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Exfoliation Syndrome and Systemic Cardiovascular Diseases

Holló, Gábor MD, PhD, DSc

doi: 10.1097/IJG.0000000000000116

Exfoliation syndrome (XFS) is a systemic condition. Intraocular alterations represent only a part of the exfoliation-related clinical signs. Exfoliation material has been identified in the visceral organs, skin, and vessel walls. This triggered several studies that investigated association between XFS and cardiovascular diseases. In many populations, significant associations between XFS and various systemic vascular diseases including elevated plasma homocysteine level, myocardial dysfunction, stroke, aortic aneurysm, and white matter lesions were found. Some of these XFS-associated vascular diseases are caused by elastosis of the vessel wall, which may be directly related to general extracellular dysfunction in XFS. Another part of the pathologic vascular alterations (reduced cutaneous capillary flow reactions, impaired baroreflex sensitivity, parasympathetic cardiovascular neuropathy, and pathologic heart rate variability indices), however, suggests that vascular dysregulation beyond the age-related normal decline may also play a role both in the development and worsening of the systemic cardiovascular diseases in XFS. The exact mechanism of the development of systemic vascular dysregulation associated with XFS is currently unknown.

Department of Ophthalmology, Semmelweis University, Budapest, Hungary

Disclosure: The author declares no conflict of interest.

Reprints: Gábor Holló, MD, PhD, DSc, Department of Ophthalmology, Semmelweis University, 1085, Mária u.39, Budapest, Hungary (e-mail:

Received July 29, 2014

Accepted August 2, 2014

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XFS is a systemic elastosis (defined as an accumulation of elastin) in which exfoliation material is present in the visceral organs, skin, myocardium, and vessel walls.1 The systemic presence of exfoliation material is independent of the presence of exfoliation glaucoma (XFG). Several investigations made on different populations found statistically significant associations between XFS and systemic vascular diseases,2,3 although in other studies including 1 population-based investigation (The Thessaloniki Eye Study) no association was identified.4,5

Systemic vascular diseases associated with XFS are clinically important but not specific for XFS. Increased plasma homocysteine levels have consistently been found in XFS. Elevated plasma homocysteine concentration promotes the onset of recurrent venous occlusions6 including retinal vein occlusions, which, in addition to the severe functional damage, frequently lead to the development of neovascular glaucoma.7 Increased vascular rigidity, cerebral microinfarctions, neurosensory hearing loss, stroke, myocardial dysfunction and infarction, renal artery stenosis, aortic aneurysm, and aortic dissection are all associated with XFS,6,8–11 although in 1 investigation their prevalence was lower than that seen in primary open-angle glaucoma.12

Despite the above associations between XFS and clinically significant systemic vascular diseases, published data do not show increased mortality in XFS and XFG.13–17 The investigations were made on Scandinavian, Finnish, and US populations, and found no increase of cardiovascular and all-cause mortality in XFS and XFG compared with the general population and other disease groups.13–17

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Although some of the XFS-associated vascular diseases (eg, venous occlusions and aortic aneurysms) can be explained by elastotic changes of the vessel wall and increased serum homocysteine level, other vascular alterations are caused by systemic vascular dysregulation. Abnormal vascular regulation involves capillaries and precapillaries, the carotid artery, and parasympathetic cardiovascular regulation.18,19 In various investigations we have shown significantly reduced cutaneous capillary reactions,18 impaired baroreflex regulation, decreased carotid artery distensibility and increased carotid artery stiffness, impaired conduit artery function,19 and severely pathologic heart rate variability indices20 in XFS. We also found a significant negative correlation between plasma homocysteine concentration and baroreflex function, which suggests a biological relationship between these parameters. In addition, whereas no age-dependent decline of these parameters was found in our age-matched normal controls, in the exfoliation group a significant decline was measured. This and the age-dependent increase of plasma homocysteine concentration in XFS patients suggest that the XFS-related vascular alterations are not simply qualitative but quantitative medical problems.

