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Hypertensive retinopathy and cerebral small vessel disease in Amerindians living in rural Ecuador: The Atahualpa Project
International Journal of Cardiology 218 (2016) 65–68
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hypertensive retinopathy and cerebral small vessel disease in Amerindians living in rural Ecuador: The Atahualpa Project Oscar H. Del Brutto a,⁎, Robertino M. Mera b, Eduardo M. Viteri c, Joaquín Pólit a, Ernesto A. Ledesma a, José A. Cano a, Karin J. Plaza a, Mauricio Zambrano d, Aldo F. Costa a a
School of Medicine, Universidad Espíritu Santo — Ecuador, Guayaquil, Ecuador Vanderbilt University Medical Center, Nashville, TN, United States Humana Visión Ophthalmological Center, Guayaquil, Ecuador d Community Center, The Atahualpa Project, Atahualpa, Ecuador b c
a r t i c l e
i n f o
Article history: Received 12 April 2016 Accepted 12 May 2016 Available online 13 May 2016 Keywords: Hypertensive retinopathy Cerebral small vessel disease White matter hyperintensities Lacunar infarcts Population study
a b s t r a c t Background: Diagnosis of cerebral small vessel disease (SVD) is a challenge in remote areas where MRI is not available. Hypertensive retinopathy (HTRP) has shown to correlate with SVD in different ethnic groups, but there is no information from indigenous Latin American people. We assessed the usefulness of retinal photographs to detect cases with SVD among Amerindians living in rural Ecuador. Methods: Atahualpa residents aged ≥60 years with arterial hypertension or prehypertension were identified during a door-to-door survey. A confocal line scanning laser ophthalmoscope was used to identify and grade HTRP (according to the Keith–Wagener–Barker classification). MRIs were read with attention to the presence of white matter hyperintensities (WMH) of presumed vascular origin and lacunar infarcts. Using logistic regression models, we evaluated whether HTRP was independently associated with neuroimaging signatures of SVD. Results: Of 323 eligible candidates, 241 (75%) were enrolled. MRI readings revealed moderate-to-severe WMH in 49 (20%) cases and lacunar infarcts in 29 (12%). HTRP Grade 1 was noticed in 90 (37%) individuals and Grade 2–3 in 42 (17%). After adjusting for demographics and cardiovascular risk factors, multivariate analyses showed a significant association between Grades 2–3 HTRP and moderate-to-severe WMH (OR: 3.87, 95% C.I.: 1.64–9.13) but not with lacunar infarcts (OR: 2.22, 95% C.I.: 0.83–5.92). Conclusion: Amerindians with HTRP Grades 2–3 are almost four times more likely to have SVD-related subcortical damage than those with no- or only Grade 1-HTRP. Retinal photographs might allow recognition of people who need further investigation and therapy. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Owing to increased life expectancy and changes in lifestyles and dietary habits, the burden of cardiovascular diseases – including stroke – is on the rise in many low- and middle-income countries [1]. Cerebral small vessel disease (SVD) – closely linked to arterial hypertension – is a major pathogenetic mechanism underlying stroke in rural areas of Latin America [2,3]. However, diagnosis of SVD requires the use of MRI, which is not readily available in these underserved populations. Efforts should be directed to find portable screening diagnostic tools that may help identify candidates for MRI screening. In this view, hypertensive retinopathy (HTRP) has been shown to correlate with imaging markers of SVD in different ethnic groups [4–7], and its recognition might be used as an inexpensive alternative to MRI to detect individuals at risk. However, there is no information on this relationship among ⁎ Corresponding author at: Air Center 3542, PO Box 522970, Miami, FL 33152-2970, United States. E-mail address: [email protected] (O.H. Del Brutto).
http://dx.doi.org/10.1016/j.ijcard.2016.05.020 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
indigenous Latin American people. In the present study, we aimed to assess the association between HTRP and neuroimaging signatures of SVD in older adults living in Atahualpa, a remote rural Ecuadorian village where previous epidemiological studies on cardiovascular risk factors have been conducted [8–10]. 2. Methods 2.1. Study population Atahualpa was selected for this study as it is representative of the region. As detailed elsewhere [11], more than 95% of the population belongs to the Native/Mestizo ethnic group (Amerindians) and their living characteristics are homogeneous. Most men belong to the bluecollar class and most women are homemakers. The diet of villagers is rich in fish and carbohydrates but poor in other types of meat and dairy products. Atahualpa is an isolated village; most residents do not migrate, and a sizable proportion of them have never visited large urban centers.
