Myocardial perfusion scintigraphy (MPS) imaging has become established as the main functional cardiac imaging technique for ruling in or out myocardial ischemia for patients with angina.1 Thallium stress scintigraphy, following an exercise test or using pharmacologic stressors, was the mainstay for myocardial ischemia diagnosis for decades. Lately technetium and single-photon emission tomography (SPECT) techniques have replaced thallium and traditional scintigraphy, respectively, in the vast majority of studies, providing high diagnostic accuracy with low radiation. Defects in stress and rest images of a myocardial SPECT scan are considered indicative of impaired myocardial perfusion, usually due to stenosis or even total occlusion of coronary arteries.2

The degree of epicardial coronary artery stenosis cannot be determined unless angiography is conducted. On angiography, normal-appearing coronary arteries are defined as having 0% or <20% luminal stenosis, and non-obstructive CAD as coronary arteries with luminal stenosis >20% but <50%. Although the traditional definition of obstructive CAD was ≥70% stenosis, recent European Society of Cardiology and American College of Cardiology/American Heart Association guidelines shifted to include stenosis of 50–70% if there is associated inducible ischemia or fractional flow reserve ≤0.80 when considering the physiological significance of stenosis and revascularization management in patients with stable CAD.3

Several studies have shown a particularly high percentage of false positive SPECT scans for significant epicardial CAD, ranging from 25% up to more than 50% depending on the study, for patients with no or non-obstructive coronary artery disease.4–6 Perfusion defects on SPECT scans of these patients may sometimes be artifacts caused by technical issues (attenuation of signal due to radiation absorption from adjacent tissues, such as the diaphragm, being the most common cause).7 However, there is also concern about other conditions in these patients (such as myocardial bridging, vasospastic angina, or impaired microvascular flow as in diabetes and hypertensive cardiomyopathy).

The clinical condition recently identified as ischemia with non-obstructive coronary arteries (INOCA)3,8–10 is associated with increased cardiovascular morbidity and poor prognosis in subsequent years. Long-term follow-up of patients after SPECT studies indicative of reversible ischemia but without proven significant CAD on coronary angiography could provide answers to these questions.

During January 2021 we retrospectively analyzed data on all patients who underwent coronary angiography in the catheterization laboratory of the Konstantopouleio General Hospital of Nea Ionia over a period of seven years (between January 1, 2011 and December 31, 2017). A total of 1643 patients (from a total of 12536 angiographies) fulfilled criteria of angina and a positive myocardial SPECT scan for reversible ischemia. No or non-significant coronary artery disease was the diagnosis after coronary angiography in 569 patients (34.63%). In the telephone survey that followed, 285 (50.1%) of these were successfully contacted, either in person or via a close relative who answered the call and agreed to participate in the study. The study flowchart is depicted in Figure 1.

Figure 1.

Flowchart of the patients analyzed in the study. CAD: coronary artery disease; LBBB: left bundle branch block; SPECT: single-photon emission tomography.

(0.15MB).

The mean age of patients included in the analysis was 67.6 (SD 8.8) years, 35.4% were female, and mean follow-up was 5.53 years (SD 1.85). At the time of telephone contact five had died (1.7%), none of them of cardiac causes. Five (1.7%) underwent revascularization (four percutaneous and one coronary artery bypass graft during valve replacement surgery) in the subsequent years, in a mean period of approximately six years after the index coronary angiogram, and six patients (2.1%) had another coronary angiogram, still without significant epicardial coronary artery disease or need for revascularization. A much higher number of patients had arrhythmic events in subsequent years, with a composite of new-onset atrial fibrillation or flutter, ablation for arrhythmias of any origin or pacemaker implantation in 21 patients (7.4%). Two patients (0.7%) reported symptoms of angina (both Canadian Cardiovascular Society class I) and two patients (0.7%) had valve replacement surgery. A total of 31 patients were hospitalized for cardiovascular reasons during follow-up (10.9%), none of them with symptoms of heart failure. Another 31 patients (10.9%) reported symptoms of heart failure during follow-up, but with a mean New York Heart Association (NYHA) class of only 1.16 and no patients in NYHA class>II. No patients reported definite symptoms of angina.