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Systemic vascular alterations seem to develop and then progress along the increasing duration of clinically manifested XFS. The underlying biochemical mechanisms are poorly understood. An increase of the plasma oxidative stress markers and a decrease of serum antioxidant level have been shown in XFS.21 An impairment of the systemic vascular endothelial function has also been shown.22 Recently, we investigated the potential relationship between the 2 main lysyl oxidase-like 1 (LOXL1) gene single-nucleotide polymorphisms and systemic vascular diseases.23 We found that the allele distributions differed significantly between the XFS patients (with and without systemic cardiovascular diseases) and the age-matched stroke patients, both for G153D and R141L. In contrast, no difference in risk allele frequencies was seen when XFS patients with and without systemic vascular diseases were compared. Similarly, in the population-based Thessaloniki Eye Study, no association between LOXL1 gene polymorphism and systemic diseases was found in XFS and XFG.24 These results suggest that environmental factors also have clinical significance in the development and progression of XFS-related systemic vascular alterations. The systemic vascular diseases and abnormal conditions associated with XFS are listed in the Table 1.



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Better understanding of molecular mechanisms that make several vascular alterations and severe vascular diseases particularly frequent in XFS is of clinical significance. The systemic vascular diseases are not specific for XFS. Thus, one may suppose that certain XFS-related biochemical changes dose dependently trigger their clinical manifestations. Increased oxidative stress and decreased antioxidant protection probably play a role in the development and progression of vessel wall damage and systemic vascular dysregulation, but no quantitative information is available in this respect. It is also unknown whether the development and increase of oxidative stress in the anterior chamber and in the serum are related or parallel phenomena. Therefore, clinical information on IOP, nuclear cataract formation, and the quantity of the exfoliation material in the anterior chamber cannot be used for detection of patients at risk for systemic vascular diseases. Various populations may differ considerably in their general risk for the development of systemic cardiovascular diseases, thus the XFS-related risk cannot be investigated without correction for other population-related risk factors. Environmental effects seem to be more important for clinical manifestation of the XFS-related systemic vascular diseases than the known LOXL1 gene single-nucleotide polymorphisms that are strongly related to population risk of XFS. Currently, no specific information is available on those environmental factors that may potentially interact with the XFS-related systemic biochemical alterations. In some recent publications addressing the systemic vascular diseases and alterations in XFS, the authors recommend systemic cardiovascular assessment for all patients with XFS. This is probably incorrect as it would generate a significant number of unnecessary investigations in healthy individuals; and a cross-sectional evaluation cannot exclude vascular diseases that develop in future. Currently no data are available either on the optimal timing of cardiovascular assessment in XFS or the frequency of reevaluations in XFS patients without symptoms. It is also unknown if for patients suffering from a cardiovascular or a cerebrovascular disease the diagnosis of XFS represents an independent risk factor for worsening of the systemic vascular disease.

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Systemic cardiovascular dysregulation and clinically significant cardiovascular and cerebrovascular diseases are strongly associated with XFS in various populations, although in some investigations such association was not found. The XFS-associated systemic diseases are not specific for XFS. Therefore, their increased frequencies in XFS may potentially be related to certain systemic biochemical alterations that contribute in their clinical manifestation. Increased serum oxidative stress and elevated serum homocysteine level in XFS patients may have a role in the development of the systemic vascular diseases, but the exact mechanisms of action and the other potential causative biochemical changes need further investigations. Such investigations need to be population based, and need to address the quantitative relationships between the potential biochemical alterations and the severity of the corresponding vascular disease or dysfunction. Without this information, no recommendation for timing and frequency of cardiovascular assessment of the XFS patient can be given.

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exfoliation syndrome; cardiovascular diseases; vascular dysregulation; baroreflex sensitivity; heart rate variability

© 2014 by Lippincott Williams & Wilkins.