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O.H. Del Brutto et al. / International Journal of Cardiology 218 (2016) 65–68
2.2. Study design Using a population-based, cross-sectional design, Atahualpa residents aged ≥ 60 years were identified during a door-to-door survey and those with arterial hypertension or prehypertension – according to the JNC 7 report [12] – were eligible to participate in this study. Individuals with pre-hypertension (systolic blood pressure 120– 139 mm Hg and/or diastolic blood pressure 80–89 mm Hg) were included as they are considered to have higher-than-average risk for vascular events compared to individuals with b120/80 mm Hg [12,13]. The protocol and the informed consent form were approved by the I.R.B. of Hospital-Clínica Kennedy, Guayaquil, Ecuador (FWA 00006867). 2.3. Blood pressure determinations Under comfortable room temperature levels, the arterial blood pressure was measured in both arms by trained medical students with the use of a manual sphygmomanometer (Welch Allyn Tycos© 7670-01), following a well-defined protocol [14]. In brief, with the person in the sitting position and after resting for at least 10 min, the blood pressure was measured three times (at each arm) at intervals of 2 min, and the highest mean value of the readings between right and left arms was used for analysis. Participants who admitted coffee intake or cigarette smoking before the procedure, were screened 1 h later.
(without cavitation) and graded according to the modified Fazekas scale [17], and lacunar infarcts were defined as fluid-filled cavities measuring 3–15 mm located in the territory of a perforating arteriole [18]. As previously detailed, two experienced readers independently reviewed all MRIs, blinded to clinical manifestations and cardiovascular risk factors. Inter-rater agreement was assessed for all findings, and disagreements were resolved by consensus. Kappa coefficients for interrater agreements were 0.91 (95% C.I.: 0.86–0.95) for WMH, and 0.90 (95% C.I.: 0.82–0.98) for lacunar infarcts. 2.7. Statistical analyses Data analyses are carried out by using STATA version 14 (College Station, TX, USA). In univariate analyses, continuous variables were compared by linear models and categorical variables by x2 or Fisher exact test as appropriate. Using multivariate logistic regression models, we evaluated whether HTRP is independently associated with WMH of presumed vascular origin and with lacunar infarcts (as the dependent variables), after adjusting for demographics and cardiovascular risk factors. 3. Results
The Easy Scan v1.2 (i-Optics B.V., The Hague, The Netherlands) was used for taking retinal photographs. This zero-dilatation smart retinal imaging system uses confocal line scanning laser ophthalmoscope technology to illuminate the retina through a 2 mm pupil, and can better penetrate media opacities than conventional fundus cameras [15]. All exams were performed at the Community Center of the Atahualpa Project by trained medical students. A certified ophthalmologist reviewed all images, blinded to clinical data and MRI findings. HTRP grading was determined according to the Keith–Wagener–Barker classification [16], which includes: Grade 1, mild generalized retinal arteriolar narrowing; Grade 2, definite focal narrowing and arteriovenous nicking; Grade 3, signs of Grade 2 retinopathy plus retinal hemorrhage, exudate, and cotton-wool spots; and Grade 4, signs of Grade 3 retinopathy plus papilledema. When HTRP Grades of the two eyes differed, the more advanced grade was recorded for that individual.
