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Microvascular retinal changes in patients presenting with acute coronary syndromes
Microvascular Research 79 (2010) 150–153
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Microvascular Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y m v r e
Microvascular retinal changes in patients presenting with acute coronary syndromes S. Kralev a,⁎, E. Zimmerer a, P. Buchholz a, J. Lin b, M. Economopoulou b, S. Lang a, T. Kälsch a, T. Süselbeck a, H.-P. Hammes b a b
1st Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutser-Ufer 1-3 68167 Mannheim, Germany
a r t i c l e
i n f o
Article history: Received 4 October 2009 Revised 21 December 2009 Accepted 25 December 2009 Available online 4 January 2010 Keywords: Acute coronary syndromes Myocardial infarction Coronary artery disease Retinopathy AVR Red dots Endothelial dysfunction
a b s t r a c t Background: Retinal microvascular changes predict cardiovascular morbidity and mortality independent of classical risk factors. However, it is unclear which retinal changes characterize patients with established coronary artery disease (CAD), and in particular, with acute coronary syndromes (ACS). The aim of the present preliminary study was to assess retinopathy in these patients. Methods: 43 consecutive patients with ACS and 19 consecutive patients with stable CAD were investigated. Among the patient group with ACS, 20 patients presented with ST-Elevation Myocardial Infarction (STEMI) and 23 patients presented with Non-STEMI (NSTEMI). Standardized protocols were used and retinal fundus photography was taken within 48 h post-coronary angiography to assess retinopathy and general arteriolar narrowing as arterio-venous ratio (AVR). Clinical and laboratory cardiovascular risk factors were recorded. Results: Despite comparable age and comparable frequency of diabetes and hypertension, patients with ACS had a much higher likelihood for retinal microaneurysms and dot bleedings than patients with stable CAD (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43–96.59; p = 0.006). Performing multivariate analysis, this association remains significant (OR 20.5, 95%CI 1.6–255, p = 0.019). CAD patients presented more often with focal signs of arteriovenous nicking / focal vasoconstriction (10 (53%) vs. 9 (21%) patients, OR 4.2; 95%CI 1.31–13.4; p = 0.018), however after multivariate analysis this association lost significance. The AVR was comparably low in both groups. Conclusion: Patients with ACS present more often with dot bleedings and microaneurysms. These findings provide preliminary evidence that retinal fundus examination may be useful to contribute to the risk profile of patients, enabling a more intensive survey and care. © 2010 Elsevier Inc. All rights reserved.
Introduction In diabetes mellitus, the development of retinal vascular damage is associated with a substantially higher risk for myocardial infarction and coronary death (Wong et al., 2003). The primary lesion in the diabetic retina is the microaneurysm, which is suggestive of a response to injury type lesion in retinal capillaries. There is now growing evidence that retinal microangiopathy is associated with the development of coronary artery disease (CAD) independently of diabetes (Tedeschi-Reiner et al., 2005; Duncan et al., 2002). These microvascular changes include focal signs of blood retinal barrier breakdown such as hemorrhages and hard exudates, as well as signs of altered vascular reactivity such as focal arteriolar narrowing and AV-nicking. In particular, arteriolar narrowing has been used as a marker for increased risk of cardiovascular disease (Wong et al., 2001, 2002, 2004). With the advance of digitized fundus photographs and computerized analysis of the ratio between retinal arteriolar and
⁎ Corresponding author. Fax: +49 621 383 2012. E-mail address: [email protected] (S. Kralev). 0026-2862/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.mvr.2009.12.007
venolar width, large studies have indicated a link between classical cardiovascular risk factors (such as age, hypertension, etc.) and generalized vascular narrowing — expressed as a decrease in the arterio-venous ratio (AVR) (Wang et al., 2007; Sharrett et al., 1999). Nonetheless, isolated retinopathy signs (as microaneurysms, hemorrhages and cotton wool spots) are more common in the general population than previously assumed. The incidence of retinopathy in persons without hypertension or diabetes has been determined between 2.2 and 13.5% (Klein et al., 1994, 1997; Hubbard et al., 1999). According to prospective studies, some 10% of individuals without diabetes and aged over 40 years may develop hemorrhages and microaneurysms within 5 years (Yu et al., 1998). All factors associated with retinopathy development (such as age, hypertension, diabetes, hyperlipidemia) are so far known as classical risk factors for CAD (Pencina et al., 2009; Wong et al., 2003; Tedeschi-Reiner et al., 2005; Leung et al., 2003). However, the transition of stable CAD into acute coronary syndromes (ACS) appears to involve also inflammation and local factors, such as proteolytic enzymes and inflammatory cell infiltration (Buffon et al., 2002). So far, a direct link between ACS and specific patterns of retinal damage (retinopathy) like altered vessel permeability, hemorrhages, hard exudates, microaneurysms,
