SAD, Denmark) and tropicamide 1 % (Alcon, Denmark) eye drops, followed by fundus photography (Canon CF 60Z, Amstelveen, Holland) with one 60 degree photograph centered on the fovea and a nasally displaced photograph centered on the optic disk. Fundus photography was followed by an examination of retinal arterioles using the Dynamic Vessel Analyzer (DVA, Imedos, Germany) and retinal thickness by Optical Coherence Tomography (OCT) scanning.
The measurements were conducted using the Fast Macular Thickness Map program of the OCT2 (Zeiss, Humphrey Division, Dublin, CA, USA) consisting of six radial B-scans centered on the fovea.
Dynamic vessel analyzer The DVA consisted of a fundus camera with a video unit connected to a computer [9]. The patient was positioned in
Fig. 1 A still image from the video sequence in one of the studied patients. The studied arteriole has been marked with a white line. The fixation bar enters the image from the bottom right
Graefes Arch Clin Exp Ophthalmol
Fig. 2 The DVA examination procedure followed
Data analysis
region (n=3), lack of willingness to participate (n=8), because ocular diseases other than diabetic retinopathy had developed (n=2) or because of inability to lift the hand weight during the DVA examination (n=4). This left 42 patients for the re-examination with a mean follow-up time of 6.8 years, range, 5.0–7.8 years. There was no significant difference in the age (Student’s unpaired t test, p=0.56) and diabetes duration (Student’s unpaired t test, p=0.16) among the patients who were lost for follow-up and the patients who were re-examined.
Vessel diameters Ophthalmological examination The diameter measurements were expressed in arbitrary units (aU) approximately corresponding to microns on the retinal plane. The diameter measurements depended on the individually varying optical parameters of the eye, and therefore the data only allowed the calculation of intra-individual changes in vascular diameters. Diameter values were sampled from the DVA computer and transferred to Excel for further analysis. Values that deviated more than 25 % from the mean diameter during larger saccadic eye movements were considered to be erroneous and were excluded. The remaining diameter measurements from each segment were averaged from respectively the resting (30–180 s) and the exercise period (300–330 s). Blood pressure The mean arterial blood pressure (MAP) of each period was calculated using the formula: MAP=(1/3 * BPsys)+(2/3 * BPdia), where BPsys is the systolic blood pressure and BPdia the diastolic blood pressure. The change in MAP during exercise was calculated as follows: MAP change=(MAPexercise – MAPrest)/ MAPrest *100.
The procedures from the first examination were repeated with the measurement of diameters on the same vascular segments, the only change being that optical coherence tomography scanning was performed using the Stratus apparatus (Stratus 4.0.2, Zeiss, Dublin, CA, USA). The test procedure was performed similarly to the first examination, except that the diameter of the rings used to delimit sub-areas for thickness measurements were 3 and 6 mm, respectively. In order to compare retinal thickness obtained at the first and the second examination, 13 eyes from seven of the patients were examined on the same day using both apparatuses. This showed a significant correlation between the mean thickness values obtained by the two methods (p
RETINAL DISORDERS
Improvement of mild retinopathy in type 2 diabetic patients correlates with narrowing of retinal arterioles. A prospective observational study Line Pedersen & Peter Jeppesen & Søren Tang Knudsen & Per Løgstrup Poulsen & Toke Bek
Received: 26 November 2013 / Revised: 27 February 2014 / Accepted: 5 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies. Methods Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were reexamined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened. Results At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal The authors had full control of the primary data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. L. Pedersen (*) : P. Jeppesen : T. Bek Department of Ophthalmology, Aarhus University Hospital, 8000 Aarhus C, Denmark e-mail: [email protected] S. T. Knudsen : P. L. Poulsen Department of Endocrinology, Aarhus University Hospital, 8000 Aarhus C, Denmark
arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy. Conclusions The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy. Keywords Retinal autoregulation . Type 2 diabetes . Retinal vessel diameter . Longitudinal study
Introduction Diabetic retinopathy is one of the leading causes of blindness in the Western world [1, 2], and the increasing incidence of type 2 diabetes mellitus can be expected to increase the incidence of vision-threatening diabetic retinopathy further [3, 4]. The prevention of this outcome might be facilitated by a more detailed knowledge about the pathophysiology of the disease. Diabetic retinopathy is characterized by morphological lesions in the retina such as microaneurysms, hemorrhages, exudates, capillary occlusion, and neovascularization signifying disturbances in retinal blood flow [5–7]. Although evidence suggests that disturbances in retinal autoregulation may be part of the disease pathogenesis [8], it is unknown whether the changes in blood flow precede or follow the development of retinal lesions. Longitudinal studies with sufficient follow-up time for studying the development of retinal vascular pathology are required for describing the order of occurrence of pathological changes in diabetic retinopathy. Therefore, a prospective study of changes in diabetic retinopathy and retinal vascular function as assessed by the diameter and autoregulation of larger retinal vessels was initiated. Sixty-two patients with type 2 diabetes mellitus and mild diabetic retinopathy entered a prospective observational study including fundus photography and video recordings of
Graefes Arch Clin Exp Ophthalmol
the retina using the Dynamic Vessel Analyzer (DVA). The present article reports 5 years of follow-up of changes in retinopathy and vascular function in this patient cohort.