The door-to-door survey identified 323 eligible candidates, 241 (75%) of whom were included. The remaining individuals either declined to sign the informed consent or did not have a brain MRI. Mean age of participants was 71 ± 7 years, 142 (59%) were women, seven (3%) were current smokers, 49 (20%) had a body mass index ≥30 kg/ m2, 16 (7%) had poor physical activity, 10 (4%) had a poor diet, 79 (33%) had fasting glucose levels ≥126 mg/dL, and 32 (13%) had total cholesterol blood levels ≥ 240 mg/dL. Blood pressure levels were ≥ 140/90 in 161 (67%) individuals and between 120 and 139/80– 89 mm Hg in the remaining 80. Changes compatible with HTRP were noticed in 132 (55%) cases, most of whom (90 out of 132, 68%) were classified as Grade 1. Of the remaining 42 cases, 39 had Grade 2 and three had Grade 3 HTRP (eight of these individuals also had evidence of diabetic retinopathy). MRI readings revealed moderate-to-severe WMH in 49 (20%) cases and lacunar infarcts in 29 (12%). Lacunar infarcts were single in all but two cases, and were located in the subcortical white matter of cerebral hemispheres in 14 cases, in the basal ganglia/thalamus in 11, and in the brainstem/cerebellum in the remaining four. Univariate analyses with individuals classified according to whether they had any Grade of HTRP or not, showed no differences in demographics, cardiovascular risk factors or in neuroimaging signatures of SVD across both groups. In contrast, when individuals with Grades 2– 3 HTRP (n = 42) were compared to those with no- and Grade 1-HTRP (n = 199), moderate-to-severe WMH were significantly more common in the former (p = 0.012), but the prevalence of lacunar infarcts was similar across groups (Table 1). Multivariate logistic regression models also showed a significant association between Grades 2–3 HTRP and the presence of moderate-to-severe WMH (OR: 3.87, 95% C.I.: 1.64– 9.13, p = 0.002) but not with lacunar infarcts (OR: 2.22, 95% C.I.: 0.83–5.92, p = 0.111), after adjusting for relevant confounders.
2.6. Neuroimaging protocol
4. Discussion
We used data from brain MRIs performed in the year prior the current survey to get information on the presence of neuroimaging signatures of SVD. All studies had been performed for the Atahualpa Project at Hospital Clínica Kennedy (Guayaquil) with the use of a Philips Intera 1.5T machine (Philips Medical Systems, the Netherlands), following a standardized protocol described elsewhere [3]. Lesions of interest included white matter hyperintensities (WMH) of presumed vascular origin and lacunar infarcts. WMH were defined as lesions appearing hyperintense on T2-weighted images that remained bright on FLAIR
This population-based study, conducted in pre-hypertensive and hypertensive older Amerindians living in rural Ecuador, shows a significant association between HTRP and WMH but not with lacunar infarcts. However, this association was confined to individuals having HTRP Grades 2–3, suggesting that the severity of microvascular damage plays a role in this relationship (Fig. 1). Our findings are in line with the Age, Gene/Environment Susceptibility—Reykjavik Study, which showed that focal narrowing of retinal arteries and arteriovenous nicking (characteristics of Grade 2 HTRP) are associated with vascular damage of the
2.4. Cardiovascular risk factors Cardiovascular risk factors were evaluated by direct interviews and procedures previously used in the Atahualpa Project [8]. Smoking status and physical activity were based on self-report, and diet was assessed with the aid of a validated food frequency questionnaire. The body mass index (BMI) was calculated after obtaining the person's height and weight. Fasting glucose and total cholesterol levels were measured after obtaining a capillary blood sample, using Accu-chek® Active and Accutrend® Plus devices (Roche Diagnostics, Mannheim, Germany), respectively. 2.5. Retinal photographs
O.H. Del Brutto et al. / International Journal of Cardiology 218 (2016) 65–68
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Table 1 Characteristics of Atahualpa residents aged ≥60 years with arterial hypertension and pre-hypertension, according to the presence and severity of hypertensive retinopathy (univariate analyses).
Age, mean ± SD Women, n (%) Current smoker, n (%) Body mass index ≥30 kg/m2, n (%) Poor physical activity, n (%) Poor diet, n (%) Fasting glucose ≥126 mg/dL, n (%) Total cholesterol ≥240 mg/dL, n (%) Blood pressure ≥140/90 mm Hg, n (%) Systolic blood pressure, mean ± SD Moderate-to-severe WMH, n (%) Lacunar infarcts, n (%)
Total series (n = 241)
Normal retina + HTRP Grade 1 (n = 199)
HTRP Grades 2–3 (n = 42)
p Value
71 ± 7 142 (59) 7 (3) 49 (20) 16 (7) 10 (4) 79 (33) 32 (13) 161 (67) 144 ± 23 49 (20) 29 (12)
71 ± 8 116 (58) 4 (2) 44 (22) 12 (6) 9 (5) 61 (31) 24 (12) 133 (67) 144 ± 22 34 (17) 21 (11)
70 ± 6 26 (62) 3 (7) 5 (12) 4 (10) 1 (2) 18 (43) 8 (19) 28 (67) 145 ± 24 15 (36) 8 (19)
0.473 0.665 0.104 0.204 0.491 0.454 0.126 0.225 0.983 0.792 0.012 0.202
HTRP: hypertensive retinopathy; WMH: white matter hyperintensities.