S. Kralev et al. / Microvascular Research 79 (2010) 150–153
cotton wool spots and endothelial dysfunction (altered AVR) has not been investigated. Therefore, in the present study, we assessed retinopathy in patients with stable CAD and ACS and investigated whether retinal vessel analysis could contribute to the risk profiling of these patients. Materials and methods Patient selection In the year 2006, 43 consecutive patients presenting with ACS (20 patients with ST-Elevation Myocardial Infarction, 23 patients with Non-ST-Elevation Myocardial Infarction) were included in this preliminary case–control study. The control group comprised 19 also consecutively included patients with stable CAD. All 62 patients underwent coronary angiography and retinal analyses. Baseline clinical data such as medical history, age, gender and cardiac risk factors were recorded. In patients presenting with ACS, the therapeutic management was carried out according to the guidelines of the American College of Cardiology / American Heart Association (ACC/ AHA Writing Committee 2004 and 2006). Procedural and angiographic details Percutaneous coronary intervention (PCI) was performed by the femoral approach. Standard 5, 6 or 7F guiding catheters and 0.014inch floppy guide wires were used. Implantation technique, balloon size and stent type were chosen at the discretion of the physician. All patients received heparin (70 units/kg) and 500 mg aspirin before the procedure. Repeated boli of 2500 units heparin were given during the procedure to maintain an activated clotting time N250 s. According to the AHA/ACC guidelines, treatment with a platelet glycoprotein (GP) IIb/IIIa inhibitor (class IIa recommendation, treatment reasonable) was initiated after diagnostic angiography in 30 patients, followed by a 12–24 h infusion with concomitant heparin infusion. Clopidogrel at a dosage of 300 mg was given before the procedure or in the catheterization laboratory followed by a daily dosage of 75 mg for the subsequent 4 weeks. All patients received aspirin (100 mg/daily). Retinal vessel analysis Within 48 h after the coronary procedure, retinal analysis was performed after written informed consent had been received. Examinations were performed in accordance with the Declaration of Helsinki and were approved by the local ethics committee. For analysis of retinopathy, both eyes were studied. The assessment of the AVR was done by analyzing the right eye. After pupillary dilation, digital retinal photographs were taken according to the United Kingdom Prospective Diabetes Study (UKPDS Group, 1998) protocol. Briefly, 30° fundus pictures centered on the optic disc, the macula, and the superior temporal vessel arch were taken using a retinal vessel analysis system (RVA, fundus camera Zeiss FF 450, Jena, Germany; RVA Imedos, Jena, Germany). Focal retinal arteriolar signs such as focal arteriolar narrowing and arteriovenous (AV) nicking, cotton wool spots, copper and silver wire, disc edema, hard exudates and “red dots (RD)” (including blot hemorrhages and microaneurysms) were evaluated. The AVR was obtained by using the Hubbard–Parr equation provided by the above mentioned RVA Imedos system (Hubbard et al., 1999; Parr and Spears, 1974a,b). Statistical analysis For normally distributed data the unpaired Student t test was applied. The nonparametric Mann–Whitney U test was used when data deviated from a Gaussian distribution as tested by the
151
Kolmogorov–Smirnov test. Non-continuous variables were analyzed by using a 2x2 table and Fisher's exact test. Data are presented as mean ± standard deviation (SD) or number and percentage for categorical variables. Values of P b 0.05 (two-tailed) were considered statistically significant. To evaluate potential confounding factors on ACS and CAD, multivariate logistic regression analysis with backward elimination with the variables mentioned in the results section was performed. The calculations were performed using SPSS-Software (SPSS-Software GmbH, München, Germany) and InStat (GraphPad Software, San Diego, USA). Results In this study, patients with ACS were of similar age and showed a similar pattern of coronary risk factors as control patients with stable CAD. Male preponderance (69% in the total group), obesity (23%), and diabetes (40%) were equally frequent in both groups. A higher CAD predisposition in the family was present in the group with stable CAD, however not reaching statistical significance. Of the other cardiovascular risk factors assessed, smoking (32%), hypercholesterolemia (81%), and hypertension (82%) were not different in both groups. Sixteen % of the patients had prior