ARIC Manuscript Proposal # 1036r. PC Reviewed: _07/26/05 Status: D Priority: SC Reviewed: Status: Priority:

Transcription

1 ARIC Manuscript Proposal # 1036r PC Reviewed: _07/26/05 Status: D Priority: SC Reviewed: Status: Priority: 1.a. Full Title: The Association between Isolated vs Combined Large and Small Artery Disease with CHD and Stroke Prevalence and Incidence b. Abbreviated Title (Length 26 characters): Combined Vascular Disease 2. Writing Group (list individual with lead responsibility first): Lead: Marsha L. Eigenbrodt, MD, MPH Address: Department of Epidemiology UAMS College of Public Health 4301 West Markham, #820 Little Rock, AR Phone: (501) Fax: (501) eigenbrodtmarshal@uams.edu Writing group members: proposed: Zoran Bursac, David Couper, Jawahar L. Mehta, Kathy Rose, Richard Tracy, Fred Brancati, Greg Evans, Tien Wong,?Ronald Klein?others 3. Timeline: Begin analyses within 3 months of receiving data and complete analyses within 6 months of receiving data. Draft of manuscript to co-authors within 2 months after analyses are completed. 4. Rationale: One limitation of current vascular measures is that none address the full spectrum of vascular damage. Damage to both small and large arteries can cause stroke 1-5 and ischemic heart disease, 2,5 so measures of clinical risk should optimally encompass both. The ARIC Study recently confirmed that cardiovascular risk factors are not uniformly associated with large and small artery disease with only some cardiovascular risk factors and clinical outcomes being related to both large and small artery disease measures. 6 Our proposal extends previous studies by proposing to combine microvascular retinal indicators with new macrovascular disease indicators (common carotid artery (CCA) wall area, diameter + IMT, IMT to diameter ratio, and lumen to total artery areas ratio). We also propose to determine whether there is evidence of a synergistic effect of having both micro and macrovascular disease by testing an interaction between the two vascular measures. If such an effect exists we will investigate the relationship with characteristics known to be associated with both micro and macrovascular disease (diabetes and hypertension). It also suggests that we may be able to obtain information about the potential causal pathway by looking at the beta changes for risk factors resulting from inclusion of the micro and macrovascular measures.

2 Recently an ARIC manuscript provided additional evidence of a relationship between micro and macrovasular diease. 7 We propose, that arteriolar compromise could contribute to atherosclerosis progression and vulnerable plaque formation. As reported by Kajino et al, the muscularis media of large arteries are supplied by vasa vasorum which penetrate the wall to varying depths depending upon wall thickness. 8 The intima and more luminal media is supplied by diffusion from the lumen. 8 We suggest that as the intima thickens and diffusion to and from the lumen becomes less efficient, additional compromise in the vasa vasora could result in LDLcholesterol trapping and oxidation which would result in increases in foam cells and lead to vulnerable plaques. Thus, vasa vasora constriction or wall thickening could contribute to relative ischemia at the intima-media junction if there is sufficient intimal thickening and so contribute to medial damage just as occurs in newborn ductus arteriosus. 8 Angiogenesis would be stimulated and could further predispose to plaque progression from hemorrhage. 9 So, it is possible that having both arteriolar disease as well as thickened intima within the CCA would be markers of increased risk for clinical events since they may be synergistic in their effects. This could explain the increased susceptibility of diabetics to CHD. While much information has been gained regarding the associations for retinopathy, 10,11 and other retinal measures, the risk associated with coexistence of both types of vascular disease is unclear. Retinal A/V ratio can indicate both an acute physiologic constriction in response to blood pressure or arteriole wall thickening with narrowing of the lumen. 2 The CCA measures indicate wall changes while retinal A/V ratios indicate luminal changes. Therefore, it is not surprising that retinal and large artery measures are not always strongly related. Plasma cholesterol, a major atherosclerosis risk factor associated with both common and internal carotid artery IMT, 12 is minimally and non-significantly associated with arteriolar narrowing after adjustment for age, race, sex, blood pressure, and use of anti-hypertensive medication. 6 Focal arteriolar narrowing has the opposite association of that often found with atherosclerosis. However, hypertension and diabetes are associated with large 11,13-17 and small artery disease measures. 11,13,14,18 So, there is likely to be at least one, or possibly more than one, common mechanism for micro and macro vascular damage 19 and this could depend upon the structural component being impacted by the risk factor. 5. Main Hypothesis/Study Questions: Persons with both small and large artery disease will have a higher prevalence of clinical CVD (ischemic heart disease and stroke) compared with those with only one type of vascular disease and using a composite measure should improve risk stratification for incident ischemic heart disease and stroke compared to either measure used alone. We hypothesize this will be true among persons with and without diabetes and hypertension The associations may vary if ischemic stroke and ischemic heart disease are evaluated as separate outcomes and the magnitude of the association will be reduced by risk factor adjustment 6. Data (variables, time window, source, inclusions/exclusions): B-mode ultrasound data from exams 3 and 4, retinal data (retinopathy, focal arteriolar narrowing, arterio-venous nicking, arteriolar and venular diameters, AV ratio), age, race, sex, center, standing height at baseline, prevalent diabetes, blood glucose, fasting information, prevalent hypertension, anti-hypertensive medication use, systolic and diastolic blood pressure, body mass index, smoking status, years of cigarette smoking, drinking status, ethanol consumption, LDL and HDL cholesterol, cholesterol medication use, plaques or shadowing in any carotid, WBC, fibrinogen, von Willebrand factor, Cornell voltage criteria, plaques/shadowing in right or left common carotid artery, mean and ten individual CCA diameter and far wall measurements for each view: optimal, anterior, and posterior B-mode ultrasound views.