subcortical white matter [7]. Likewise, other large studies conducted in white populations reported similar findings, confirming that HTRP is related to the presence of WMH independent of blood pressure levels and cardiovascular risk factors [4,19]. The association of HTRP with cerebral infarcts is less consistent. Some cross-sectional and longitudinal studies have shown increased prevalence and incidence of ischemic strokes in patients with HTRP [4, 19,20], while in others, this relationship disappeared for most stroke subtypes after adjustment for relevant confounders [5–7]. Heterogeneity of pathogenetic mechanisms causing strokes is likely responsible for these discrepancies. In our study, the lack of association between HTRP and lacunar infarcts may be related to the different mechanisms underlying these type of infarcts, since many of them are not related to SVD but to artery-to-artery emboli originating in plaques located in the carotid arteries or to intracranial artery stenosis; in those settings, no association with HTRP should be expected. These results are in line with previous findings showing different correlates for WMH and lacunar infarcts in Atahualpa residents. In particular, we have found that abnormal ankle-brachial index determinations (a signature of medium-to-large vessels damage) correlate with lacunar infarcts but not with WMH of presumed vascular origin [21], and vitamin D deficiency – implicated in increased thrombogeneity and inflammation resulting in damage of
small vessels – is associated with WMH but not with lacunar infarcts [22]. Major strengths of our study include the population based design with unbiased enrollment of participants, the method selected for retinal imaging, and the standardized MRI protocol. A potential limitation is the fact that MRIs were not obtained simultaneously with retinal photographs. However, diffuse subcortical damage related to cerebral SVD is a chronic process that is not expected to change in a few months. In addition, as part of the protocol of the Atahualpa Project, all individuals who experience clinical manifestations suggestive of an overt stroke are immediately scheduled for a new MRI. Therefore, with the possible exception of one or two cases of silent strokes that might have occurred in the months before the current survey, it is unlikely that we have missed individuals with lacunar infarcts in the present study. In summary, Amerindians with HTRP Grades 2–3 are almost four times more likely to have SVD-related diffuse subcortical damage than those with no- or only Grade 1-HTRP. Examination of retinal photographs might allow recognition of asymptomatic people who need further investigation and preventive therapy. Further cooperative studies are needed to settle the actual role of retinal imaging in mass screening of MRI candidates for SVD assessment.
Fig. 1. Fluid Attenuated Inversion Recovery MRI of a study participant showing severe white matter hyperintensities of presumed vascular origin (left) and retinal photograph showing Grade 3 hypertensive retinopathy (right).
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Conflict of interest Nothing to disclose.
[12]
Funding This study was supported by Universidad Espíritu Santo — Ecuador. References [1] V.L. Feigin, G.A. Mensah, B. Norving, C.J. Murray, G.A. Roth, GBD, Stroke panel experts group, Atlas of the global burden of stroke (1990–2013): the GBD 2013 study, Neuroepidemiology 45 (2015) (2013) 230–236. [2] G. Saposnik, O.H. Del Brutto, Iberoamerican Society of Cerebrovascular Diseases, stroke in South America: a systematic review of incidence, prevalence, and stroke subtypes, Stroke 34 (2003) 2103–2107. [3] O.H. Del Brutto, R.M. Mera, V.J. Del Brutto, M. Zambrano, J. Lama, White matter hyperintensities of presumed vascular origin: a population-based study in rural Ecuador (the Atahualpa Project), Int. J. Stroke 10 (2015) 372–375. [4] T.Y. Wong, R. Klein, A.R. Sharrett, D.J. Couper, B.E. Klein, D.P. Liao, L.D. Hubbard, T.H. Mosley, ARIC investigators, Atherosclerosis risk in communities study, cerebral white matter lesions, retinopathy, and incident clinical stroke, JAMA 288 (2002) 67–74. [5] M.K. Ikram, F.J. de Jong, J.R. Vingerling, A. Hofman, P.J. Koudstaal, P.T. de Jong, M.M. Breteler, Retinal vessel diameter and risk of stroke; the Rotterdam Study, Neurology 66 (2006) 1339–1343. [6] H.M. Kwon, B.J. Kim, J.Y. Oh, S.J. Kim, S.H. Lee, B.H. Oh, B.W. Yoon, Retinopathy as an indicator of silent brain infarction in asymptomatic hypertensive subjects, J. Neurol. Sci. 252 (2007) 159–162. [7] C. Qiu, M.F. Cotch, S. Sigurdsson, R. Klein, F. Jonasson, B.E. Klein, M. Garcia, P.V. Jonsson, T.B. Harris, G. Eiriksdottir, O. Kjartnsson, M.A. van Buchem, V. Gudnason, L.J. Launer, Microvascular lesions in the brain and retina: the Age, Gene/Environment Susceptibility—Reykjavik Study, Ann. Neurol. 