Although there have been many studies on INOCA, the pathogenesis, diagnosis, treatment, and prognosis of stable chest pain and INOCA remain very controversial [15]. We used MPI to evaluate INOCA prognoses; after a follow-up of 24.15 ± 1.02 months, about half (83/167) of all patients evidenced abnormal MPI data (SSS ≥ 4). The incidence of MACEs was 3.2-fold higher in the SSS ≥ 4 group than in the SSS 0–3 group. For patients with normal coronary arteries, the incidence was 6.1-fold higher in the SSS ≥ 4 group than in the SSS 0–3 group; for those with non-obstructive coronary arteries, the incidence was 2.4-fold higher in the SSS ≥ 4 group than in the SSS 0–3 group. When the SSS score and CAG data were combined, patients with an SSS score ≥ 4 and non-obstructive coronary artery status evidenced the highest incidence of MACEs (36%). The SSS score and non-obstructive coronary artery status were independent risk factors for MACE.
All included patients with chest pain were normal in CAG but almost half evidenced abnormal SPECT MPI results (Fig. 4) and were at increased risk for adverse cardiovascular outcomes. The reason may be that such patients suffer from coronary microvascular disease and/or epicardial coronary artery spasms that mismatch coronary blood supply and demand [8]. Many recent studies have confirmed that coronary microvascular dysfunction is associated with an increased risk for adverse cardiac outcomes in patients with INOCA [18, 19]. No existing technique directly observes the anatomy of the human coronary artery microcirculation. We found that the incidences of MACEs in patients with SSS scores of 0–3 and SSS scores ≥ 4 were 4.5% and 27.6%, respectively, comparable to those reported by Alqaisi [20] and Liu et al. [21]. The multivariate proportional hazard model showed that every unit increase in the SSS score increased the MACE risk by 12.6%. Thus, even if there is no obstructive coronary artery disease, the probability of MACEs in patients with abnormal SPECT MPI data is still significant, and their prognosis is often worse. All patients were further grouped by their SSS scores (a measure of ischemia severity). The Kaplan-Meier curve showed that the prognosis of the non-ischemia group was the best, and that of the severe ischemia group was the worst, similar to the results of previous studies [22, 23], indicating that the prognosis of INOCA patients is affected by myocardial ischemia and that survival becomes increasingly poorer as ischemia becomes aggravated. Unexpectedly, the prognosis of patients with moderate ischemia was better than that of those with mild ischemia, possibly for the following reasons: after patients with SSS scores ≥ 4 were re-grouped, the sample sizes were greatly reduced; an important index of prognosis is recurrence of angina pectoris symptoms but evaluation is not objective, being largely based on subjective patient reports; and the SSS score is derived via manual semi-quantitative analysis and there is no significant difference between 8 and 9, although such patients belong to different groups. SPECT MPI is demanding in terms of equipment, and on patients and operators; it is less popular than CAG in clinics. Many institutions perform only CAG. However, if patients have clinical symptoms of coronary heart disease, particularly angina pectoris, these should not be taken lightly even if CAG reveals no obstructive coronary heart disease. SPECT MPI evaluates myocardial ischemia status and its severity, assisting in treatment decisions.
Multivariate regression analysis also showed that the risk for MACEs was 2.6-fold higher in patients with non-obstructive coronary arteries than in patients with normal coronary arteries; we thus further examined the prognosis and survival of such patients. Using the CAG data, all patients, and patients with SSS scores of 0–3 and ≥ 4, were divided into normal and non-obstructive coronary artery groups. The survival rates of the non-obstructive coronary artery groups were always lower than those of the other groups. Jespersen et al. [15] showed that, compared to a reference population with no ischemic heart disease, patients with normal coronary arteries but symptoms of angina pectoris, and patients with non-obstructive coronary arteries but symptoms of angina pectoris have an increased risk of MACE by 52% and 85% respectively, and as the extent of vascular stenosis rose, the risk for MACEs and mortality from various causes gradually increased. Another study [24] showed that the risks for repeat CAG examination in patients with normal and non-obstructive coronary arteries were 2.3% and 5.5%, respectively. For each additional segment of non-obstructive coronary artery disease, the mortality rate increased by 6% (95% CI 1–12%, P = 0.021). Both our findings and those described above indicate that even when coronary artery stenosis is less than 50% in INOCA patients, non-obstructive coronary lesions predict an increased risk for adverse cardiovascular outcomes, perhaps because the endothelial function of non-obstructive coronary arteries is impaired and development of atherosclerotic coronary artery disease is thus more likely [25], and/or a non-obstructive coronary artery features diffuse non-obstructive atherosclerosis with “compensatory” coronary remodeling [26] and the normal structure has thus been damaged. For such patients, the rates of re-hospitalization and repeat angiography caused by increasingly problematic symptoms rise, adding to the economic and psychological burdens on patients and their families, social medical pressure, and economic costs. Clinicians must strive to avoid such negative effects.
We combined SSS scores and CAG data to analyze the survival of all patients. The survival curves showed that the early prognosis of non-obstructive coronary artery patients with SSS scores of 0–3 was similar to that of normal coronary artery patients with SSS scores ≥ 4, but over time the prognosis of the latter patients was poorer than that of the former. In other words, in the long run, the predictive power of SPECT MPI was higher than that of CAG. The best prognosis was that for patients with normal coronary arteries and SSS scores of 0–3 (annual survival 100%), whereas patients with SSS scores ≥ 4 had the worst prognosis (annual survival 78.2%); such patients require much more attention than they presently receive. In institutions that prefer CAG, non-obstructive coronary artery lesions should not be ignored; SPECT MPI is essential. A combination of the data of both examinations increased the prognostic accuracy for INOCA patients.
In addition, we found that the proportion of non-obstructive coronary artery patients was higher in the SSS 0–3 group than in the SSS ≥ 4 group. In other words, there was no direct correlation between SSS scores and the extent of coronary artery stenosis in the INOCA patients. Coronary atherosclerosis was not the principal cause of myocardial ischemia in the INOCA patients.
Some limitations to our study should be mentioned. First, we found that drugs did not improve the INOCA prognosis, whereas previous studies have found that statins significantly reduced the incidence of MACEs in INOCA patients [16]. This could have been because of drug non-compliance by our patients, which may have affected our findings. Second, our sample size was small; more patients are required to draw more accurate conclusions. In addition, this was a retrospective single-center study and the results are thus not necessarily generally applicable. There may have been some selection bias. Larger multicenter studies are needed to verify our conclusions. Our average follow-up time was short. Some patients did not develop MACEs; cardiovascular deaths and nonfatal myocardial infarctions were rare.
we not only confirmed the prognostic utility of SPECT MPI in patients with INOCA but also combined SPECT MPI and CAG data to develop a new and accurate risk-stratification method for INOCA patients. We found that SPECT MPI yielded valuable prognostic information on INOCA patients, identifying those at higher risk. By measuring the response to myocardial perfusion, SPECT MPI identifies myocardial ischemia, and its location and severity, and also comprehensively evaluates coronary artery anatomy and function. The long-term predictive efficacy of the data is even higher than that of CAG data. The combination of the two datasets enhanced the accuracy of INOCA patients’ risk stratification.
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