{"product_id":"two-simple-noninvasive-tests-predict-heart-and-blood-vessel-events-in-patients-with-coronary-artery-disease","title":"Two Simple Noninvasive Tests Predict Heart and Blood Vessel Events in Patients With Coronary Artery Disease","description":"\u003cp\u003eIn 152 patients with established coronary artery disease (CAD), the patients were followed for an average of 34 months. Two noninvasive tests independently predicted future vascular events. The tests were brachial artery flow-mediated dilation (FMD) and carotid plaque area. FMD is a measure of how well the artery lining works. Carotid plaque area is a measure of how much fatty buildup is present in the neck arteries. The ratio of FMD to nitroglycerin-mediated dilation (NMD) was the strongest independent predictor of events (p\u0026lt;0.0001). Patients with preserved endothelial function had low event rates regardless of how much plaque they had, while patients with poor endothelial function plus high plaque burden had the highest event rate (9.4 per 100 patient-years, p\u0026lt;0.05).\u003c\/p\u003e\n\n\u003ch1\u003eTwo Simple Noninvasive Tests Predict Heart and Blood Vessel Events in Patients With Coronary Artery Disease\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#participants\"\u003eWho Participated in the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#carotid\"\u003eCarotid Ultrasound: Measuring Plaque Buildup\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#endothelial\"\u003eEndothelial Function Testing: How Well the Artery Lining Works\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#followup\"\u003eFollowing Patients Over Time\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#results\"\u003eKey Findings: What the Study Discovered\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#predictors\"\u003eWhich Measurements Predicted Future Events\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#interaction\"\u003eThe Critical Interaction Between Plaque and Artery Function\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#changes\"\u003eChanges Over Time: Does Worsening Function Matter?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#discussion\"\u003eWhat These Findings Mean\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Take-Home Points\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn 152 patients with coronary artery disease, two noninvasive tests—carotid ultrasound and brachial artery FMD—independently predicted future vascular events over about 34 months.\u003c\/li\u003e\n\u003cli\u003ePatients with preserved endothelial function had low event rates regardless of plaque amount; those with poor function plus high plaque had the highest rate, 9.4 per 100 patient-years.\u003c\/li\u003e\n\u003cli\u003eWorsening endothelial function over time predicted events in 106 reassessed patients, while changes in carotid ultrasound measurements did not.\u003c\/li\u003e\n\u003cli\u003eMost participants were fit and treated for cholesterol and blood pressure, so traditional risk factors did not predict events well in this group.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eDoctors have long known that atherosclerosis (hardening and narrowing of the arteries from fatty deposits) develops silently over many years before it causes symptoms. Predicting which patients will suffer a heart attack, stroke, or need surgery remains one of the most important challenges in cardiology.\u003c\/p\u003e\n\n\u003cp\u003eTwo noninvasive tests have shown promise for predicting vascular events. The first is \u003cstrong\u003ecarotid ultrasound\u003c\/strong\u003e, which uses sound waves to measure the thickness of the artery wall and the amount of plaque (fatty buildup) in the neck arteries. The second is \u003cstrong\u003ebrachial artery flow-mediated dilation (FMD)\u003c\/strong\u003e, which measures how well the inner lining of the artery (the endothelium) responds to changes in blood flow.\u003c\/p\u003e\n\n\u003cp\u003eEndothelial dysfunction (poor function of the artery's inner lining) is both an early warning sign of vascular disease and an active process that helps atherosclerosis develop. Some earlier studies suggested that endothelial dysfunction predicts future heart problems. However, those early results had important weaknesses.\u003c\/p\u003e\n\n\u003cp\u003eOnly a few studies used noninvasive methods to measure endothelial function. One study failed to show that noninvasively measured endothelial dysfunction was an independent predictor when the extent of coronary artery disease was also considered. Two other studies did not compare endothelial function testing against other imaging methods. One of those studies focused only on hypertensive postmenopausal women and excluded women with normal endothelial function. Another study followed patients for only 30 days after elective vascular surgery.