IJCA-18509; No of Pages 2 International Journal of Cardiology xxx (2014) xxx–xxx

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Retinal vessel analysis and heart rate variability☆,☆☆ Alexander K. Schuster a,1, Marc N. Jarczok a,1, Joachim E. Fischer a, Julian F. Thayer b, Urs Vossmerbaeumer a,⁎,c a b c

Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Germany Department of Psychology, The Ohio State University, OH, USA Department of Ophthalmology, University of Mainz, Germany

a r t i c l e

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Article history: Received 3 July 2014 Accepted 27 July 2014 Available online xxxx Keywords: Heart rate variability Retinal vessels analysis Central retinal equivalent Parasympathetic Sympathetic

Heart rate variability (HRV) is used to index the vegetative nervous system and is linked with cardiovascular and nervous diseases [1]. Funduscopic assessment of the retinal vasculature can be utilized to evaluate the health status of microcirculation and to assess the predisposition of major vascular diseases [2]. The purpose of this study was, for the first time, to examine the influence of HRV on microcirculation as an early marker of cardiovascular alteration. The study population was comprised of apparently healthy employees of a high-tech company in Germany. The participants spanned the entire age of the work force (18–65 years) and all levels of socioeconomic status. A total of 292 subjects were included in this study and took part in a health screening examination including fundus photography and a full day recording of heart rate. The institutional review board and the ethical committee of the University of Heidelberg approved the study in accordance with the Declaration of Helsinki. All participants gave written informed consent and were Caucasians. All participants were examined during daylight time. Blood pressure via sphygmomanometry was recorded from the dominant arm in the seated position after a standardized 5 min rest period. 24-hour heart rate was recorded as beat-to-beat intervals using t6 Suunto Memory Belt (SuuntoVantaa, Finland) at a 1 kHz sample rate. HRV parameters ☆ Financial interest: none. ☆☆ Grant Support: Julian F. Thayer was supported by a Humboldt Senior Research Award. ⁎ Corresponding author at: Consultant Ophthalmic Surgeon, Head Refractive Surgery Unit, Department of Ophthalmology, University of Mainz Medical Center, Langenbeckstr. 1, 55131 Mainz, Germany. Tel.: +49 6131 174061, fax: +49 6131 176620. E-mail addresses: [email protected] (A.K. Schuster), [email protected] (U. Vossmerbaeumer). 1 These authors contributed equally to the manuscript and serve as joint first authors.

were calculated as reported previously in accordance with the Task Force Guidelines of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology published in 1996 using the “ANS-Explorer” Software [3]. Details are described elsewhere [4]. Root mean square of successive differences (RMSSD) primarily reflects vagally mediated HRV, the standard deviation of all N–N (normal-to-normal) intervals (SDNN) reflects sympathetically and parasympathetically mediated HRVs. Frequency domain power was determined as low (LF) (0.04–0.15 Hz) and high frequency (HF) (0.15–0.4 Hz). HF primarily indicates parasympathetically mediated respiratory sinus arrhythmia, in contrast to LF, that reflects sympathetic and parasympathetic inputs to the sinus node and is described to be related to the baroreceptor function. In addition, a comprehensive ophthalmological examination including 45° non-mydriatic digital fundus photography (Topcon 3D OCT2000, Topcon Corp., Tokyo, Japan) was carried out. Retinal vessel analysis was performed using a semi-automated software for non-mydriatic fundus photos [5]. Within this software, the central retinal arterial equivalent (CRAE) and the central retinal venous equivalent (CRVE) were automatically calculated, representing a parameter of the central retinal artery/vein as the actual vessels lay behind the optic disc and cannot be directly examined. CRAE is inversely correlated to arterial hypertension while CRVE is positively correlated to the risk of stroke. These equivalents are determined based on the analysis of retinal vessels around the optic disc and an iterative calculation. The arterialvenous ratio (AVR) was computed as the quotient of CRAE and CRVE. Right eyes were evaluated, as correlations of retinal vessel equivalents between the right and left eyes are high [6]. The distribution of all continuous variables was determined and transformations were used when it was necessary to meet the assumptions of modeling [7]. In these analyses, potential explanatory and confounding variables were entered separately before measures of HRV and retinal vessel parameters. These parameters were measured individually and rater-blinded to all other variables. Two-sided Pearson correlation coefficients and partial correlation coefficients (PCCs) were used to reflect the associations between two variables independent of other variables in the model. As confounding variables, age, gender and mean arterial blood pressure (MAP) were evaluated as these parameters influence both HRV and retinal vasculature. A p-value of 0.05 was regarded as statistically significant. We used SPSS (Version 21, SPSS Inc., Chicago, IL) for data management and analysis. In the examined sample 40% of the participants (overall 292 subjects) were female and 17% were smokers. The mean age of the

http://dx.doi.org/10.1016/j.ijcard.2014.07.190 0167-5273/© 2014 Published by Elsevier Ireland Ltd.