myocardial infarction and 34% prior coronary revascularization (previous angioplasty or coronary artery bypass graft) before the event recorded in this study. The clinical baseline data are summarized in Table 1. In all patients, pharmacological mydriasis yielded pupillary dilatation of at least 4 mm. At univariate analysis, retinae of patients with stable CAD showed significantly more focal signs of vasoconstriction (AV nicking/focal vasoconstriction) than patients with ACS (10 (53%) vs. 9 (21%) pat., OR 4.2; 95%CI 1.31–13.4; p = 0.018). Upon multivariate logistic regression analysis with stepwise backward factor elimination, the association lost significance. Age, sex, smoking, hypercholesterolemia, hypertension, obesity, family history of CAD, diabetes mellitus, prior myocardial infarction, previous angioplasty, previous bypass surgery, retinal microaneurysms and vasoconstriction were selected as independent variables. In contrast, patients with ACS were more affected by blot hemorrhages and microaneurysms (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43–96.59; p = 0.006, Fig. 1). Following multivariate analysis, after adjustment with the previous mentioned variables, the association of blot hemorrhages and microaneurysms with ACS remained significant (OR 20.5, 95%CI 1.6–255, p = 0.019). Additional associations were found for hypercholesterolemia (OR 11.5, 95%CI 2.0–66, p = 0.006) and previous angioplasty (OR 0.11, 95%CI 0.016– 0.71, p = 0.021). Hard exudates, cotton wool spots, copper and silver wire and disc edema were equally common in the ACS and CAD group (Fig. 2), with each group consisting of patients with one or more of these characteristics (8 (19%) vs. 6 (32%) patients, OR 0.495; 95%CI
Table 1 Baseline clinical characteristics. Patients
ACS (n = 43)
CAD (n = 19)
PValue
Age (Years) Male sex Risk factors Smoking Hypercholesterolemia Hypertension Obesity Family history of CAD Diabetes mellitus Medical history Prior myocardial infarction Previous angioplasty Previous bypass surgery
63.4 ± 12.0 29 [67%]
65.4 ± 10.6 14 [74%]
0.46 0.77
14 [33%] 36 [84%] 34 [79%] 9 [21%] 4 [9%] 17 [40%]
6 [32%] 14 [74%] 17 [89%] 5 [26%] 5 [26%] 8 [42%]
1.00 0.49 0.48 0.74 0.12 1.00
8 [19%] 6 [14%] 5 [12%]
2 [11%] 7 [37%] 3 [16%]
0.71 0.09 0.69
ACS: Acute coronary syndromes, CAD: Coronary artery disease.
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Fig. 1. Incidence of microaneurysms and blood hemorrhages (“red dots”) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD).
0.144–1.704; p = 0.33). The AVR was identical between both groups (0.766 ± 0.015 in the ACS group vs. 0.747 ± 0.020 in the CAD group; p N 0.05, Fig. 3). Of note, in patients presenting with ACS and treated with a GP IIb/IIIa inhibitor (30 patients) or without a GP IIb/IIIa inhibitor (13 patients), there was no significant difference in the incidence of blot hemorrhages and microaneurysms (11 (37%) vs. 6 (46%) patients, OR 0.67; 95%CI 0.18–2.53; p = 0.74). Discussion This is the first preliminary study investigating retinal (micro-) vascular changes in patients presenting with ACS. The results suggest that ACS patients are more likely to present with focal signs of increased vessel fragility, which is indicated by the leakage of red blood cells, manifested by the presence of dot blots. Patients with stable CAD show more often focal signs of vasoconstriction, despite similar history of prior ACS events. It was previously reported that generalized arteriolar narrowing, resulting in low AVR, is associated with an increased cardiovascular (CV) mortality over 10 years in patients aged 43–74 years (Wong et al., 2003). In the present study, no significant difference between AVR data in patients with ACS or CAD was detected. In the ARIC study, AVR in the lowest quintile compares with our AVR data, being identified as a strong cardiovascular risk factor, indicating clinical and subclinical cerebrovascular disease (Wong et al., 2002). Thus, our results are consistent with the concept that low AVR cannot distinguish between patients with ACS and stable CAD, but indicates a generalized vascular change associated with a high CV risk. In our study, patients with stable CAD had a similar CV risk profile compared to patients with ACS, but a threefold higher risk of endothelial hyperreactivity as reflected by focal arteriolar narrowing and AV-nicking (AVN). The ARIC study found similar alterations in 6% of all patients with hypertension, indicating an increased CV mortality risk, independent of classical risk factors such as age and diabetes (Tedeschi-Reiner et al., 2005; Wong et al., 2002; Duncan et al., 2002).
Fig. 2. Percentage of ACS and CAD patients presenting with one or more of hard exudates, cotton wool spots, copper and silver wire and disc edema.
Fig. 3. AVR data did not differ significantly in patients with ACS and stable CAD. Data are presented as medians with 25th and 75th percentiles (boxes). The top and the bottom of the whiskers (I bars) show the maximum and the minimum values.