\u003c\/p\u003e\n\n\u003cp\u003eThe purpose of this investigation was to assess the prognostic value of noninvasive endothelial function measurement in a broader population of patients with coronary artery disease (CAD). The main goal was to determine whether endothelial function testing adds useful risk information beyond what exercise stress testing and carotid ultrasound already provide.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThis was a prospective observational study conducted at the University of British Columbia in Vancouver, Canada. The research was supported in part by an unrestricted educational grant from Merck Frosst Canada.\u003c\/p\u003e\n\n\u003cp\u003ePatients were recruited from consecutive patients enrolled in a lifestyle modification program. To be included, patients had to be able to exercise and willing to undergo extensive biochemical and imaging assessments.\u003c\/p\u003e\n\n\u003cp\u003eAll patients had known coronary artery disease, defined by at least one of the following:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eHistory of myocardial infarction (heart attack)\u003c\/li\u003e\n\u003cli\u003ePrevious percutaneous coronary angioplasty (PTCA, a procedure to open blocked arteries with a balloon)\u003c\/li\u003e\n\u003cli\u003ePrevious coronary artery bypass grafting (CABG, heart bypass surgery)\u003c\/li\u003e\n\u003cli\u003ePositive myocardial perfusion scan (an imaging test showing reduced blood flow to the heart)\u003c\/li\u003e\n\u003cli\u003ePositive exercise stress test (EST)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAll patients underwent metabolic testing that included measurements of lipids (cholesterol and fats), glucose (blood sugar), and homocysteine (an amino acid linked to heart disease risk). Lipids and apolipoprotein B were measured using enzymatic methods on fasting blood samples. Lipoprotein(a) concentration was measured with an immunoassay. Glucose was measured by a standard enzymatic method. Total homocysteine was measured by enzyme immunoassay.\u003c\/p\u003e\n\n\u003cp\u003eAll patients also underwent an exercise stress test using the Bruce protocol, which is a standardized treadmill test that increases in speed and incline every three minutes.\u003c\/p\u003e\n\n\u003ch2 id=\"participants\"\u003eWho Participated in the Study\u003c\/h2\u003e\n\n\u003cp\u003eA total of 152 patients were recruited. The average age was 55.9 years (plus or minus 6.2 years). There were 131 men and 21 women.\u003c\/p\u003e\n\n\u003cp\u003eKey characteristics of the patient group at the start of the study included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e53.3%\u003c\/strong\u003e had a previous heart attack\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e48.0%\u003c\/strong\u003e had a previous coronary angioplasty (PTCA)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e25.7%\u003c\/strong\u003e had a previous coronary bypass surgery (CABG)\u003c\/li\u003e\n\u003cli\u003eAverage ejection fraction (a measure of how well the heart pumps) was \u003cstrong\u003e56% (plus or minus 10%)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e1.3%\u003c\/strong\u003e were current smokers, \u003cstrong\u003e64.7%\u003c\/strong\u003e were former smokers, and \u003cstrong\u003e34.0%\u003c\/strong\u003e had never smoked\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e42.3%\u003c\/strong\u003e had a history of hypertension (high blood pressure)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e11.5%\u003c\/strong\u003e had diabetes mellitus\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eLaboratory values at baseline showed:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eTotal cholesterol: \u003cstrong\u003e4.67 mmol\/L (plus or minus 0.97)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eLDL (bad) cholesterol: \u003cstrong\u003e2.72 mmol\/L (plus or minus 0.83)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eHDL (good) cholesterol: \u003cstrong\u003e1.17 mmol\/L (plus or minus 0.33)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eTriglycerides: \u003cstrong\u003e1.69 mmol\/L (plus or minus 0.95)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eApolipoprotein B: \u003cstrong\u003e0.95 g\/L (plus or minus 0.24)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eFasting glucose: \u003cstrong\u003e5.5 mmol\/L (plus or minus 1.1)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eCreatinine: \u003cstrong\u003e88 micromol\/L (plus or minus 17)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eLipoprotein(a): \u003cstrong\u003e480 mg\/L (plus or minus 