3 Prevalent CHD and prevalent stroke at exams 3 and 4 will be required as will incident CHD and incident stroke occurring after the visit where ultrasound exam was performed. Reader/Trend adjustment: While IMT has had reader trend adjustment performed, CCA diameter has not been corrected. We therefore propose to perform adjustment for both CCA diameter and IMT for reader differences and for drift associated with time during exams 3 and 4 and for equipment change during the time period. This will assure that adjustments are performed in the same way for both CCA variables. We will limit analyses initially to a low risk subset of the ARIC study so that differences in diameters or IMT will not be the result of major differences in atherosclerosis severity between exams 3 and 4. The low risk subset will be defined by the absence of prevalent stroke, CHD, plaques or shadowing, diabetes (self-reported physician diagnosis, medication within 2 weeks, or fasting blood glucose 126 mg/dl, or non-fasting blood glucose 200 mg/dl); hypertension (anti-hypertensive medication within 2 weeks or BP>140/90); obesity (body mass index (BMI) 30, computed as weight in kg divided by height in meters 2 ); current cigarette smoking ; hyperlipidemia (LDL cholesterol 160 mg/dl and/or use of cholesterol lowering medication) at the time of the ultrasound examination. Linear regression analyses will be run with CCA diameter or CCA IMT as the outcome and include variables for exam when the ultrasound was performed (or time from start of exam 3), reader, and equipment to test whether there is a significant difference in these variables after we adjust for race, sex, age, and height. In addition, similar analyses, restricted to persons with plaques/shadowing will be compared to determine whether any of the potential nuisance factors (equipment, time, or reader) would have different estimates of the adjustment that would be needed among the high and low risk subsets. Data sets: Developmental and test data sets will be selected: a random sample of about 2/3 of participants who have B-mode ultrasound measurements of the right common carotid artery (CCA) at exams 3 or 4 and retinal A/V ratio measurements at exam 3 will be used as the developmental sample and the remaining sample will be used for model testing/validation. Analytic models: 1) First, simple cross tabulations will evaluate the prevalence of CHD, stroke, or either by whether the individual has evidence of microvascular disease, macrovascular disease, both or neither among persons with and without diabetes. 2) Logistic regression analyses will be used to evaluate models predicting prevalent CHD or stroke (or both) identified by exams 3 or 4 depending upon when the ultrasound exam was performed. For incidence of events, we can test both logistic regression analyses and time to event analyses allowing for the varying point for the start of the follow-up period which would begin after the exam when the ultrasound was performed (either exam 3 or 4). The main exposure of interest would be CCA measures (IMT, diameter, ratio of CCA IMT to diameter, ratio of CCA lumen to artery areas) and retinal arteriole/venous ratios. The main exposure will be categorized as follows: microvascular disease only, macrovascular disease only, both micro and macrovascular disease, and neither macro nor microvascular disease which will be the reference category. (To determine whether there is a significant interaction between micro and macrovascular disease, a model can be run that includes the microvascular measure, the macrovascular measure and an interaction term.) For identifying improvement in model predictivity, models containing CCA measures (IMT and diameter or wall area or ratio measures) and retinal measures (A/V ratio) will be compared to models containing either of the measures alone. Models containing CCA IMT will be considered the reference model. The area under the receiver operating characteristic (ROC) curve will be compared to identify improvement in model prediction, and the deviance test, using the

