Patients referred for angiography to evaluate chest pain are frequently found to have no """"""""obstructive"""""""" coronary artery disease (CAD), i.e., no angiographic stenosis of e50%. For such patients, the reason for chest pain or other ischemic symptoms may not be clear. Prior research has shown that some patients with symptoms and without obstructive CAD have objective abnormalities that may represent the cause of chest pain, such as ischemia on stress imaging, abnormal coronary flow reserve, acetylcholine-induced vasospasm, or atherosclerosis that is more extensive than appreciated on the angiogram. Each of these objective findings is associated with increased risk of events during follow up, such as death and MI. Despite prior mechanistic research, it remains unclear whether ischemic symptoms are in fact due to myocardial ischemia in some or all patients, because other lines of research have shown abnormal pain sensitivity and processing in patients without obstructive CAD. Further, there has been no well-powered study linking the evolution of symptoms and objective measurement of ischemia over time. There remains the possibility that some patients may have symptoms that are not ischemic in origin, in which case ischemia could be silent or a false positive result. Reflecting this lack of clarity, guideline recommendations are very limited and focus on symptom management. We hypothesize that a) changes in ischemia and angina over time are correlated, because angina is due to ischemia in these patients;b) anti-anginal therapy leads to reduction in angina and ischemia;and c) ischemia and angina are more severe with a greater burden of atherosclerosis. The ISCHEMIA trial is a large randomized trial of a routine invasive vs. conservative strategy for the management of stable CAD with core lab-confirmed moderate-severe ischemia. Participants undergo coronary CT angiography (CCTA) after enrollment and those without obstructive CAD (e50% stenosis) are excluded from randomization. These ISCHEMIA anatomic screen failures represent an ideal population in which to investigate our hypotheses because ischemia will be confirmed by a core laboratory and thus the target cohort should be more likely to have true ischemia. In addition, atherosclerosis will be assessed by a core laboratory in the same patients and the target cohort will already have demonstrated interest in participating in research. Therefore patients can be recruited and additional information obtained with a minimum of extra effort and cost. The CIAO-ISCHEMIA ancillary study will add repeat stress echocardiography and angina assessment at 1 year and collection of events (death, MI, stroke, cardiovascular hospitalizations/ER visits). The primary specific aim is to investigate the association between change in angina severity and change in severity of ischemia of stress echocardiography over one year in patients with an initial finding of moderate-severe ischemia and with no obstructive CAD on CCTA. The association between angina, ischemia and atherosclerosis severity at baseline will be examined. Both sexes will be represented;most prior studies have been restricted to women.

Public Health Relevance

Some people with chest pain are found to have open arteries on angiograms instead of blocked arteries and many, but not all, of these people have abnormal stress tests or other tests showing there is not enough blood flow to the heart. Prior research has not made clear whether chest pain in such patients is due to heart disease or something else, in part because no one has found out whether chest pain and stress test results change in the same direction over time. This study will use two measurements of chest pain and two stress tests, one year apart, to find out if chest pain and abnormal stress tests are both caused by the same problem: not enough blood flow to the heart. (End of abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-I (F2))
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Fleg, Jerome
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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