499)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eHomocysteine: \u003cstrong\u003e8.5 micromol\/L (plus or minus 2.5)\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBlood pressure averaged \u003cstrong\u003e128\/80 mm Hg\u003c\/strong\u003e. The average maximal workload on the stress test was \u003cstrong\u003e11.7 METS (plus or minus 2.9)\u003c\/strong\u003e, indicating a relatively fit group. Average weight was \u003cstrong\u003e84.1 kg (plus or minus 14.9)\u003c\/strong\u003e, average body mass index was \u003cstrong\u003e28.0 (plus or minus 4.1)\u003c\/strong\u003e, and average waist circumference was \u003cstrong\u003e94.1 cm (plus or minus 11.4)\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eMost patients were taking medications: \u003cstrong\u003e91.0%\u003c\/strong\u003e were on aspirin, \u003cstrong\u003e76.3%\u003c\/strong\u003e were on statins (cholesterol-lowering drugs), \u003cstrong\u003e48.1%\u003c\/strong\u003e were on beta-blockers, \u003cstrong\u003e29.5%\u003c\/strong\u003e were on ACE inhibitors, \u003cstrong\u003e28.2%\u003c\/strong\u003e were on calcium channel blockers, and \u003cstrong\u003e7.7%\u003c\/strong\u003e were on nitrates.\u003c\/p\u003e\n\n\u003ch2 id=\"carotid\"\u003eCarotid Ultrasound: Measuring Plaque Buildup\u003c\/h2\u003e\n\n\u003cp\u003eAll patients underwent carotid ultrasound to evaluate intima medial thickness (IMT, the thickness of the two inner layers of the artery wall) and plaques. The scans used high-resolution ultrasound equipment with a 10-MHz linear array transducer.\u003c\/p\u003e\n\n\u003cp\u003eTechnicians took longitudinal views of the left and right common carotid arteries, the carotid bifurcations (where the artery splits), and the internal and external carotid arteries. All images were recorded on Super-VHS videotapes and analyzed off-line by specially trained technicians who did not know the patients' other test results.\u003c\/p\u003e\n\n\u003cp\u003eIMT was measured over 10 mm in the far wall of the common carotid artery, within 2 cm below the bulb. The region with the thickest IMT but no focal lesions was measured. Left and right carotid IMT measurements were averaged.\u003c\/p\u003e\n\n\u003cp\u003ePlaques were identified in all carotid segments. A plaque was defined as any focal protrusion above the intima (the innermost layer of the artery wall). Plaque thickness was the sum of the maximal thickness of all plaques. Plaque area was the sum of the total area of all plaques.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers also created two combined measurements:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eTotal area\u003c\/strong\u003e was the sum of all plaque areas plus the areas of IMT measured in both the left and right carotid arteries (over 10 mm in each)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTotal thickness\u003c\/strong\u003e was the total area divided by the total length of plaques plus the length of the regions used to measure IMT\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe carotid ultrasound results showed the following average values:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eIMT: \u003cstrong\u003e0.865 mm (plus or minus 0.135)\u003c\/strong\u003e, with a range of 0.632 to 1.268 mm\u003c\/li\u003e\n\u003cli\u003ePlaque thickness: \u003cstrong\u003e3.22 mm (plus or minus 3.02)\u003c\/strong\u003e, with a range of 0.00 to 17.38 mm\u003c\/li\u003e\n\u003cli\u003ePlaque area: \u003cstrong\u003e6.13 mm² (plus or minus 10.68)\u003c\/strong\u003e, with a range of 0.00 to 92.09 mm²\u003c\/li\u003e\n\u003cli\u003eTotal thickness: \u003cstrong\u003e1.06 mm (plus or minus 0.25)\u003c\/strong\u003e, with a range of 0.64 to 2.05 mm\u003c\/li\u003e\n\u003cli\u003eTotal area: \u003cstrong\u003e28.48 mm² (plus or minus 16.68)\u003c\/strong\u003e, with a range of 12.76 to 159.77 mm²\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eFocal carotid plaques were found in \u003cstrong\u003e118 patients (77.6%)\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003ch2 id=\"endothelial\"\u003eEndothelial Function Testing: How Well the Artery Lining Works\u003c\/h2\u003e\n\n\u003cp\u003eEndothelial function was assessed using brachial artery flow-mediated dilation (FMD), a technique modified from the method described by Celermajer and colleagues. This test was not available for the first 28 patients enrolled in the program but was performed in the remaining 124 patients.\u003c\/p\u003e\n\n\u003cp\u003eThe FMD test was carried out after an overnight fast. All vasoactive medications (drugs that affect blood vessel tone) were withheld on the day of the study. The brachial artery (the main artery in the upper arm) was imaged using the same ultrasound equipment used for the carotid studies.