Nonobstructive coronary artery disease on CT coronary angiography and abnormal coronary flow reserve: two sides of the same coin.

Early publications pertaining to the use of CT coronary angiography (CTCA) for evaluation of patients with chest pain, emphasized the excellent negative predictive value for excluding significant CAD as well as the somewhat limited positive predictive value for detection of C50% stenoses because of the tendency of the test to overestimate severity of coronary artery lesions. With respect to the latter, inducible ischemic perfusion defects were reported to be associated with only 40% of the coronary artery stenoses deemed significant by CCTA. Thus, the test was considered mainly of value in low-intermediate risk patients when no CAD was detected. More recently, studies have shown that the presence and the extent of nonobstructive CAD (B50% stenoses) are associated with an intermediate risk of cardiac events between those patients with obstructive CAD and those with completely normal, plaque-free CAD. 1 The greater the number of coronary vessels with nonobstructive plaque, the greater the mortality during follow-up. The inclusion of nonobstructive plaque as a variable has enhanced the prognostic value of CTCA because patients with nonobstructive CAD would presumably have normal exercise or pharmacologic SPECT myocardial perfusion imaging studies. Focal reversible defects are most often seen in the presence of flowlimiting coronary stenoses. Lin et al 1 highlight the importance of identifying nonobstructive CAD when CCTA is utilized as a noninvasive test for CAD detection in symptomatic patients. They showed that in individuals with no CCTA-recognized plaque, the annualized mortality was just 0.34%, whereas a higher risk of future events was observed for individuals with any obstructive plaque. Of interest is that in the low risk subjects by the Framingham Risk Score (\10 estimated 10-year risk), the finding of nonobstructive plaque conferred an increased mortality similar to what would be observed in the intermediaterisk Framingham group. An increased probability of death was seen with the presence of nonobstructive plaque even in the absence of traditional CAD risk factors including diabetes, dyslipidemia, and hypertension (6.7% mortality over the study period vs 1.2% for those without any plaque). What is of most importance is that the presence of any plaque showed an improved net reclassification improvement of 20.5% for all-cause mortality compared with estimated Framingham risk. Can functional imaging identify those patients described above who have nonobstructive CAD and an increased risk of coronary events compared to patients with pristine coronary arteries and no plaque detected? It turns out that the answer is probably, ‘‘yes.’’ Recent studies using quantitative dynamic PET imaging have shown that coronary flow reserve can be accurately assessed, and flow reserve values provide additional prognostic information over the presence or the absence of focal relative perfusion defects. 2-4 The presence of nonobstructive plaque and any evidence for atherosclerosis by coronary calcium imaging is associated with abnormal coronary flow reserve. Like those patients with nonobstructive CAD on CCTA, patients with abnormal coronary flow reserve and no significant perfusion defects have an intermediate risk of future coronary events when compared to patients with normal flow reserve. Naya et al 5 found that 38% of vessels with nonobstructive plaques had an abnormal regional myocardial flow reserve of\2.0. Liga et al 6 reported that the presence of coronary calcium without focal significant coronary artery stenoses reduced flow reserve to a mean of 1.91, compared to 2.13 for normal coronary vessels and 1.63, for vessels with C50% stenoses. In another study, 64% of patients with normal stress perfusion scans had subclinical CAD by concomitant CT coronary calcium imaging. 7 Had coronary flow reserve been measured, surely many of these patients with subclinical CAD by coronary calcium criteria would have had abnormal flow measurements reflective of nonobstructive CAD. PET determination of coronary flow reserve was performed in asymptomatic individuals by Vaccarino et al, 8 who found abnormal flow reserve in the presence of elevated biomarkers for inflammation. This finding was independent of CAD risk factors and the presence of focal defects. The abnormal flow reserve associated with