4 -2Loglikelihood, will be compared for determining improvement in model fit. A method similar to that reported for ARIC in the investigation of prediction of stroke will be used. 20 3) To study the pathway from the risk factor to vascular damage to the clinical outcome, we will look at changes in betas for risk factors in models with and without different vascular measures. For models predicting CHD, models with CCA IMT, diameter or both, with and without retinal A/V ratios will be evaluated to identify changes in betas for the risk factors. This will potentially indicate the pathway by which the risk factor contributes to the clinical outcomes which could be through macrovascular, microvascular damage or both types of vascular damage. For models evaluating stroke, we will also adjust for prevalence of CHD at baseline since both macro and microvascular damage to the heart could predispose to strokes. Betas for standardized variables, ranked variables, and for absolute variable measures will be evaluated. 4) To test whether retinal A/V ratio and CCA IMT are synergistic an interaction between the CCA wall thickness and A/V ratio can be tested to identify whether risk is increased among persons with both retinal disease and thickened CCA IMT. Studying the impact on the diabetes variable beta before and after adjusting for the interaction term could provide insight into whether the increased risk associated with diabetes is because of co-existence of both micro and macrovascular disease. Analyses will be also be stratified by diabetes status and hypertension status (and among those with either and neither) to be assured the effect is not merely the effect of having diabetes or hypertension which often have both large and small artery disease. The numbers of incident strokes may not be sufficient for this last evaluation until additional follow-up is achieved. 7.a. Will the data be used for non-cvd analysis in this manuscript? Yes x_ No b. If Yes, is the author aware that the file ICTDER02 must be used to exclude persons with a value RES_OTH = CVD Research for non-dna analysis, and for DNA analysis RES_DNA = CVD Research would be used? Yes No (This file ICTDER02 has been distributed to ARIC PIs, and contains the responses to consent updates related to stored sample use for research.) 8.a. Will the DNA data be used in this manuscript? Yes x_ No 8.b. If yes, is the author aware that either DNA data distributed by the Coordinating Center must be used, or the file ICTDER02 must be used to exclude those with value RES_DNA = No use/storage DNA? Yes No 9.The lead author of this manuscript proposal has reviewed the list of existing ARIC Study manuscript proposals and has found no overlap between this proposal and previously approved manuscript proposals either published or still in active status. ARIC Investigators have access to the publications lists under the Study Members Area of the web site at: X Yes No