\u003c\/p\u003e\n\n\u003cp\u003eThe test procedure followed these steps:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003eBaseline diameter of the brachial artery was measured.\u003c\/li\u003e\n\u003cli\u003eA blood pressure cuff placed just below the elbow was inflated to 300 mm Hg for 5 minutes, which blocked blood flow.\u003c\/li\u003e\n\u003cli\u003eThe cuff was then released, and imaging began 30 seconds before release and continued for 5 minutes. The increase in artery diameter after blood flow returns is called flow-mediated dilation (FMD), and it reflects how well the endothelium (artery lining) is working.\u003c\/li\u003e\n\u003cli\u003eThe artery was allowed to return to baseline, and a new baseline diameter was measured.\u003c\/li\u003e\n\u003cli\u003eThen 0.3 mg of nitroglycerin (NTG) was given under the tongue, and the artery was imaged for the next 6 minutes to measure nitroglycerin-mediated dilation (NMD). This measures how well the smooth muscle in the artery wall can relax, independent of the endothelium.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eUltrasound images were recorded on Super-VHS videotapes and analyzed off-line. A 1-cm segment of the artery was selected for analysis. FMD was calculated as the percentage change in artery diameter from rest to peak diameter after cuff deflation. NMD was calculated as the percentage change in diameter from rest to peak diameter after nitroglycerin. The FMD\/NMD ratio was calculated by dividing peak FMD by NMD.\u003c\/p\u003e\n\n\u003cp\u003eThe brachial artery test results showed:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePeak FMD: \u003cstrong\u003e5.93% (plus or minus 3.80%)\u003c\/strong\u003e, with a range of -0.4% to 27.1%\u003c\/li\u003e\n\u003cli\u003eNMD: \u003cstrong\u003e15.98% (plus or minus 6.70%)\u003c\/strong\u003e, with a range of 1.0% to 37.9%\u003c\/li\u003e\n\u003cli\u003eFMD\/NMD ratio: \u003cstrong\u003e0.40 (plus or minus 0.24)\u003c\/strong\u003e, with a range of -0.04 to 1.54\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"followup\"\u003eFollowing Patients Over Time\u003c\/h2\u003e\n\n\u003cp\u003ePatients were followed for an average of \u003cstrong\u003e34 months (plus or minus 10 months)\u003c\/strong\u003e. Major adverse cardiovascular events were tracked and defined as:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eDeath from vascular causes\u003c\/li\u003e\n\u003cli\u003eAcute vascular events included cerebrovascular events (stroke or transient ischemic attack). Acute vascular events included cardiovascular events (heart attack or unstable angina requiring hospitalization). Acute vascular events included peripheral vascular events (new onset of claudication, which is leg pain with walking due to poor circulation).\u003c\/li\u003e\n\u003cli\u003eSymptom-driven revascularization procedures (carotid endarterectomy to clear neck arteries, coronary angioplasty, or coronary bypass surgery)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRevascularization was recommended by each patient's personal physician, who did not know the results of the carotid or endothelial function tests. The decision was based on clinically significant worsening of symptoms or new onset of significant symptoms of ischemia (reduced blood flow to the heart).\u003c\/p\u003e\n\n\u003cp\u003eCerebrovascular events were defined as transient or permanent neurological dysfunction verified by a neurologist. Acute heart attack was defined as elevation in creatine kinase or troponin I to at least 2 times the upper limit of normal. Creatine kinase or troponin I are heart muscle proteins released into the blood when heart muscle is damaged. The definition applied with or without electrocardiogram changes.\u003c\/p\u003e\n\n\u003ch2 id=\"results\"\u003eKey Findings: What the Study Discovered\u003c\/h2\u003e\n\n\u003cp\u003eDuring the 34-month follow-up period, \u003cstrong\u003e22 major adverse cardiac events occurred in 22 patients\u003c\/strong\u003e. These events included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003e1 death\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e8 acute coronary syndromes\u003c\/strong\u003e (7 heart attacks and 1 case of unstable angina)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e2 neurological events\u003c\/strong\u003e (1 transient ischemic attack and 1 stroke)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e11 revascularization procedures\u003c\/strong\u003e (5 coronary angioplasties, 5 coronary bypass surgeries, and 1 carotid endarterectomy)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe researchers compared patients who had events to those who did not. The researchers found that peak brachial FMD and the FMD\/NMD ratio were significantly lower in patients who experienced events. The difference in peak FMD was statistically significant at p=0.012, and the difference in FMD\/NMD ratio was significant at p=0.008. This means there is roughly a 1 in 100 chance or less that these differences were due to random chance.