Methods Design A prospective observational study with 5 years of follow-up. The study was approved by the local ethical committee for medical sciences and fulfilled the Declaration of Helsinki.
front of the camera and was asked to fixate at a bar inside its viewing system. The image of the retinal fundus was displayed on the computer monitor real-time, which allowed the examiner to define a vessel segment to be analyzed (Fig. 1). During the subsequent recording, the software calculated the diameter of the vessel segment 25 times per second based on the contrast between the vessel and the surrounding retina. The DVA computer software automatically adjusted the retinal image to compensate for saccadic eye movements, and interrupted the data sampling during larger eye movements or blinking. Diameter measurements
Patients From 2003-2005, 66 patients (42 males and 23 females) with type 2 diabetes mellitus patients were enrolled in a prospective study of the relation between changes in diabetic retinopathy and retinal autoregulation. The participants were below the age of 65 years and had no other known ocular diseases than mild non-proliferative diabetic retinopathy defined as the presence of 1–4 microaneurysms. The patients were recruited successively among patients attending the screening clinic for diabetic retinopathy at the Department of Ophthalmology, Aarhus University Hospital, and both oral and written consent was obtained before inclusion in the study. Type 2 diabetes mellitus was defined as onset of diabetes over 30 years of age and no insulin treatment within the first year of the disease. The mean age at inclusion was 57.5±5.7 years (mean ± SD) and duration of diabetes 10.0±6.5 years (mean ± SD).
The examination was performed in one eye from each patient, and if retinopathy changes were present in both eyes, the left eye was chosen. The diameter measurements were performed on the longest arteriolar segment located between two bifurcations, which was within three disk diameters from the optic disk and clearly separated from other vessels. An examination consisted of three periods each lasting 180 s. During the first period, the arteriolar diameter was recorded at rest. During the second (exercise) period, the patient lifted a hand weight of 2 kg using the right arm in order to increase the arterial blood pressure, and during the third (restitution) period the patient rested in order for the blood pressure to return to normal (Fig. 2). The blood pressure was measured by an oscillometric technique with a cuff placed on the left arm (705IT, Omron Healthcare, Kyoto, Japan) 30 s after the beginning of the resting period and 120 s after the beginning of the following two periods.
Baseline examination Retinal thickness Ophthalmological examination The patients underwent a standard ophthalmological examination including the measurement of best-corrected visual acuity (BCVA) using Snellen charts, intraocular pressure (Nidek, Tonoref II, Japan), and slit-lamp examination. Dilatation of the pupils was induced with phenylephrine 10 % (SAD, Denmark) and tropicamide 1 % (Alcon, Denmark) eye drops, followed by fundus photography (Canon CF 60Z, Amstelveen, Holland) with one 60 degree photograph centered on the fovea and a nasally displaced photograph centered on the optic disk. Fundus photography was followed by an examination of retinal arterioles using the Dynamic Vessel Analyzer (DVA, Imedos, Germany) and retinal thickness by Optical Coherence Tomography (OCT) scanning.
The measurements were conducted using the Fast Macular Thickness Map program of the OCT2 (Zeiss, Humphrey Division, Dublin, CA, USA) consisting of six radial B-scans centered on the fovea.
Dynamic vessel analyzer The DVA consisted of a fundus camera with a video unit connected to a computer [9]. The patient was positioned in
Fig. 1 A still image from the video sequence in one of the studied patients. The studied arteriole has been marked with a white line. The fixation bar enters the image from the bottom right
Graefes Arch Clin Exp Ophthalmol
Fig. 2 The DVA examination procedure followed
Data analysis
region (n=3), lack of willingness to participate (n=8), because ocular diseases other than diabetic retinopathy had developed (n=2) or because of inability to lift the hand weight during the DVA examination (n=4). This left 42 patients for the re-examination with a mean follow-up time of 6.8 years, range, 5.0–7.8 years. There was no significant difference in the age (Student’s unpaired t test, p=0.56) and diabetes duration (Student’s unpaired t test, p=0.16) among the patients who were lost for follow-up and the patients who were re-examined.
Vessel diameters Ophthalmological examination The diameter measurements were expressed in arbitrary units (aU) approximately corresponding to microns on the retinal plane. The diameter measurements depended on the individually varying optical parameters of the eye, and therefore the data only allowed the calculation of intra-individual changes in vascular diameters. Diameter values were sampled from the DVA computer and transferred to Excel for further analysis. Values that deviated more than 25 % from the mean diameter during larger saccadic eye movements were considered to be erroneous and were excluded. The remaining diameter measurements from each segment were averaged from respectively the resting (30–180 s) and the exercise period (300–330 s). Blood pressure The mean arterial blood pressure (MAP) of each period was calculated using the formula: MAP=(1/3 * BPsys)+(2/3 * BPdia), where BPsys is the systolic blood pressure and BPdia the diastolic blood pressure. The change in MAP during exercise was calculated as follows: MAP change=(MAPexercise – MAPrest)/ MAPrest *100.
The procedures from the first examination were repeated with the measurement of diameters on the same vascular segments, the only change being that optical coherence tomography scanning was performed using the Stratus apparatus (Stratus 4.0.2, Zeiss, Dublin, CA, USA). The test procedure was performed similarly to the first examination, except that the diameter of the rings used to delimit sub-areas for thickness measurements were 3 and 6 mm, respectively. In order to compare retinal thickness obtained at the first and the second examination, 13 eyes from seven of the patients were examined on the same day using both apparatuses. This showed a significant correlation between the mean thickness values obtained by the two methods (p