However, depending on the type of study and the cohort investigated, not all studies confirmed this (Ikram et al., 2006; Wong et al., 2004) and further investigations with larger patient populations are necessary to prove this hypothesis. An important result of this study provides evidence that capillary fragility and focal endothelial injury is increased in patients with ACS. “Red dots”, i.e. microaneurysms and focal dot blots, are both indications of impaired endothelial integrity. Ultrastructural studies have suggested that microaneurysms develop as a local response to hypoxia in the vicinity of areas of capillary non-perfusion (Stitt et al., 1995). These retinal changes, although originally investigated in diabetic patients, are not unique to hyperglycemia-induction, but occur also in hypertensive retinopathy and in a variety of other conditions, as it is previously described by large studies (Wong et al., 2003, 2004; Yu et al., 1998). Since both, patients with ACS and CAD, had comparable risk factors such as diabetes and hypertension, it is unlikely that our findings are a result of differences in traditional risk profiles. For the understanding of the pathophysiological development of microaneurysms, a few main factors have to be discussed. In principle, the treatment with anticoagulants in the ACS group may have contributed to focal bleedings, occurring more frequently in this group. There are several indications that this may not be the case. First, previous studies have demonstrated that a larger dose of aspirin does not increase the number of focal bleedings in the retina (Chew et al., 1995). Second, large trials using systemic thrombolysis did not find a substantial increase in retinal hemorrhages, when proliferative vascular changes were excluded (Higgs et al., 1995). Finally, in this study the incidence of red dots did not differ significantly in patients treated with or without a GP IIb/IIIa inhibitor. Therefore, it seems unlikely that the anticoagulation therapy may have influenced our results. Considering the possibility that the higher incidence of blot hemorrhages and microaneurysms might be a result of ACS rather than reflecting an increased risk for ACS, a previous study (Lawrenson et al., 2002) must be mentioned. The authors demonstrated that acute ischemic retinal capillaries do not develop a significant alteration in cross-sectional or luminal areas. Therefore, the authors state that a short time course of retinal ischemia would not be sufficient for VEGF levels to rise appreciably. These mechanisms of VEGF support the hypothesis that recurrent episodes of myocardial ischemia can cause repetitive increases in circulating growth factor levels, which can induce focal endothelial responses such as microaneurysms or focal microvascular dysruptions. It is thus conceivable that retinal vascular changes indicate intermittent myocardial perfusion deficits associated with a higher CV risk. However, this hypothesis needs further
S. Kralev et al. / Microvascular Research 79 (2010) 150–153
confirmation by larger studies. Also, the incidence of blot hemorrhages and microaneurysms in patients with stable CAD and previous myocardial infarction needs further investigation. In this study, only 2 patients with this characteristic pattern could be included. Corresponding with our data, recent studies (Nunes et al., 2009) suggest that progressive endothelial damage with a high microaneurysm formation rate, appears to be a common denominator of clinically significant macular edema. Clearly, endothelial hyperreactivity deserves specific attention in further studies as a high risk factor in patients with CAD. In summary, our results provide evidence that specific retinal vascular changes indicate an increased risk for development of ACS, while the AVR as a representative of generalized arteriolar changes cannot distinguish between ACS and stable CAD. Given the availability and the non-invasiveness of the test, retinal fundus examination could be a useful novel parameter for contributing to the assessment of the risk profile of patients, who may the benefit from intensified survey and care. References ACC/AHA Writing Committee, 2004. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction), 2004. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction—executive summary. Circulation 110, 588–636. ACC/AHA Writing Committee, 2006. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention), 2006. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. J. Am. Coll. Cardiol. 47, e1–e121. Buffon, A., et al., 2002. Widespread coronary inflammation in unstable angina. N. Engl. J. Med. 347, 5–12. Chew, E.Y., et al., 1995. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early treatment diabetic retinopathy study report no. 20. Arch. Ophthamol. 113, 52–55. Duncan, B.B., et al., 2002. Hypertensive retinopathy and incident coronary heart disease in high risk men. Br. J. Ophthalmol. 86, 1002–1006. Higgs, E.R., et al., 1995. Use of thrombolysis for acute myocardial infarction in the presence of diabetic retinopathy in the UK, and associated ocular haemorrhagic complications. Diabet. Med. 12, 426–428.