\u003c\/p\u003e\n\n\u003cp\u003eNone of the carotid ultrasound measurements were significantly different between patients who had events and those who did not when examined individually. The carotid ultrasound measurements were IMT, plaque thickness, plaque area, total thickness, or total area.\u003c\/p\u003e\n\n\u003ch2 id=\"predictors\"\u003eWhich Measurements Predicted Future Events\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers used a statistical method called Cox proportional hazards modeling to identify which baseline measurements predicted future vascular events. In the univariate analysis (examining each variable on its own), the following factors were significant predictors:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePlaque area (p=0.0047)\u003c\/li\u003e\n\u003cli\u003eTotal area (p=0.0085)\u003c\/li\u003e\n\u003cli\u003ePeak FMD (p=0.01)\u003c\/li\u003e\n\u003cli\u003eFMD\/NMD ratio (p=0.008)\u003c\/li\u003e\n\u003cli\u003eStress test workload (p=0.027)\u003c\/li\u003e\n\u003cli\u003eUse of long-acting nitroglycerin (p=0.0071)\u003c\/li\u003e\n\u003cli\u003eUse of calcium channel blockers (p=0.0057)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eVariables that qualified for entry into the multivariate model had p values less than 0.15. These variables included peak FMD (p=0.03), FMD\/NMD ratio (p=0.005), plaque area (p=0.09), total area (p=0.09), and plaque thickness (p=0.11). They also included diastolic blood pressure (p=0.13), exercise stress test workload (p=0.027), nitroglycerin use (p=0.03), and calcium channel blocker use (p=0.06).\u003c\/p\u003e\n\n\u003cp\u003eIn the multivariate analysis, which examines all variables simultaneously to find which ones are truly independent predictors, three factors remained significant:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eFMD\/NMD ratio\u003c\/strong\u003e (p\u0026lt;0.0001) — the strongest independent predictor\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eCarotid plaque area\u003c\/strong\u003e (p=0.06)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUse of long-acting nitroglycerin\u003c\/strong\u003e (p=0.005)\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe p value of less than 0.0001 for the FMD\/NMD ratio means there is less than a 1 in 10,000 chance that this result occurred by random chance. This makes it a highly statistically significant finding.\u003c\/p\u003e\n\n\u003ch2 id=\"interaction\"\u003eThe Critical Interaction Between Plaque and Artery Function\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers divided patients into groups based on median values of plaque area and FMD\/NMD ratio. The median FMD\/NMD ratio was 0.34, and the median plaque area was 6.59 mm².\u003c\/p\u003e\n\n\u003cp\u003eThis division created four groups, and the results were striking:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePatients with \u003cstrong\u003ehigh FMD\/NMD\u003c\/strong\u003e (good endothelial function, ratio 0.34 or higher) had \u003cstrong\u003elow event rates\u003c\/strong\u003e regardless of how much plaque they had. Their event rate was less than 5 per 100 patient-years.\u003c\/li\u003e\n\u003cli\u003ePatients with \u003cstrong\u003elow FMD\/NMD\u003c\/strong\u003e (poor endothelial function, ratio below 0.34) \u003cstrong\u003eand high plaque area\u003c\/strong\u003e (6.59 mm² or greater) had the \u003cstrong\u003ehighest event rate at 9.4 per 100 patient-years\u003c\/strong\u003e.\u003c\/li\u003e\n\u003cli\u003eThis high event rate was significantly greater than the rate in patients with high plaque area but preserved endothelial function (p\u0026lt;0.05).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn other words, having good endothelial function appeared to protect patients from the risks associated with a high plaque burden. The structural problem (plaque buildup) and the functional problem (poor artery lining function) worked together to determine risk.\u003c\/p\u003e\n\n\u003ch2 id=\"changes\"\u003eChanges Over Time: Does Worsening Function Matter?\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers also examined whether changes in these measurements during follow-up predicted events. This analysis included 106 patients who had at least one reassessment before any event occurred. Measurements taken after an event could not be included in this analysis.