Please cite this article as: Schuster AK, et al, Retinal vessel analysis and heart rate variability, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.07.190

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A.K. Schuster et al. / International Journal of Cardiology xxx (2014) xxx–xxx

Fig. 1. Relationship of central retinal arterial equivalent and RMSSD as an index of heart rate variability. Table 1 Bivariate and partial correlation coefficients (PCC) between heart rate variability (HRV) indices and retinal vessel parameters (N = 292; CRAE: central retinal arterial equivalent; CRVE: central retinal venous equivalent, AVR: arterio-venous ratio). Significant correlation coefficients (p b 0.05) are given in bold numbers (two-tailed). Partial correlations adjusted for age, or mean arterial blood pressure (MAP) or gender. HRV

rMSSD SDNN LF-power HF-power

CRAE

CRVE

AVR

Pear-son

PCC (age)

PCC (MAP)

PCC (gender)

Pearson

Pear-son

PCC (age)

PCC (MAP)

PCC (gender)

0.17 0.13 0.16 0.15

0.00 0.01 0.04 −0.01

0.10 0.09 0.12 0.10

0.15 0.14 0.20 0.12

0.09 0.06 0.05 0.10

0.11 0.09 0.13 0.09

−0.01 0.01 0.07 −0.03

0.03 0.04 0.09 0.02

0.10 0.09 0.16 0.07

study sample was 39.1 ± 11.0 (standard deviation) years and the mean arterial blood pressure was 96 ± 11 mm Hg. These values and other examined systemic cardiovascular parameters were comparable to other studies examining apparently healthy adults [8]. Bivariate analysis indicated significantly positive correlations between all indices of HRV and CRAE, while there was no association of CRVE to any index of HRV. CRAE was correlated to RMSSD (Fig. 1), SDNN, LF- and HF-power. Regarding the arterio-venous ratio there was an association for LF-power with this retinal vessel parameter, while RMSSD, SDNN or HF-power showed no association (Table 1). Partial correlation analysis with age or mean arterial blood pressure as confounding variables showed no statistically significant correlation between indices of HRV and any retinal vessel parameter except for CRAE to LF-power (Table 1). Gender as confounder did not alter the findings except in one finding (Table 1). We are the first to report associations between the retinal vasculature as an indicator of microcirculation and heart rate variability as an index of the vegetative and autonomic nervous systems, both being associated with cardiovascular diseases [1,2]. Our results show that there is an association of HRV indices with the arterial vasculature of the retina, while none for the venous part. This novel finding must be tempered by the influencing factor MAP and age both known as parameters influencing also cardiovascular risk [9]. There is a minor but perhaps clinically relevant role of the vagal autonomic nervous system as indicated by HRV on the retinal vessels. This is in concordance with earlier findings of the autonomy of the retinal vasculature [10].

Conflict of interest No conflicting relationship exists for any author. References [1] Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol 2010; 141:122–31. [2] Li LJ, Lee YS, Wong TY, Cheung CY. Can the retinal microvasculature offer clues to cardiovascular risk factors in early life? Acta Paediatr 2013;102:941–6 [Oslo, Norway: 1992]. [3] Wittling A. ANS Explorer. URL: http://www.neurocor.de/produkte_ansexplorer_de. html; 2013. [Retrieved May 31st, 2013]. [4] Jarczok MN, Li J, Mauss D, Fischer JE, Thayer JF. Heart rate variability is associated with glycemic status after controlling for components of the metabolic syndrome. Int J Cardiol 2013;167:855–61. [5] Schuster AK, Fischer JE, Vossmerbaeumer U. Semi-automated retinal vessel analysis in nonmydriatic fundus photography. Acta Ophthalmol 2014;92:e42–9. [6] Wong TY, Knudtson MD, Klein R, Klein BE, Meuer SM, Hubbard LD. Computerassisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology 2004;111:1183–90. [7] Tukey J. Exloratory data analysis. 1st ed. Pearson; 1977. [8] Thayer JF, Fischer JE. Heart rate variability, overnight urinary norepinephrine, and plasma cholesterol in apparently healthy human adults. Int J Cardiol 2013;162:240–4. [9] Stokes 3rd J, Kannel WB, Wolf PA, Cupples LA, D'Agostino RB. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation 1987;75:V65–73. [10] Pournaras CJ, Rungger-Brandle E, Riva CE, Hardarson SH, Stefansson E. Regulation of retinal blood flow in health and disease. Prog Retin Eye Res 2008;27: 284–330.

Please cite this article as: Schuster AK, et al, Retinal vessel analysis and heart rate variability, Int J Cardiol (2014), http://dx.doi.org/10.1016/ j.ijcard.2014.07.190

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