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Hubbard, L.D., et al., 1999. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities (ARIC) Study. Opthalmology 106, 2269–2280. Ikram, M.K., et al., 2006. Retinal vessel diameters and risk of stroke: the Rotterdam Study. Neurology 66, 1339–1343. Klein, R., et al., 1994. Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch. Opthalmol. 112, 92–98. Klein, R., et al., 1997. The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study. Trans. Am. Opthalmol. Soc. 95, 329–348. Lawrenson, J.G., et al., 2002. Ultrastructural and morphometric comparison of retinal and myocardial capillaries following acute ischaemia. Microvasc. Res. 64, 65–74. Leung, H., et al., 2003. Relationships between Age, blood pressure and retinal vessel diameters in an older population. Invest. Ophthalmol. Vis. Sci. 44, 2900–2904. Nunes, S., et al., 2009. Microaneurysm turnover is a biomarker for diabetic retinopathy progression to clinically significant macular edema: findings for type 2 diabetes with nonproliferative retinopathy. Ophthalmologica 223, 292–297. Parr, J.C., Spears, G.F.S., 1974a. General caliber of the retinal arteries expressed as the equivalent width of the central retinal artery. Am. J. Ophthalmol. 77, 472–477. Parr, J.C., Spears, G.F.S., 1974b. Mathematic relationships between the width of a retinal artery and the widths of its branches. Am. J. Ophthalmol. 77, 478–483. Pencina, M.J., et al., 2009. Predicting the 30-year risk of cardiovascular disease. The Framingham Heart Study. Circulation, Epub ahead of print. Jun. 8. Sharrett, A.R., et al., 1999. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. Am. J. Epidemiol. 150, 263–270. Stitt, A.W., et al., 1995. Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br. J. Ophthalmol. 79, 362–367. Tedeschi-Reiner, E., et al., 2005. Relation of atherosclerotic changes in retinal arteries to the extent of coronary artery disease. Am. J. Cardiol. 96, 1107–1109. UK Prospective Diabetes Study (UKPDS) Group, 1998. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853. Wang, J.J., et al., 2007. Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. Eur. Heart J. 28, 1984–1992. Wong, T.Y., et al., 2001. Retinal microvascular abnormalities and incident strokes. The Atherosclerosis Risk in Communities Study. Lancet 358, 1134–1140. Wong, T.Y., et al., 2002. Retinal arteriolar narrowing and risk of incident coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA 287, 1153–1159. Wong, T.Y., et al., 2003. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology 110, 933–940. Wong, T.Y., et al., 2004. A prospective cohort study of retinal arteriolar narrowing and mortality. Am. J. Epidemiol. 159, 819–825. Yu, T., et al., 1998. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch. Opthalmol. 116, 83–89.
Contents lists available at ScienceDirect
Microvascular Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y m v r e
Microvascular retinal changes in patients presenting with acute coronary syndromes S. Kralev a,⁎, E. Zimmerer a, P. Buchholz a, J. Lin b, M. Economopoulou b, S. Lang a, T. Kälsch a, T. Süselbeck a, H.-P. Hammes b a b
1st Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutser-Ufer 1-3 68167 Mannheim, Germany
a r t i c l e
i n f o
Article history: Received 4 October 2009 Revised 21 December 2009 Accepted 25 December 2009 Available online 4 January 2010 Keywords: Acute coronary syndromes Myocardial infarction Coronary artery disease Retinopathy AVR Red dots Endothelial dysfunction
a b s t r a c t Background: Retinal microvascular changes predict cardiovascular morbidity and mortality independent of classical risk factors. However, it is unclear which retinal changes characterize patients with established coronary artery disease (CAD), and in particular, with acute coronary syndromes (ACS). The aim of the present preliminary study was to assess retinopathy in these patients. Methods: 43 consecutive patients with ACS and 19 consecutive patients with stable CAD were investigated. Among the patient group with ACS, 20 patients presented with ST-Elevation Myocardial Infarction (STEMI) and 23 patients presented with Non-STEMI (NSTEMI). Standardized protocols were used and retinal fundus photography was taken within 48 h post-coronary angiography to assess retinopathy and general arteriolar narrowing as arterio-venous ratio (AVR). Clinical and laboratory cardiovascular risk factors were recorded. Results: Despite comparable age and comparable frequency of diabetes and hypertension, patients with ACS had a much higher likelihood for retinal microaneurysms and dot bleedings than patients with stable CAD (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43–96.59; p = 0.006). Performing multivariate analysis, this association remains significant (OR 20.5, 95%CI 1.6–255, p = 0.019). CAD patients presented more often with focal signs of arteriovenous nicking / focal vasoconstriction (10 (53%) vs. 9 (21%) patients, OR 4.2; 95%CI 1.31–13.4; p = 0.018), however after multivariate analysis this association lost significance. The AVR was comparably low in both groups. Conclusion: Patients with ACS present more often with dot bleedings and microaneurysms. These findings provide preliminary evidence that retinal fundus examination may be useful to contribute to the risk profile of patients, enabling a more intensive survey and care. © 2010 Elsevier Inc. All rights reserved.