\u003c\/p\u003e\n\n\u003cp\u003eBased on 106 patients and 8 events, the researchers found:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eDeterioration of endothelial function was predictive of adverse cardiac events.\u003c\/strong\u003e The change in FMD was significant at p=0.05, and the change in FMD\/NMD ratio was significant at p=0.071.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eChanges in carotid ultrasound measurements were not predictive.\u003c\/strong\u003e The p value was 0.53 for change in IMT and 0.73 for change in plaque area.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThis finding suggests that worsening artery function over time may be more important than worsening plaque measurements for predicting future events.\u003c\/p\u003e\n\n\u003ch2 id=\"discussion\"\u003eWhat These Findings Mean\u003c\/h2\u003e\n\n\u003cp\u003eThe main finding of this investigation is that both endothelial dysfunction and atheroma burden, measured noninvasively, have prognostic importance in coronary patients. The degree of endothelial dysfunction at baseline, and its change during follow-up, was more discriminating than carotid measurements for predicting outcomes.\u003c\/p\u003e\n\n\u003cp\u003eThe prognostic value of plaque burden was also influenced by the degree of endothelial dysfunction. This supports the concept that both the structural and functional properties of the blood vessels are key co-determinants of cardiovascular outcome.\u003c\/p\u003e\n\n\u003cp\u003eThe FMD\/NMD ratio at baseline was a more powerful predictor of vascular events than baseline FMD alone. During follow-up, both change in FMD and change in FMD\/NMD were significant predictors, and FMD deterioration was slightly more significantly associated with adverse events than FMD\/NMD. These results may have occurred because the parameters were significantly correlated with each other, so the slight differences do not represent a difference in concept.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers believe the baseline results are more robust than those during follow-up. Only measurements made before events could be considered in the statistical model of changes detected during follow-up. This diminished statistical power.\u003c\/p\u003e\n\n\u003cp\u003eThe FMD\/NMD ratio may have some advantages as a measurement. NMD may be slightly impaired in patients with endothelial dysfunction, but this may not be evident except in very large groups. The researchers did not find a difference between the NMD of patients who suffered events and those who did not. However, they did find a significant correlation between NMD and FMD. In contrast, there was no correlation between NMD and FMD\/NMD. This suggests that this ratio is a convenient way to express specifically endothelium-dependent vasodilation (the part of artery widening that depends on the artery lining).\u003c\/p\u003e\n\n\u003cp\u003eThe link between reduced FMD\/NMD ratio and future vascular events suggests that the portion of vascular dilation specifically related to an endothelial mechanism is most important. The portion of vascular dilation specifically related to a smooth muscle mechanism is not most important. These results are also consistent with previous literature demonstrating the utility of the FMD\/NMD ratio.\u003c\/p\u003e\n\n\u003cp\u003eThe prognostic importance of carotid ultrasound measures of atherosclerosis is well recognized. The prognostic importance of endothelial dysfunction noted in this study is in keeping with the results of several other studies. However, this paper provides information not previously available. No study to date had examined the independent value of noninvasive endothelial function assessment in comparison with stress testing and carotid ultrasound for risk stratification.\u003c\/p\u003e\n\n\u003cp\u003eEven more importantly, the prognostic importance of endothelial dysfunction measurements and carotid ultrasound analyses were evaluated. The evaluation took into account multiple biochemical and physical measurements in a group of patients at high risk on the basis of established coronary artery disease.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers also noted that long-acting nitroglycerin use was an independent predictor of events. Previous studies have shown that long-acting nitrates may be associated with adverse outcomes, including heart attack, death from heart failure, and sudden death. Although it is possible that long-acting nitroglycerin was a marker of more symptomatic disease in these patients, the researchers do not think this is likely. The presence of angina was not predictive of adverse cardiac events. This finding should be interpreted with caution because the use of long-acting nitroglycerin was not randomized, and there were only 12 patients using it.