Potential clinical value of detecting intermediate stenosis
An intermediate stenosis has a negative prognostic impact on future cardiac events only if associated with a reduced coronary (CFR) or fractional flow reserve (FFR); CFR or FFR have been found reduced in more than half of patients with known intermediate stenosis, non-invasively studied using stress-echocardiography (CFR assessment), or invasively studied with Doppler flow-wire measurements (FFR assessment) [2, 4]. The detection of an intermediate stenosis may consequently be relevant for the clinical prognosis of patients, although the management of such intermediate stenosis needs to be tailored on a single patient basis.
The long-term prognostic value of MPI for hard cardiac events, independently by WM, has been clearly demonstrated [12, 13], however no single study specifically addressed the prognostic value of a MPI defect subtended by an intermediate stenosis.
In conclusion, whether a reversible perfusion defect in patients with isolated intermediate stenosis implies an unfavorable prognosis is a question that remains unanswered.
Wall motion criteria in intermediate stenosis
Contemporary studies using either dipyridamole or dobutamine echocardiography clearly demonstrated the suboptimal sensitivity of pharmacologic stress protocols to detect intermediate stenosis when using standard WM criteria [1, 2, 14, 15]. In a study using MPI in conjunction with dobutamine-atropine SE, pooled sensitivity of WM criteria for intermediate stenosis was only 30%, increasing to 67% when MPI was added .
A recent study, in which high dose dipyridamole was used, reported a 20% sensitivity for WM criteria to detect 50%-75% coronary stenosis in patients with isolated intermediate stenosis of the anterior descending coronary artery; transthoracic Doppler CFR in this study was very effective to overcome the limited sensitivity of WM, but in the clinical practice the undisputable value of non-invasive CFR measurement is technically limited to the anterior coronary circulation .
The incremental value of contrast MPI is instead maintained for all coronary territories, as previously reported . In our study the anterior circulation was affected in only 60% of patients with isolated intermediate stenosis.
Another study demonstrated a major step-up in sensitivity for detection of an intermediate stenosis (associated with fractional flow reserve < 0.75) by the use of contrast for left ventricle opacification during dobutamine echocardiography; in this case sensitivity increased from 48% for standard echocardiography without contrast, to 83% with the use of contrast for opacification, reflecting the usefulness of better endocardial border delineation .
Sensitivity data in this study, which is otherwise particularly interesting for the choice of a hemodynamic functional endpoint, are presumably much higher than real because of the bias of performing and interpreting the tests in patients with previously known intermediate stenosis, which was the reason for stress-testing.
Clinical value of contrast MPI, costs and safety issues
Contrast use to date is not approved specifically for MPI by the European Medicines Agency (EMEA) and its use remains consequently investigational. In our study contrast MPI is useful to increase the sensitivity of pharmacologic stress-echocardiography when the diagnosis of less severe CAD/stenosis is the diagnostic endpoint, while for more severe CAD/stenosis the profound loss in specificity leads to a significant loss in accuracy, compared with standard WM analysis; whether the diagnostic cost-benefit profile of adding contrast MPI is worth the potential safety issues and contrast-related costs is still a matter of discussion. An isolated MPI abnormality (ie, with normal WM) should not be used as the sole indication to coronary angiography, due to its low specificity for epicardial obstructive CAD.
False positives and coronary angiography
Patients with a positive provocative test (whatever stress-test considered) and no obstructive epicardial CAD at coronary angiography are usually defined as false-positives. It is now widely recognized that in many different clinical situations (microvascular disease, diffused coronary atherosclerosis, subcritical disease with coronary remodeling, myocardial bridges, coronary spasm, cardiomyopathies and others) coronary blood flow under stress condition may be significantly reduced in the absence of epicardial > 50% stenosis, up to the level capable to cause chest pain, ECG and perfusion abnormalities and, less frequently, WM abnormalities . MPI is intrinsically incline to a higher "false positivity" rate than WM, due to its earlier role in the pathophysiology of the ischemic cascade.
Few stress-echocardiography studies reported that patients with so called "normal coronaries" and an abnormal stress-test (for WM or CFR-LAD) have a worse cardiac prognosis than patients with a normal test [17, 18].
The specificity of WM in our study was lower than reported by several previous studies; this may be due to the non-conservative reading criteria adopted (≥1 segment with new dyssynergy in a region with normal rest function or worsening of rest dyssynergy), that were anyway similarly applied to MPI (≥1 segment with reversible MPI defect). Analysis of echocardiographic data was performed on a patient-basis and not on a territory-basis, since we felt it inappropriate, stress-echocardiograms being always interrupted in our centre at the very first sign of positivity, for safety reasons. The limitations of angiographic comparisons in relation to the discrepancy between stenosis severity and functional significance are pertinent to our study too. Use of angiographic data alone ignores patients with non-ischemic cardiomyopathies, the previous occurrence of coronary events in patients without significant stenosis or microcirculation disease. Wall motion abnormalities or MPI defects in these patients are classified as false-positives; in our experience this has a major impact on MPI data, more than on WM data.