Introduction In diabetes mellitus, the development of retinal vascular damage is associated with a substantially higher risk for myocardial infarction and coronary death (Wong et al., 2003). The primary lesion in the diabetic retina is the microaneurysm, which is suggestive of a response to injury type lesion in retinal capillaries. There is now growing evidence that retinal microangiopathy is associated with the development of coronary artery disease (CAD) independently of diabetes (Tedeschi-Reiner et al., 2005; Duncan et al., 2002). These microvascular changes include focal signs of blood retinal barrier breakdown such as hemorrhages and hard exudates, as well as signs of altered vascular reactivity such as focal arteriolar narrowing and AV-nicking. In particular, arteriolar narrowing has been used as a marker for increased risk of cardiovascular disease (Wong et al., 2001, 2002, 2004). With the advance of digitized fundus photographs and computerized analysis of the ratio between retinal arteriolar and
⁎ Corresponding author. Fax: +49 621 383 2012. E-mail address: [email protected] (S. Kralev). 0026-2862/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.mvr.2009.12.007
venolar width, large studies have indicated a link between classical cardiovascular risk factors (such as age, hypertension, etc.) and generalized vascular narrowing — expressed as a decrease in the arterio-venous ratio (AVR) (Wang et al., 2007; Sharrett et al., 1999). Nonetheless, isolated retinopathy signs (as microaneurysms, hemorrhages and cotton wool spots) are more common in the general population than previously assumed. The incidence of retinopathy in persons without hypertension or diabetes has been determined between 2.2 and 13.5% (Klein et al., 1994, 1997; Hubbard et al., 1999). According to prospective studies, some 10% of individuals without diabetes and aged over 40 years may develop hemorrhages and microaneurysms within 5 years (Yu et al., 1998). All factors associated with retinopathy development (such as age, hypertension, diabetes, hyperlipidemia) are so far known as classical risk factors for CAD (Pencina et al., 2009; Wong et al., 2003; Tedeschi-Reiner et al., 2005; Leung et al., 2003). However, the transition of stable CAD into acute coronary syndromes (ACS) appears to involve also inflammation and local factors, such as proteolytic enzymes and inflammatory cell infiltration (Buffon et al., 2002). So far, a direct link between ACS and specific patterns of retinal damage (retinopathy) like altered vessel permeability, hemorrhages, hard exudates, microaneurysms,
S. Kralev et al. / Microvascular Research 79 (2010) 150–153
cotton wool spots and endothelial dysfunction (altered AVR) has not been investigated. Therefore, in the present study, we assessed retinopathy in patients with stable CAD and ACS and investigated whether retinal vessel analysis could contribute to the risk profiling of these patients. Materials and methods Patient selection In the year 2006, 43 consecutive patients presenting with ACS (20 patients with ST-Elevation Myocardial Infarction, 23 patients with Non-ST-Elevation Myocardial Infarction) were included in this preliminary case–control study. The control group comprised 19 also consecutively included patients with stable CAD. All 62 patients underwent coronary angiography and retinal analyses. Baseline clinical data such as medical history, age, gender and cardiac risk factors were recorded. In patients presenting with ACS, the therapeutic management was carried out according to the guidelines of the American College of Cardiology / American Heart Association (ACC/ AHA Writing Committee 2004 and 2006). Procedural and angiographic details Percutaneous coronary intervention (PCI) was performed by the femoral approach. Standard 5, 6 or 7F guiding catheters and 0.014inch floppy guide wires were used. Implantation technique, balloon size and stent type were chosen at the discretion of the physician. All patients received heparin (70 units/kg) and 500 mg aspirin before the procedure. Repeated boli of 2500 units heparin were given during the procedure to maintain an activated clotting time N250 s. According to the AHA/ACC guidelines, treatment with a platelet glycoprotein (GP) IIb/IIIa inhibitor (class IIa recommendation, treatment reasonable) was initiated after diagnostic angiography in 30 patients, followed by a 12–24 h infusion with concomitant heparin infusion. Clopidogrel at a dosage of 300 mg was given before the procedure or in the catheterization laboratory followed by a daily dosage of 75 mg for the subsequent 4 weeks. All patients received aspirin (100 mg/daily). Retinal vessel analysis Within 48 h after the coronary procedure, retinal analysis was performed after written informed consent had been received. Examinations were performed in accordance with the Declaration of Helsinki and were approved by the local ethics committee. For analysis of retinopathy, both eyes were studied. The assessment of the AVR was done by analyzing the right eye. After pupillary dilation, digital retinal photographs were taken according to the United Kingdom Prospective Diabetes Study (UKPDS Group, 1998) protocol. Briefly, 30° fundus pictures centered on the optic disc, the macula, and the superior temporal vessel arch were taken using a retinal vessel analysis system (RVA, fundus camera Zeiss FF 450, Jena, Germany; RVA Imedos, Jena, Germany). Focal retinal arteriolar signs such as focal arteriolar narrowing and arteriovenous (AV) nicking, cotton wool spots, copper and silver wire, disc edema, hard exudates and “red dots (RD)” (including blot hemorrhages and microaneurysms) were evaluated. The AVR was obtained by using the Hubbard–Parr equation provided by the above mentioned RVA Imedos system (Hubbard et al., 1999; Parr and Spears, 1974a,b). Statistical analysis For normally distributed data the unpaired Student t test was applied. The nonparametric Mann–Whitney U test was used when data deviated from a Gaussian distribution as tested by the
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Kolmogorov–Smirnov test. Non-continuous variables were analyzed by using a 2x2 table and Fisher's exact test. Data are presented as mean ± standard deviation (SD) or number and percentage for categorical variables. Values of P b 0.05 (two-tailed) were considered statistically significant. To evaluate potential confounding factors on ACS and CAD, multivariate logistic regression analysis with backward elimination with the variables mentioned in the results section was performed. The calculations were performed using SPSS-Software (SPSS-Software GmbH, München, Germany) and InStat (GraphPad Software, San Diego, USA). Results In this study, patients with ACS were of similar age and showed a similar pattern of coronary risk factors as control patients with stable CAD. Male preponderance (69% in the total group), obesity (23%), and diabetes (40%) were equally frequent in both groups. A higher CAD predisposition in the family was present in the group with stable CAD, however not reaching statistical significance. Of the other cardiovascular risk factors assessed, smoking (32%), hypercholesterolemia (81%), and hypertension (82%) were not different in both groups. Sixteen % of the patients had prior myocardial infarction and 34% prior coronary revascularization (previous angioplasty or coronary artery bypass graft) before the event recorded in this study. The clinical baseline data are summarized in Table 1. In all patients, pharmacological mydriasis yielded pupillary dilatation of at least 4 mm. At univariate analysis, retinae of patients with stable CAD showed significantly more focal signs of vasoconstriction (AV nicking/focal vasoconstriction) than patients with ACS (10 (53%) vs. 9 (21%) pat., OR 4.2; 95%CI 1.31–13.4; p = 0.018). Upon multivariate logistic regression analysis with stepwise backward factor elimination, the association lost significance. Age, sex, smoking, hypercholesterolemia, hypertension, obesity, family history of CAD, diabetes mellitus, prior myocardial infarction, previous angioplasty, previous bypass surgery, retinal microaneurysms and vasoconstriction were selected as independent variables. In contrast, patients with ACS were more affected by blot hemorrhages and microaneurysms (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43–96.59; p = 0.006, Fig. 1). Following multivariate analysis, after adjustment with the previous mentioned variables, the association of blot hemorrhages and microaneurysms with ACS remained significant (OR 20.5, 95%CI 1.6–255, p = 0.019). Additional associations were found for hypercholesterolemia (OR 11.5, 95%CI 2.0–66, p = 0.006) and previous angioplasty (OR 0.11, 95%CI 0.016– 0.71, p = 0.021). Hard exudates, cotton wool spots, copper and silver wire and disc edema were equally common in the ACS and CAD group (Fig. 2), with each group consisting of patients with one or more of these characteristics (8 (19%) vs. 6 (32%) patients, OR 0.495; 95%CI
Table 1 Baseline clinical characteristics. Patients
ACS (n = 43)
CAD (n = 19)
PValue
Age (Years) Male sex Risk factors Smoking Hypercholesterolemia Hypertension Obesity Family history of CAD Diabetes mellitus Medical history Prior myocardial infarction Previous angioplasty Previous bypass surgery
63.4 ± 12.0 29 [67%]
65.4 ± 10.6 14 [74%]
0.46 0.77
14 [33%] 36 [84%] 34 [79%] 9 [21%] 4 [9%] 17 [40%]
6 [32%] 14 [74%] 17 [89%] 5 [26%] 5 [26%] 8 [42%]
1.00 0.49 0.48 0.74 0.12 1.00
8 [19%] 6 [14%] 5 [12%]
2 [11%] 7 [37%] 3 [16%]
0.71 0.09 0.69
ACS: Acute coronary syndromes, CAD: Coronary artery disease.
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Fig. 1. Incidence of microaneurysms and blood hemorrhages (“red dots”) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD).
0.144–1.704; p = 0.33). The AVR was identical between both groups (0.766 ± 0.015 in the ACS group vs. 0.747 ± 0.020 in the CAD group; p N 0.05, Fig. 3). Of note, in patients presenting with ACS and treated with a GP IIb/IIIa inhibitor (30 patients) or without a GP IIb/IIIa inhibitor (13 patients), there was no significant difference in the incidence of blot hemorrhages and microaneurysms (11 (37%) vs. 6 (46%) patients, OR 0.67; 95%CI 0.18–2.53; p = 0.74). Discussion This is the first preliminary study investigating retinal (micro-) vascular changes in patients presenting with ACS. The results suggest that ACS patients are more likely to present with focal signs of increased vessel fragility, which is indicated by the leakage of red blood cells, manifested by the presence of dot blots. Patients with stable CAD show more often focal signs of vasoconstriction, despite similar history of prior ACS events. It was previously reported that generalized arteriolar narrowing, resulting in low AVR, is associated with an increased cardiovascular (CV) mortality over 10 years in patients aged 43–74 years (Wong et al., 2003). In the present study, no significant difference between AVR data in patients with ACS or CAD was detected. In the ARIC study, AVR in the lowest quintile compares with our AVR data, being identified as a strong cardiovascular risk factor, indicating clinical and subclinical cerebrovascular disease (Wong et al., 2002). Thus, our results are consistent with the concept that low AVR cannot distinguish between patients with ACS and stable CAD, but indicates a generalized vascular change associated with a high CV risk. In our study, patients with stable CAD had a similar CV risk profile compared to patients with ACS, but a threefold higher risk of endothelial hyperreactivity as reflected by focal arteriolar narrowing and AV-nicking (AVN). The ARIC study found similar alterations in 6% of all patients with hypertension, indicating an increased CV mortality risk, independent of classical risk factors such as age and diabetes (Tedeschi-Reiner et al., 2005; Wong et al., 2002; Duncan et al., 2002).
Fig. 2. Percentage of ACS and CAD patients presenting with one or more of hard exudates, cotton wool spots, copper and silver wire and disc edema.
Fig. 3. AVR data did not differ significantly in patients with ACS and stable CAD. Data are presented as medians with 25th and 75th percentiles (boxes). The top and the bottom of the whiskers (I bars) show the maximum and the minimum values.
However, depending on the type of study and the cohort investigated, not all studies confirmed this (Ikram et al., 2006; Wong et al., 2004) and further investigations with larger patient populations are necessary to prove this hypothesis. An important result of this study provides evidence that capillary fragility and focal endothelial injury is increased in patients with ACS. “Red dots”, i.e. microaneurysms and focal dot blots, are both indications of impaired endothelial integrity. Ultrastructural studies have suggested that microaneurysms develop as a local response to hypoxia in the vicinity of areas of capillary non-perfusion (Stitt et al., 1995). These retinal changes, although originally investigated in diabetic patients, are not unique to hyperglycemia-induction, but occur also in hypertensive retinopathy and in a variety of other conditions, as it is previously described by large studies (Wong et al., 2003, 2004; Yu et al., 1998). Since both, patients with ACS and CAD, had comparable risk factors such as diabetes and hypertension, it is unlikely that our findings are a result of differences in traditional risk profiles. For the understanding of the pathophysiological development of microaneurysms, a few main factors have to be discussed. In principle, the treatment with anticoagulants in the ACS group may have contributed to focal bleedings, occurring more frequently in this group. There are several indications that this may not be the case. First, previous studies have demonstrated that a larger dose of aspirin does not increase the number of focal bleedings in the retina (Chew et al., 1995). Second, large trials using systemic thrombolysis did not find a substantial increase in retinal hemorrhages, when proliferative vascular changes were excluded (Higgs et al., 1995). Finally, in this study the incidence of red dots did not differ significantly in patients treated with or without a GP IIb/IIIa inhibitor. Therefore, it seems unlikely that the anticoagulation therapy may have influenced our results. Considering the possibility that the higher incidence of blot hemorrhages and microaneurysms might be a result of ACS rather than reflecting an increased risk for ACS, a previous study (Lawrenson et al., 2002) must be mentioned. The authors demonstrated that acute ischemic retinal capillaries do not develop a significant alteration in cross-sectional or luminal areas. Therefore, the authors state that a short time course of retinal ischemia would not be sufficient for VEGF levels to rise appreciably. These mechanisms of VEGF support the hypothesis that recurrent episodes of myocardial ischemia can cause repetitive increases in circulating growth factor levels, which can induce focal endothelial responses such as microaneurysms or focal microvascular dysruptions. It is thus conceivable that retinal vascular changes indicate intermittent myocardial perfusion deficits associated with a higher CV risk. However, this hypothesis needs further
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confirmation by larger studies. Also, the incidence of blot hemorrhages and microaneurysms in patients with stable CAD and previous myocardial infarction needs further investigation. In this study, only 2 patients with this characteristic pattern could be included. Corresponding with our data, recent studies (Nunes et al., 2009) suggest that progressive endothelial damage with a high microaneurysm formation rate, appears to be a common denominator of clinically significant macular edema. Clearly, endothelial hyperreactivity deserves specific attention in further studies as a high risk factor in patients with CAD. In summary, our results provide evidence that specific retinal vascular changes indicate an increased risk for development of ACS, while the AVR as a representative of generalized arteriolar changes cannot distinguish between ACS and stable CAD. Given the availability and the non-invasiveness of the test, retinal fundus examination could be a useful novel parameter for contributing to the assessment of the risk profile of patients, who may the benefit from intensified survey and care. References ACC/AHA Writing Committee, 2004. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction), 2004. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction—executive summary. Circulation 110, 588–636. ACC/AHA Writing Committee, 2006. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention), 2006. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. J. Am. Coll. Cardiol. 47, e1–e121. Buffon, A., et al., 2002. Widespread coronary inflammation in unstable angina. N. Engl. J. Med. 347, 5–12. Chew, E.Y., et al., 1995. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early treatment diabetic retinopathy study report no. 20. Arch. Ophthamol. 113, 52–55. Duncan, B.B., et al., 2002. Hypertensive retinopathy and incident coronary heart disease in high risk men. Br. J. Ophthalmol. 86, 1002–1006. Higgs, E.R., et al., 1995. Use of thrombolysis for acute myocardial infarction in the presence of diabetic retinopathy in the UK, and associated ocular haemorrhagic complications. Diabet. Med. 12, 426–428.
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