65 (2009) 569–576. [8] O.H. Del Brutto, M. Santamaría, E. Ochoa, E. Peñaherrera, R. Santibañez, F. PowChon-Long, M. Zambrano, V.J. Del Brutto, Population-based study of cardiovascular health in Atahualpa, a rural village of coastal Ecuador, Int. J. Cardiol. 168 (2013) 1618–1620. [9] O.H. Del Brutto, M. Montalván, D. Tettamanti, E. Peñaherrera, R. Santibáñez, F. PowChon-Long, V.J. Del Brutto, The “know your numbers” program in Atahualpa — a pilot study aimed to reduce cardiovascular diseases and stroke burden in rural communities of developing countries, Int. J. Cardiol. 168 (2013) 3123–3124. [10] O.H. Del Brutto, R.M. Mera, V.J. Del Brutto, M. Zambrano, J.E. Montenegro, P.R. Castillo, Edentulism associates with poor cardiovascular health. Results from the Atahualpa Project, Int. J. Cardiol. 176 (2014) 1013–1014. [11] O.H. Del Brutto, E. Peñaherrera, E. Ochoa, M. Santamaría, M. Zambrano, V.J. Del Brutto, Door-to-door survey of cardiovascular health, stroke, and ischemic heart
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hypertensive retinopathy and cerebral small vessel disease in Amerindians living in rural Ecuador: The Atahualpa Project Oscar H. Del Brutto a,⁎, Robertino M. Mera b, Eduardo M. Viteri c, Joaquín Pólit a, Ernesto A. Ledesma a, José A. Cano a, Karin J. Plaza a, Mauricio Zambrano d, Aldo F. Costa a a
School of Medicine, Universidad Espíritu Santo — Ecuador, Guayaquil, Ecuador Vanderbilt University Medical Center, Nashville, TN, United States Humana Visión Ophthalmological Center, Guayaquil, Ecuador d Community Center, The Atahualpa Project, Atahualpa, Ecuador b c
a r t i c l e
i n f o
Article history: Received 12 April 2016 Accepted 12 May 2016 Available online 13 May 2016 Keywords: Hypertensive retinopathy Cerebral small vessel disease White matter hyperintensities Lacunar infarcts Population study
a b s t r a c t Background: Diagnosis of cerebral small vessel disease (SVD) is a challenge in remote areas where MRI is not available. Hypertensive retinopathy (HTRP) has shown to correlate with SVD in different ethnic groups, but there is no information from indigenous Latin American people. We assessed the usefulness of retinal photographs to detect cases with SVD among Amerindians living in rural Ecuador. Methods: Atahualpa residents aged ≥60 years with arterial hypertension or prehypertension were identified during a door-to-door survey. A confocal line scanning laser ophthalmoscope was used to identify and grade HTRP (according to the Keith–Wagener–Barker classification). MRIs were read with attention to the presence of white matter hyperintensities (WMH) of presumed vascular origin and lacunar infarcts. Using logistic regression models, we evaluated whether HTRP was independently associated with neuroimaging signatures of SVD. Results: Of 323 eligible candidates, 241 (75%) were enrolled. MRI readings revealed moderate-to-severe WMH in 49 (20%) cases and lacunar infarcts in 29 (12%). HTRP Grade 1 was noticed in 90 (37%) individuals and Grade 2–3 in 42 (17%). After adjusting for demographics and cardiovascular risk factors, multivariate analyses showed a significant association between Grades 2–3 HTRP and moderate-to-severe WMH (OR: 3.87, 95% C.I.: 1.64–9.13) but not with lacunar infarcts (OR: 2.22, 95% C.I.: 0.83–5.92). Conclusion: Amerindians with HTRP Grades 2–3 are almost four times more likely to have SVD-related subcortical damage than those with no- or only Grade 1-HTRP. Retinal photographs might allow recognition of people who need further investigation and therapy. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Owing to increased life expectancy and changes in lifestyles and dietary habits, the burden of cardiovascular diseases – including stroke – is on the rise in many low- and middle-income countries [1]. Cerebral small vessel disease (SVD) – closely linked to arterial hypertension – is a major pathogenetic mechanism underlying stroke in rural areas of Latin America [2,3]. However, diagnosis of SVD requires the use of MRI, which is not readily available in these underserved populations. Efforts should be directed to find portable screening diagnostic tools that may help identify candidates for MRI screening. In this view, hypertensive retinopathy (HTRP) has been shown to correlate with imaging markers of SVD in different ethnic groups [4–7], and its recognition might be used as an inexpensive alternative to MRI to detect individuals at risk. However, there is no information on this relationship among ⁎ Corresponding author at: Air Center 3542, PO Box 522970, Miami, FL 33152-2970, United States. E-mail address: [email protected] (O.H. Del Brutto).