Another important finding is that mortality in the group of patients that could not be contacted (12 patients out of 284, 4.2%) did not differ significantly from that of the contacted patients (X2 [1,n=569]=2.07, p=0.15). These results are depicted in Table 2. Moreover, since INOCA are more frequent in women than (50-70%) we analyzed separately the group of women (results in Table 3). In our study, the subgroup of female patients numbered 101 individuals with a mean age of 69.2 (SD 8.4) years and a mean follow-up time of 5.51 (SD 1.69) years. Mortality was less than 1% (one death from non-cardiac cause, 0.99%) and cardiovascular events during follow-up included one percutaneous revascularization, eight arrhythmic events/interventions and eight hospitalizations. These results are depicted in Table 3. Finally, another noteworthy result is that all the observed myocardial bridges (nine, 3.2%) were in male patients in the course of the left anterior descending artery and were not associated with adverse long-term outcomes (except for mild dyspnea on exertion in two).

In this small retrospective single-center study, we showed that patients with angina and a positive SPECT scan indicating reversible ischemia but no significant epicardial coronary artery disease on coronary angiography have excellent long-term prognosis in subsequent years and very low cardiovascular morbidity and mortality. The particularly long mean follow-up of the study (more than 5.5 years), the evidence of no cardiac deaths, and a very low rate of revascularization during follow-up enhance the value of our results. The fact that mortality in patients lost to follow-up was not significantly different could be considered an indication of similarity between the two groups, at least for major outcomes. The rate of hospitalization for cardiovascular causes during the follow-up period was fairly low, and the majority were related to arrhythmic events and conduction disturbances rather than acute coronary syndromes. Symptoms of heart failure were reported by one in 10 patients, but most of them were in NYHA class I and there were no related hospitalizations. The particularly low number of patients complaining of angina is quite striking, although the questionnaire used is not validated and we cannot exclude the possibility of misinterpretation of symptoms of angina or heart failure.

Our study certainly lacks sufficient data to identify how many of our patients had real dynamic macro- or microvascular impairment, which could explain the positive SPECT scan results, and how many cases were simply artifacts of the SPECT study. However, the very low overall rate of poor outcomes in the majority of patients during a long follow-up period probably renders such a question unnecessary.

Our study had a lower rate of SPECT studies indicative of reversible ischemia but without proven significant CAD on coronary angiography (569 patients out of 1643, 34.63%) than other contemporary studies. Similar rates are reported in early studies of MPS performed in the diagnosis of coronary artery disease, with a significant number of gated SPECT scans and supine and prone acquisitions.13 However, later real-world series report significantly higher rates (over 50%) of false positive scans, raising questions concerning the accuracy of the method for ruling in patients for coronary angiography and the resulting cost of such a strategy. An explanation for the low number of false positive scans in our study could be that we excluded from the analysis all patients with LBBB morphology on the resting ECG before coronary angiography. Furthermore, recent literature suggests that this morphology could be a source of a higher rate of false positive SPECT scans and subsequently misdiagnosis, leading to unnecessary coronary angiograms.11

Our study has several limitations. First, the retrospective nature of the study, and the lack of comprehensive clinical information on the patients’ medical history when they underwent the SPECT scan and the index coronary angiography, deprives us from data regarding the etiology of positive SPECT studies without significant CAD. Second, the considerable number of patients who could not be contacted is an issue that could raise suspicion of higher mortality and/or morbidity and cardiovascular event rate in this group. Nevertheless, the fact that the data, which were obtained from public social security records, did not show statistically significant differences in terms of mortality (irrespective of etiology) is partially reassuring. Another limitation is that follow-up was via telephone contact with a non-validated questionnaire and the accuracy of the answers could be questioned, particularly when quantitative data like NYHA functional class were assessed. We also had no data in our sample regarding the percentage of exercise stress versus vasodilator stress SPECT scans, parameters that are known to affect the sensitivity and specificity of CAD diagnosis in MPS, together with the low percentage of gated SPECT scans. Finally, the limited SPECT scan data regarding the amount and distribution of area at risk in non-revascularized patients, albeit with a diagnosis of positive SPECT, may have contributed to the very low cardiovascular morbidity and mortality in the years following the index coronary angiography.

Finally, we observed very low morbidity and mortality in women participants during more than five years of follow-up. This result is not in accord with other INOCA studies. For example, the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study revealed that the prognosis of women with INOCA is far from benign.14 The small number of women in our study, as well as our inability to determine the reason for positive SPECT studies without significant CAD (artifacts, INOCA or others), may be responsible for this discrepancy with previous data.

MPS is an important step between clinical assessment and coronary angiography for patients with symptoms of angina. In this small retrospective study, we showed that the long-term prognosis for INOCA patients with a positive SPECT scan for reversible myocardial ischemia is excellent as far as cardiovascular morbidity and mortality are concerned. We also demonstrated that excluding patients with LBBB morphology on the resting ECG can improve the diagnostic accuracy of myocardial SPECT scans regarding detection of significant CAD.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors have no conflicts of interest to declare.