Short summary

We hypothesize that non-invasive retinal measurements will reveal close relations to alterations in the molecular, structural and functional state of extra-ocular arteries and their clinical consequences. We believe that retinal structural and metabolic imaging can be used as valid systemic biomarkers of molecular and functional arterial changes in patients with ischemic heart disease.

Rationale

Cardiovascular disease is a leading cause of death worldwide. Coronary artery bypass grafting (CABG) is a well-established revascularization procedure for ischemic heart disease (IHD), but current risk tools are insufficient and novel biomarkers are needed to optimize care. Microvascular biomarkers of endothelial dysfunction and microarchitectural changes in human resistance arteries are important, but can only be assembled by invasive biopsy. 

The retinal vascular tree is the only part of the human body available for direct, in vivo structural inspection. It has previously been demonstrated that in type 1 diabetes the retinal vascular structure is not only associated with but also predictive of long-term extraocular microvascular complications like diabetic nephropathy and neuropathy. In 1926 Murray proposed the theory of the principle of minimum work in the human circulatory system. He hypothesized that an optimal structure of blood vessels was needed to ensure sufficient blood flow at a minimal metabolic cost. The theory has passed the test of time, and it has in particular been confirmed in various studies of diabetes.

Structural retinal measurements include calibers, fractals and advanced markers like the vascular tortuosity, branching coefficient, and length-diameter-ratio. Contemporary software models allow easy, semiautomatic measurements based on standard retinal fundus photography. Optical coherence tomography (OCT) is another well-established, non-invasive measurement of the retinal structure. In contrast to vascular measurements, OCT provides a high-resolution, cross-sectional image of the various retinal layers. State-of-the-art-techniques enable visualization and measurements of 18 different retinal and choroidal layers. While retinal thinning in neurodegenerative diseases has been a longstanding observation, recent attention has been given to choroidal thickness measurements with recent associations demonstrated between chorioretinal thinning, inflammation and endothelial dysfunction in patients with chronic kidney disease.

The retinal oxygen metabolism can also be measured non-invasively. This can be performed by retinal oximetry based on dual-wavelength fundus photography, given that there is a difference in the color of oxygenated and deoxygenated hemoglobin. Based on this, the retinal vascular oxygen saturation can be given numerically or as a color saturation map. In retinal ischemic diseases, retinal oxygen saturation alterations have consistently been demonstrated but, interestingly, retinal hypoxia can also be observed in systemic neurodegenerative and hypoxic diseases like Alzheimer's disease16 and chronic obstructive pulmonary disease.

The aim of the study is to test if retinal microvascular structural and metabolic parameters 1) are resistant to short-term changes after a large vascular surgery intervention, 2) are altered in patients operated for IHD as compared to age- and gender-matched healthy controls, and 3) correlate to functional, structural, and biochemical alterations causing vascular dysfunction.

If we can establish proof-of-concept for non-invasive retinal imaging to assess systemic vascular dysfunction, our next step will be to test the predictive value of these markers on long-term outcomes of the established cohort. Such outcomes will include the 5-year risk of graft closure, stroke and cardiovascular mortality.

Description of the cohort

The study will include three sub-studies 1), 2) and 3).

In sub-study 1) we will do pre- and post-surgical retinal measurements in 20 patients in relation to large vascular surgery intervention (carotid endarterectomies). 

Sub-study 2) is a case-control study comparing retinal structural and metabolic markers between patients who have had open heart surgery (n=50) within the last 14 days and age- and gender-matched controls without known cardiovascular disease (n=50, recruited among patients undergoing cataract surgery).

Sub-study 3) evaluates the cases of Sub-study 2, in which we will test if the retinal microvascular structure and metabolism correlate with specific functional, structural (histological), and biochemical alterations in resistance (pericardial) and transitional (internal mammary/thoracic) arteries causing arterial dysfunction.

Data and biological material

Sub-study 1+2:

Retinal measurements includes; Fundusphotography, OCT (standard and angio) and Oxymetri.

Controls sub-study 2 (Cataract patients):

Blood samples (2 x 4 ml EDTA plasma, 2 x 6 ml serum, and 2 x 5 ml buffy coat).

Cases sub-study 2 (CABG): 

Preoperative blood samples, pericardial fluid and spare arterial material (internal mammary/thoracic artery from CABG patients and parietal pericardium biopsies containing resistance arteries from all open heart surgeries) are already collected in connection with project S-20140202 and stored in a research biobank.

Collaborating researchers and departments

Department of Ophthalmology, Odense University Hospital and CIMA ('Centre of Individualized Medicine in Arterial Diseases')

• Pre-graduate Medical Student Sebastian Dinesen

Department of Ophthalmology, Odense University Hospital.

• Professor Jakob Grauslund, MD, DMSc.

Head of CIMA, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital. 

• Professor Lars Melholt Rasmussen, MD, DMSc.

Principal Investigator of CIMA, Department of Cardiac, Thoracic, and Vascular Surgery, Odense University Hospital

• Professor Jes Sanddal Lindholt, MD, DMSc.

Cardiovascular and Renal Research, Department of Biochemistry and Molecular Biology, University of Southern Denmark.

• Professor Jo De Mey, PhD.

Cardiovascular and Renal Research, Department of Biochemistry and Molecular Biology, University of Southern Denmark.

• Assistant Professor Maria Bloksgaard, PhD.

Department of Clinical Biochemistry and Pharmacology and CIMA, Odense University Hospital.

• Senior Scientist Pia Soendergaard Jensen.