http://dx.doi.org/10.1016/j.ijcard.2016.05.020 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
indigenous Latin American people. In the present study, we aimed to assess the association between HTRP and neuroimaging signatures of SVD in older adults living in Atahualpa, a remote rural Ecuadorian village where previous epidemiological studies on cardiovascular risk factors have been conducted [8–10]. 2. Methods 2.1. Study population Atahualpa was selected for this study as it is representative of the region. As detailed elsewhere [11], more than 95% of the population belongs to the Native/Mestizo ethnic group (Amerindians) and their living characteristics are homogeneous. Most men belong to the bluecollar class and most women are homemakers. The diet of villagers is rich in fish and carbohydrates but poor in other types of meat and dairy products. Atahualpa is an isolated village; most residents do not migrate, and a sizable proportion of them have never visited large urban centers.
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2.2. Study design Using a population-based, cross-sectional design, Atahualpa residents aged ≥ 60 years were identified during a door-to-door survey and those with arterial hypertension or prehypertension – according to the JNC 7 report [12] – were eligible to participate in this study. Individuals with pre-hypertension (systolic blood pressure 120– 139 mm Hg and/or diastolic blood pressure 80–89 mm Hg) were included as they are considered to have higher-than-average risk for vascular events compared to individuals with b120/80 mm Hg [12,13]. The protocol and the informed consent form were approved by the I.R.B. of Hospital-Clínica Kennedy, Guayaquil, Ecuador (FWA 00006867). 2.3. Blood pressure determinations Under comfortable room temperature levels, the arterial blood pressure was measured in both arms by trained medical students with the use of a manual sphygmomanometer (Welch Allyn Tycos© 7670-01), following a well-defined protocol [14]. In brief, with the person in the sitting position and after resting for at least 10 min, the blood pressure was measured three times (at each arm) at intervals of 2 min, and the highest mean value of the readings between right and left arms was used for analysis. Participants who admitted coffee intake or cigarette smoking before the procedure, were screened 1 h later.
(without cavitation) and graded according to the modified Fazekas scale [17], and lacunar infarcts were defined as fluid-filled cavities measuring 3–15 mm located in the territory of a perforating arteriole [18]. As previously detailed, two experienced readers independently reviewed all MRIs, blinded to clinical manifestations and cardiovascular risk factors. Inter-rater agreement was assessed for all findings, and disagreements were resolved by consensus. Kappa coefficients for interrater agreements were 0.91 (95% C.I.: 0.86–0.95) for WMH, and 0.90 (95% C.I.: 0.82–0.98) for lacunar infarcts. 2.7. Statistical analyses Data analyses are carried out by using STATA version 14 (College Station, TX, USA). In univariate analyses, continuous variables were compared by linear models and categorical variables by x2 or Fisher exact test as appropriate. Using multivariate logistic regression models, we evaluated whether HTRP is independently associated with WMH of presumed vascular origin and with lacunar infarcts (as the dependent variables), after adjusting for demographics and cardiovascular risk factors. 3. Results
The Easy Scan v1.2 (i-Optics B.V., The Hague, The Netherlands) was used for taking retinal photographs. This zero-dilatation smart retinal imaging system uses confocal line scanning laser ophthalmoscope technology to illuminate the retina through a 2 mm pupil, and can better penetrate media opacities than conventional fundus cameras [15]. All exams were performed at the Community Center of the Atahualpa Project by trained medical students. A certified ophthalmologist reviewed all images, blinded to clinical data and MRI findings. HTRP grading was determined according to the Keith–Wagener–Barker classification [16], which includes: Grade 1, mild generalized retinal arteriolar narrowing; Grade 2, definite focal narrowing and arteriovenous nicking; Grade 3, signs of Grade 2 retinopathy plus retinal hemorrhage, exudate, and cotton-wool spots; and Grade 4, signs of Grade 3 retinopathy plus papilledema. When HTRP Grades of the two eyes differed, the more advanced grade was recorded for that individual.