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers emphasized several important limitations:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eThe majority of patients were treated for hyperlipidemia (high cholesterol) and hypertension (high blood pressure) and were physically fit. This probably contributes to the apparent lack of association of traditional risk factors with adverse events in the multivariate model. Traditional risk factors include lipid and blood pressure values, waist circumference, apolipoprotein B, lipoprotein(a), or medications associated with improved prognosis like statins and ACE inhibitors.\u003c\/li\u003e\n\u003cli\u003eThis may also account for the low event rate, although this rate is similar to that noted in another study of patients with stable coronary disease evaluated with carotid ultrasound.\u003c\/li\u003e\n\u003cli\u003eThe study did not assess coronary angiographic burden of disease (the amount of blockage in the heart's own arteries), only carotid atheroma burden. Whether coronary angiographic assessment would negate the prognostic value of endothelial function testing remains unknown.\u003c\/li\u003e\n\u003cli\u003eThe use of long-acting nitroglycerin was not randomized, and only 12 patients were using it, so that finding should be interpreted with caution.\u003c\/li\u003e\n\u003cli\u003eHigh-sensitivity C-reactive protein (a marker of inflammation) analyses were not being performed at the time this study began enrolling patients.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis study has several important implications for patients with coronary artery disease:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eTwo simple, noninvasive tests can help predict your risk.\u003c\/strong\u003e Carotid ultrasound and brachial artery FMD testing provide independent information about your likelihood of future heart attacks, strokes, or need for procedures.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHow well your arteries function matters as much as how much plaque you have.\u003c\/strong\u003e Patients with good endothelial function had low event rates even when they had a lot of plaque. This means that preserving the health of your artery lining is critically important.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eWorsening artery function over time is a warning sign.\u003c\/strong\u003e If your endothelial function deteriorates, your risk of events increases. This suggests that monitoring changes over time may be valuable.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTraditional risk factors may not tell the whole story, especially in well-treated patients.\u003c\/strong\u003e In this study, patients were mostly on statins and blood pressure medications. The patients were physically fit. Traditional risk factors did not predict events as well as the specialized tests.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Take-Home Points\u003c\/h2\u003e\n\n\u003cp\u003eBased on this research, the following points are important for patients with coronary artery disease:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk your doctor about noninvasive vascular testing.\u003c\/strong\u003e Carotid ultrasound and brachial artery FMD testing can provide additional risk information beyond standard risk factors and stress testing.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFocus on preserving endothelial function.\u003c\/strong\u003e While this study did not test specific interventions, several steps are known to support healthy artery function. These steps are maintaining good blood pressure control, taking prescribed medications (especially statins and ACE inhibitors), exercising regularly, and not smoking.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnderstand that plaque burden alone does not determine your risk.\u003c\/strong\u003e If you have significant plaque but good endothelial function, your risk may be lower than expected. Conversely, poor endothelial function combined with high plaque burden indicates the highest risk.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFollow-up testing may be valuable.\u003c\/strong\u003e Since deterioration in endothelial function predicted events, periodic reassessment may help you and your doctor adjust your treatment plan.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss any use of long-acting nitroglycerin with your doctor.\u003c\/strong\u003e This study found an association between long-acting nitroglycerin use and adverse events, though the number of patients using it was small and the finding requires confirmation in other studies.