EDITOR’S PAGE

Nonobstructive coronary artery disease on CTcoronary angiography and abnormal coronaryflow reserve: Two sides of the same coin

George A. Beller, MD

Early publications pertaining to the use of CT cor-

onary 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 sig-

nificant 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 pre-

sumably have normal exercise or pharmacologic SPECT

myocardial perfusion imaging studies. Focal reversible

defects are most often seen in the presence of flow-

limiting coronary stenoses.

Lin et al1 highlight the importance of identifying

nonobstructive CAD when CCTA is utilized as a non-

invasive test for CAD detection in symptomatic patients.

They showed that in individuals with no CCTA-recog-

nized 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 intermediate-

risk 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 hyperten-

sion (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 atheroscle-

rosis 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 per-

fusion defects have an intermediate risk of future

coronary events when compared to patients with normal

flow reserve. Naya et al5 found that 38% of vessels with

nonobstructive plaques had an abnormal regional myo-

cardial flow reserve of\2.0. Liga et al6 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 nonobstruc-

tive 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

J Nucl Cardiol 2012;19:9–10.

1071-3581/$34.00

Copyright � 2011 American Society of Nuclear Cardiology.

doi:10.1007/s12350-011-9500-y

9

inflammatory biomarkers such as C-reactive protein

(CRP) was attributed to coronary microvascular dys-

function, which can reflect the atherosclerotic process in

many individuals.

Thus, it appears that for both the anatomic approach

(i.e., CTCA) and the functional approach (quantitative

PET myocardial perfusion imaging) permit similar

supplementary risk assessment for patients with nonob-

structive CAD over standard test results. The more

quantitative functional approach requires the measure-

ment of coronary flow reserve with vasodilator stress,

whereas the more comprehensive anatomic approach

requires an estimation of total plaque burden. Whichever

test is performed, the direct (CTCA) or indirect (flow

reserve) approach to identifying individuals with non-

obstructive CAD, enhanced risk stratification is achieved.

When flow reserve is abnormal, a more aggressive med-

ical management might be undertaken compared to less

intensive therapy based on the ‘‘normal’’ results of

standard functional testing as with stress SPECT or stress

Echo . This is because these standard tests are designed

to detect focal ischemia attributed to a flow-limiting

stenosis, and would be normal in the presence of non-

obstructive CAD. Unfortunately, in The Prospective

Multicenter Imaging Study for Evaluation of Chest Pain

trial (PROMISE), patients are randomized to CTCA or a

functional test (stress myocardial perfusion imaging,

stress ECG testing or stress echo), without measurement

of coronary flow reserve. Similarly, noninvasive frac-

tional flow reserve (FFR) can now be computed from

CTCA studies adding physiologic information to a tra-

ditionally anatomic-based test.9 Ideally, such functional

measurements with CCTA should supplement mere

anatomic delineation of coronary narrowings. Nonivasive

FFR measurements are not being undertaken in all centers

in those patients randomized to the CCTA arm.

One can speculate on decision-making scenarios

based on the enhanced knowledge gained from these

various techniques. Stress perfusion imaging with coro-

nary flow reserve measurement (e.g., quantitative

dynamic PET) might be the initial test performed. If no

focal defects are present, and coronary flow reserve is

normal, no further testing is necessary. This finding would

predict an excellent prognosis, even in the presence of

CAD risk factors. If focal defects, either with or without

other coronary territories showing abnormal CFR, was

found, invasive coronary angiography or CTCA would be

performed to identify multivessel disease and evaluate its

severity (obstructive or nonobstructive). If only abnormal

flow reserve is detected and no reversible defects are seen,

then CCTA would be performed to evaluate extent of

plaque burden and to exclude 3-vessel or left main disease

that was producing a balanced ischemia pattern with

homogeneous tracer uptake in the myocardium. Other

scenarios starting with the anatomic approach should also

be tested. For example, if the CCTA was entirely normal

with no obstructive or nonobstructive CAD seen, no fur-

ther testing would be necessary. If only nonobstructive

disease was identified, then aggressive risk reduction

would be undertaken. If intermediate grade stenoses are

observed (50%-50%), then the functional test could be

performed to determine if such lesions were ischemia

producing and thus, the possible cause of symptoms. If

high-grade stenoses are detected on CCTA, then invasive

catheterization would be strongly considered, particularly

if observed in a multivessel disease pattern.

Thus, the main message of this essay is that by

extracting more quantitative information from the non-

invasive tests we use currently use clinically, we would

achieve better risk stratification guiding therapy and

hopefully improving outcomes.

References

1. Lin FY, Shaw LJ, Dunning AM, LaBounty TM, Choi J-H, Weinsaft

JW, et al. Mortality risk in symptomatic patients with nonobstruc-

tive coronary artery disease: A prospective 2-center study of 2,583

patients undergoing 64-detector row coronary computed tomogra-

phy angiography. J Am Coll Cardiol 2011;58:510-9.

2. Ziadi MC, Beanlands RSB. The clinical utility of assessing

myocardial blood flow using positron emission tomography.

J Nucl Cardiol 2010;17:571-81.

3. Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic

value of 13N-ammonia myocardial perfusion positron emission

tomography: Added value of coronary flow reserve. J Am Coll

Cardiol 2009;54:150-6.

4. Knuuti J, Kajander S, Maki M, Ukkonen H. Quantification of

myocardial blood flow will reform the detection of CAD. J Nucl

Cardiol 2009;16:497-506.

5. Maya M, Murthy VL, Blankstein R, et al. Quantitative relationship

between the extent and morphology of coronary atherosclerotic

plaque and downstream myocardial perfusion. J Am Coll Cardiol

2011;58:1807-16.

6. Liga R, Marini C, Coceani M, et al. Structural abnormalities of the

coronary arterial wall—in addition to luminal narrowing—affect

myocardial blood flow reserve. J Nucl Med 2011;52:1704-12.

7. Bybee KA, Lee J, Markiewicz R, et al. Diagnostic and clinical

benefit of combined coronary calcium and perfusion assessment in

patients undergoing PET/CT myocardial perfusion stress imaging.

J Nucl Cardiol 2010;17:188-96.

8. Vaccarino V, Kahn D, Votaw J, et al. Inflammation is related to

coronary flow reserve detected by positron emission tomography in

asymptomatic male twins. J Am Coll Cardiol 2011;57:1271-9.

9. Koo B-W, Erglis A, Doh J-H, et al. Diagnosis of ischemia-causing

coronary stenoses by noninvasive fractional flow reserve computed

from coronary computed tomographic angiograms: Results from the

Prospective Multicenter DISCOVER-FLOW (Diagnosis of Ische-

mia-Causing Stenoses Obtained Via Noninvasive Fractional Flow

Reserve) Study. J Am Coll Cardiol 2011;58:1989-97.

10 Beller Journal of Nuclear Cardiology

Nonobstructive coronary artery disease January/February 2012