The door-to-door survey identified 323 eligible candidates, 241 (75%) of whom were included. The remaining individuals either declined to sign the informed consent or did not have a brain MRI. Mean age of participants was 71 ± 7 years, 142 (59%) were women, seven (3%) were current smokers, 49 (20%) had a body mass index ≥30 kg/ m2, 16 (7%) had poor physical activity, 10 (4%) had a poor diet, 79 (33%) had fasting glucose levels ≥126 mg/dL, and 32 (13%) had total cholesterol blood levels ≥ 240 mg/dL. Blood pressure levels were ≥ 140/90 in 161 (67%) individuals and between 120 and 139/80– 89 mm Hg in the remaining 80. Changes compatible with HTRP were noticed in 132 (55%) cases, most of whom (90 out of 132, 68%) were classified as Grade 1. Of the remaining 42 cases, 39 had Grade 2 and three had Grade 3 HTRP (eight of these individuals also had evidence of diabetic retinopathy). MRI readings revealed moderate-to-severe WMH in 49 (20%) cases and lacunar infarcts in 29 (12%). Lacunar infarcts were single in all but two cases, and were located in the subcortical white matter of cerebral hemispheres in 14 cases, in the basal ganglia/thalamus in 11, and in the brainstem/cerebellum in the remaining four. Univariate analyses with individuals classified according to whether they had any Grade of HTRP or not, showed no differences in demographics, cardiovascular risk factors or in neuroimaging signatures of SVD across both groups. In contrast, when individuals with Grades 2– 3 HTRP (n = 42) were compared to those with no- and Grade 1-HTRP (n = 199), moderate-to-severe WMH were significantly more common in the former (p = 0.012), but the prevalence of lacunar infarcts was similar across groups (Table 1). Multivariate logistic regression models also showed a significant association between Grades 2–3 HTRP and the presence of moderate-to-severe WMH (OR: 3.87, 95% C.I.: 1.64– 9.13, p = 0.002) but not with lacunar infarcts (OR: 2.22, 95% C.I.: 0.83–5.92, p = 0.111), after adjusting for relevant confounders.
2.6. Neuroimaging protocol
4. Discussion
We used data from brain MRIs performed in the year prior the current survey to get information on the presence of neuroimaging signatures of SVD. All studies had been performed for the Atahualpa Project at Hospital Clínica Kennedy (Guayaquil) with the use of a Philips Intera 1.5T machine (Philips Medical Systems, the Netherlands), following a standardized protocol described elsewhere [3]. Lesions of interest included white matter hyperintensities (WMH) of presumed vascular origin and lacunar infarcts. WMH were defined as lesions appearing hyperintense on T2-weighted images that remained bright on FLAIR
This population-based study, conducted in pre-hypertensive and hypertensive older Amerindians living in rural Ecuador, shows a significant association between HTRP and WMH but not with lacunar infarcts. However, this association was confined to individuals having HTRP Grades 2–3, suggesting that the severity of microvascular damage plays a role in this relationship (Fig. 1). Our findings are in line with the Age, Gene/Environment Susceptibility—Reykjavik Study, which showed that focal narrowing of retinal arteries and arteriovenous nicking (characteristics of Grade 2 HTRP) are associated with vascular damage of the
2.4. Cardiovascular risk factors Cardiovascular risk factors were evaluated by direct interviews and procedures previously used in the Atahualpa Project [8]. Smoking status and physical activity were based on self-report, and diet was assessed with the aid of a validated food frequency questionnaire. The body mass index (BMI) was calculated after obtaining the person's height and weight. Fasting glucose and total cholesterol levels were measured after obtaining a capillary blood sample, using Accu-chek® Active and Accutrend® Plus devices (Roche Diagnostics, Mannheim, Germany), respectively. 2.5. Retinal photographs
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Table 1 Characteristics of Atahualpa residents aged ≥60 years with arterial hypertension and pre-hypertension, according to the presence and severity of hypertensive retinopathy (univariate analyses).
Age, mean ± SD Women, n (%) Current smoker, n (%) Body mass index ≥30 kg/m2, n (%) Poor physical activity, n (%) Poor diet, n (%) Fasting glucose ≥126 mg/dL, n (%) Total cholesterol ≥240 mg/dL, n (%) Blood pressure ≥140/90 mm Hg, n (%) Systolic blood pressure, mean ± SD Moderate-to-severe WMH, n (%) Lacunar infarcts, n (%)
Total series (n = 241)
Normal retina + HTRP Grade 1 (n = 199)
HTRP Grades 2–3 (n = 42)
p Value
71 ± 7 142 (59) 7 (3) 49 (20) 16 (7) 10 (4) 79 (33) 32 (13) 161 (67) 144 ± 23 49 (20) 29 (12)
71 ± 8 116 (58) 4 (2) 44 (22) 12 (6) 9 (5) 61 (31) 24 (12) 133 (67) 144 ± 22 34 (17) 21 (11)
70 ± 6 26 (62) 3 (7) 5 (12) 4 (10) 1 (2) 18 (43) 8 (19) 28 (67) 145 ± 24 15 (36) 8 (19)
0.473 0.665 0.104 0.204 0.491 0.454 0.126 0.225 0.983 0.792 0.012 0.202
HTRP: hypertensive retinopathy; WMH: white matter hyperintensities.
subcortical white matter [7]. Likewise, other large studies conducted in white populations reported similar findings, confirming that HTRP is related to the presence of WMH independent of blood pressure levels and cardiovascular risk factors [4,19]. The association of HTRP with cerebral infarcts is less consistent. Some cross-sectional and longitudinal studies have shown increased prevalence and incidence of ischemic strokes in patients with HTRP [4, 19,20], while in others, this relationship disappeared for most stroke subtypes after adjustment for relevant confounders [5–7]. Heterogeneity of pathogenetic mechanisms causing strokes is likely responsible for these discrepancies. In our study, the lack of association between HTRP and lacunar infarcts may be related to the different mechanisms underlying these type of infarcts, since many of them are not related to SVD but to artery-to-artery emboli originating in plaques located in the carotid arteries or to intracranial artery stenosis; in those settings, no association with HTRP should be expected. These results are in line with previous findings showing different correlates for WMH and lacunar infarcts in Atahualpa residents. In particular, we have found that abnormal ankle-brachial index determinations (a signature of medium-to-large vessels damage) correlate with lacunar infarcts but not with WMH of presumed vascular origin [21], and vitamin D deficiency – implicated in increased thrombogeneity and inflammation resulting in damage of
small vessels – is associated with WMH but not with lacunar infarcts [22]. Major strengths of our study include the population based design with unbiased enrollment of participants, the method selected for retinal imaging, and the standardized MRI protocol. A potential limitation is the fact that MRIs were not obtained simultaneously with retinal photographs. However, diffuse subcortical damage related to cerebral SVD is a chronic process that is not expected to change in a few months. In addition, as part of the protocol of the Atahualpa Project, all individuals who experience clinical manifestations suggestive of an overt stroke are immediately scheduled for a new MRI. Therefore, with the possible exception of one or two cases of silent strokes that might have occurred in the months before the current survey, it is unlikely that we have missed individuals with lacunar infarcts in the present study. In summary, Amerindians with HTRP Grades 2–3 are almost four times more likely to have SVD-related diffuse subcortical damage than those with no- or only Grade 1-HTRP. Examination of retinal photographs might allow recognition of asymptomatic people who need further investigation and preventive therapy. Further cooperative studies are needed to settle the actual role of retinal imaging in mass screening of MRI candidates for SVD assessment.
Fig. 1. Fluid Attenuated Inversion Recovery MRI of a study participant showing severe white matter hyperintensities of presumed vascular origin (left) and retinal photograph showing Grade 3 hypertensive retinopathy (right).
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Conflict of interest Nothing to disclose.
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