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe overall conclusion of this study is that the structural and functional status of the blood vessels are independent predictors of coronary events. Preserved endothelial function attenuates the risk of future events associated with a high plaque burden. This means that keeping your arteries functioning well may help protect you even if you already have significant plaque buildup.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat were the two noninvasive tests used in this research?\u003c\/h3\u003e\n\u003cp\u003eThe tests were carotid ultrasound, which measures plaque buildup in the neck arteries, and brachial artery flow-mediated dilation (FMD), which measures how well the artery lining works. In 152 patients with coronary artery disease followed for about 34 months, both tests independently predicted future vascular events.\u003c\/p\u003e\n\u003ch3\u003eDid plaque buildup alone predict future events?\u003c\/h3\u003e\n\u003cp\u003eCarotid plaque area was a significant predictor on its own, but its effect depended on artery function. Patients with good endothelial function had low event rates even with a lot of plaque. Those with poor endothelial function plus high plaque area had the highest event rate, 9.4 per 100 patient-years.\u003c\/p\u003e\n\u003ch3\u003eWhat did the study find about changes over time?\u003c\/h3\u003e\n\u003cp\u003eAmong 106 patients reassessed before any event, worsening endothelial function predicted adverse cardiac events, while changes in carotid ultrasound measurements did not. This suggests that monitoring how well the artery lining works over time may be more informative than repeating plaque measurements.\u003c\/p\u003e\n\u003ch3\u003eWhat are the limitations of this research?\u003c\/h3\u003e\n\u003cp\u003eMost patients were physically fit and already treated for cholesterol and blood pressure, which may explain the low event rate and why traditional risk factors did not predict events. The study assessed carotid plaque, not the heart's own arteries. The nitroglycerin finding involved only 12 patients and was not randomized.\u003c\/p\u003e\n\u003ch3\u003eWhat can patients do with these findings?\u003c\/h3\u003e\n\u003cp\u003ePatients with coronary artery disease can ask their doctor about noninvasive vascular testing such as carotid ultrasound and brachial artery FMD. Steps known to support healthy artery function include controlling blood pressure, taking prescribed medications, exercising regularly, and not smoking. Periodic reassessment may help guide treatment.\u003c\/p\u003e\n\u003ch3\u003eI have coronary artery disease and my doctor says my stress test and cholesterol numbers are fine — when should I ask for a second opinion about my heart and stroke risk?\u003c\/h3\u003e\n\u003cp\u003eWhen standard risk factors and a stress test look reassuring but you have known coronary artery disease, a second opinion can address whether noninvasive vascular testing adds information. Carotid ultrasound and brachial artery flow-mediated dilation independently predicted future vascular events over an average 34 months. The FMD\/NMD ratio was the strongest independent predictor, and poor endothelial function plus high plaque burden carried the highest event rate, 9.4 per 100 patient-years. Deteriorating endothelial function over time also predicted events. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e chan-et-al-2003-the-prognostic-importance-of-endothelial-dysfunction-and-carotid-atheromaburden-in-patients-with\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Sammy Y. Chan, MD, FRCP(C); G. B. John Mancini, MD, FRCP(C), FACC; Lisa Kuramoto, BSC; Michael Schulzer, MD, PHD; Jiri Frohlich, MD, FRCP(C); Andrew Ignaszewski, MD, FRCP(C)\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eInstitutions:\u003c\/strong\u003e Division of Cardiology, Department of Medicine; Department of Statistics; and Department of Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Journal of the American College of Cardiology, Volume 42, No. 6, 2003, pages 1037-1043\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1016\/S0735-1097(03)00927-6\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Supported in part by an unrestricted educational grant from Merck Frosst Canada.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace discussion with your healthcare provider about your individual medical situation.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807310889116,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-two-simple-noninvasive-tests-predict-heart-and-blood-vessel-events-in-patients-with-coronary-artery-disease-hero.png?v=1792732925","url":"https:\/\/diagnosticdetectives.com\/pt\/products\/two-simple-noninvasive-tests-predict-heart-and-blood-vessel-events-in-patients-with-coronary-artery-disease","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}