5 10. What are the most related manuscript proposals in ARIC (authors are encouraged to contact lead authors of these proposals for comments on the new proposal or collaboration)? Kathy Rose reviewed the proposals. And found the following possibly related proposals. Many of the published proposals were used as references, but I am not aware that any of the articles consider or propose to consider diameter as well as IMT and small artery disease measures. 337 (A) Atherosclerosis/retinal vascular abnormalities Klein R 08/17/95 Apprd 1 10/05/95 Apprd 1 11/29/ PDF 337A Retinopathy in persons without diabetes in the ARIC study Klein R 09/19/00 Apprd 1 --/--/ /--/ PDF 401 (A) Retinal microvascular abnormalities and stroke/lacunar syndromes/ TIA- The ARIC Study Mo J 07/25/96 Apprd 2 08/05/96 Apprd (A) IMT is predictive of incident clinical stroke Chambless LE 12/11/96 Apprd 2 01/22/97 Apprd 2 11/11/ PDF 513 (J) Association of arterial stiffness and cerebrovascular diseases Chambless LE 08/27/97 Apprd 2 09/03/97 Apprd 2 --/--/ PDF 514 (J) Association of arterial stiffness and retinal microvascular Liao D 08/27/97 Apprd 2 09/03/97 Apprd 2 --/--/ PDF 540 (A) Association of diabetic retinopathy with CHD Duncan BB 11/13/97 Apprd 2 11/24/97 Apprd 2 --/--/ PDF 53 Retinal microvascular abnormalities are independent predictors of stroke Cooper LS 01/21/98 Apprd K 01/23/98 Apprd K --/--/ PDF 611 (J) ARIC CHD risk prediction Chambless LE 09/11/98 Apprd K 09/15/98 Apprd K 12/16/ PDF 705 Atherosclerosis and diabetic retinopathy. The Atherosclerosis Risk in Communities Study Klein R 01/06/00 Apprd 1 01/06/00 Apprd 1 --/--/ PDF 735 Retinal microvascular abnormalities and coronary heart disease: The Atherosclerosis Risk in Communities Study Wong TY 08/29/00 Apprd 1 08/29/00 Apprd 1 --/--/ PDF 818 Carotid artery atherosclerosis, coronary heart disease and stroke incidence and mortality from cardiovascular disease in type 2 diabetic and nondiabetic men and women with and without history of myocardial infarction: ARIC Lee CD 08/23/01 Apprd 2 09/06/01 Apprd 2 11/21/ PDF 11. Manuscript preparation is expected to be completed in one to three years. If a

6 manuscript is not submitted for ARIC review at the end of the 3-years from the date of the approval, the manuscript proposal will expire. Selected References: 1. Reed DM, Resch JA, Hayashi T, MacLean C, Yano K. A prospective study of cerebral artery atherosclerosis. Stroke1988;19: Wong T, Mitchell P. Hypertensive retinopathy. New England Journal of Medicine 2004;351: Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001;358: Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. American Journal of Epidemiology 2000;151: Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96: Klein R, Sharrett AR, Klein BE, et al. Are retinal arteriolar abnormalities related to atherosclerosis?: The Atherosclerosis Risk in Communities Study. Arteriosclerosis, Thrombosis & Vascular Biology 2000;20: Liao D, Wong TY, Klein R, Jones D, Hubbard L, Sharrett AR. Relationship between carotid artery stiffness and retinal arteriolar narrowing in healthy middle-aged persons. Stroke2004;35: Kajino H, Goldbarg S, Roman C, et al. Vasa vasorum hypoperfusion is responsible for medial hypoxia and anatomic remodeling in the newborn lamb ductus arteriosus. Pediatric Research 2002;51: Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. New England Journal of Medicine 2003;349: Klein R, Marino EK, Kuller LH, et al. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. British Journal of Ophthalmology 2002;86: Klein R, Sharrett AR, Klein BE, et al. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the Atherosclerosis Risk in Communities Study. Ophthalmology 2002;109: Crouse JR, Goldbourt U, Evans G, et al. Risk factors and segment-specific carotid arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke1996;27: Sharrett AR, Hubbard LD, Cooper LS, et al. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. American Journal of Epidemiology 1999;150: Cuspidi C, Macca G, Sampieri L, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. Journal of Hypertension 2001;19: Lamont D, Parker L, White M, et al. Risk of cardiovascular disease measured by carotid intima-media thickness at age 49-51: lifecourse study. BMJ 2000;320: Chobanian AV, Alexandrov R. Exacerbation of atherosclerosis by hypertension: potential mechanisms and clinical implications. Archives of Internal Medicine 1996;156: Crouse JR, 3rd, Tang R, Espeland MA, Terry JG, Morgan T, Mercuri M. Associations of extracranial carotid atherosclerosis progression with coronary status and risk factors in patients with and without coronary artery disease. Circulation2002;106: Yamamoto M, Egusa G, Yamakido M. Carotid atherosclerosis and serum lipoprotein(a) concentrations in patients with NIDDM. Diabetes Care 1997;20: Tracy RE. Histologic characteristics of coronary artery in relation to the renovasculopathies of hypertension. Annals of Diagnostic Pathology 1998;2: Chambless LE, Heiss G, Shalar E, Earp MJ, Toole J. Prediction of ischemic stroke risk in the Atherosclerosis Risk in Communities Study. American Journal of Epidemiology 2004;160: