Our study found that individuals with CMD tend to have lower levels VO2peak and peak O2-pulse, and higher levels of VE/VCO2 slope in STEMI patients with complete revascularization after primary PCI. Correlation analysis also showed that coronary microvascular function assessed by AccuIMR had a significant linear relationship with these cardiorespiratory fitness parameters, and it was independently associated with decreased cardiorespiratory fitness, abnormal ECG stress test (EST) results and early O2-pulse flattening.
Coronary microvascular dysfunction assessment in patients with STEMI
Strong evidence supports the use of the IMR to assess coronary microcirculatory function in patients with STEMI. This objective and accurate coronary functional index for detecting CMD can predict the development of adverse events in patients with STEMI after primary PCI [12, 13]. However, the additional use of pressure-temperature sensor wires and hyperemic drugs, which would prolong the procedure time and usually induce a hypotensive response, limits the adoption of wire-based IMR in daily practice, particularly in patients with acute STEMI. Recent technological advances have made it possible to derive the IMR from coronary angiography without the need for using pressure wires or hyperemic drugs [14–16], which would expand the use of IMR in everyday clinical practice.
A recent study that used the same software and methodology as the present study to calculate AccuIMR showed that, in patients with STEMI, NSTEMI, and chronic coronary syndrome (CCS), the AccuIMR correlated well with conventional IMR (STEMI: r = 0.78, P < 0.001; NSTEMI: r = 0.78, P < 0.001; CCS: r = 0.75, P < 0.001) [8]. This study also showed that AccuIMR had good diagnostic performance in detecting abnormal IMR (overall diagnostic accuracy, sensitivity, and specificity were 94.83% [91.14–97.30%], 92.11% [78.62–98.34%], and 95.36% [91.38–97.86%], respectively). Using IMR > 40 U as the cutoff value for AccuIMR, the AUC of AccuIMR for predicting abnormal IMR values was 1.000 (0.937–1.000) in patients with STEMI [8]. In this case, we used the AccuIMR as a fair criterion for the assessment of CMD, with a cutoff value of 40 U.
Relationship between coronary microvascular function and CPET parameters
As cardiac rehabilitation progresses, the focus is increasingly on improving the overall cardiovascular fitness of patients with cardiovascular diseases. The treatment of cardiac patients now involves more than revascularization procedures, such as PCI or CABG and drug therapy. For individuals with coronary artery disease, particularly those with serious cases who have experienced STEMI, it has become increasingly important to assess cardiopulmonary function, develop exercise training programs, and plan other follow-up treatments, using CPET as part of disease management.
Our study found that patients with STEMI after primary PCI had lower VO2peak and peak O2-pulse and a relatively high VE/VCO2 slope if they had CMD. AccuIMR had a significant relationship with these parameters according to the correlation analysis. Multivariable logistic analysis also showed that AccuIMR was independently related with reduced VO2peak, elevated VE/VCO2 slope and ischemia-related indicators.
Cardiorespiratory fitness, which is typically defined by VO2peak, measured during maximal CPET, is an important sign in both healthy and diseased populations because of its strong prognostic value [3, 17, 18]. Previous research has demonstrated that patients with no obstructive coronary artery and CMD diagnosed by echocardiographic assessment of coronary flow velocities in the LAD, had a lower VO2peak, which indicated reduced exercise capacity [19]. Li et al. also found that patients with ischemic heart disease (IHD) had lower peak oxygen uptake and cardiac output than the healthy population, and similar outcomes were observed in the IHD patients with non-obstructive coronary artery after adjusted analysis [20]. Patients with epicardial coronary obstruction or microvascular obstruction may show a similar response on CPET despite different coronary catheterization findings [21], therefore, the value of CPET assessment of patients with complete revascularization after PCI is also of particular importance in terms of the value of the disease and prognosis. Previous studies have generally concluded that abnormal coronary microvascular dilatation and coronary microvascular spasm are pathogenic mechanisms in chronic and acute ischemic heart disease [22, 23]. We obtained a similar result in this study that in patients with STEMI with complete revascularization, the VO2peak was lower along with the LVEF, and VO2peak had a significant linear correlation with AccuIMR. Moreover, AccuIMR was the independent predictor of reduced VO2peak, which further demonstrated the influence of AccuIMR on the cardiorespiratory function. Therefore, it is reasonable to hypothesize that microvascular ischemia due to CMD can lead to impairment of cardiac function, which in turn leads to a decrease in VO2peak.
The VE/VCO2 slope, at which ventilation increases with increasing CO2 production, reflects ventilatory efficiency. An increase in the VE/VCO2 slope indicates an abnormal ventilatory response to exercise and has been used as a prognostic indicator of chronic cardiopulmonary disease, relatively independent of other CPET-derived variables, such as VO2peak. In patients with heart failure, ventilatory inefficiency, as suggested by an increased VE/VCO2 slope, characterizes those with more severe heart disease. Thus, this is considered an independent marker of event-free survival [24, 25]. To date, few studies have addressed the relationship between coronary microcirculation and ventilation efficiency. Our study showed that the VE/VCO2 slope was elevated in STEMI patients with CMD as compared to those without CMD, and it had a linear correlation with IMR. Moreover, AccuIMR was independently related to the elevated VE/VCO2 slope. Previous studies have shown that an IMR > 40 is an independent predictor of heart failure readmission in patients with STEMI [9, 13]. Individuals with CAD tended to have higher VE/VCO2 slopes than did those without CAD [26]. Dominguez-Rodriguez et al. also showed that the VE/VCO2 slope predicts perfusion defect in subjects with chest pain and suspected CAD (AUC 0.89, 95%CI 0.80–0.97, P < 0.0001) [27]. In this context, we thought that patients with CMD have worse ventilatory efficiency, and the higher the microcirculatory resistance, the worse the ventilatory inefficiency. Poor ventilatory efficiency in patients with STEMI with CMD may suggest poor cardiac function, which might explain the possible mechanism by which microvascular dysfunction affects prognostic events.
Peak O2-pulse is a crucial indicator of the state of cardiac, vascular, and pulmonary function. It reveals the overall efficiency and interaction of the respiratory and cardiovascular systems and has a significant correlation with cardiovascular function. It is an important tool for assessing cardiovascular health [28]. Our study showed that STEMI patients with CMD had a lower peak O2-pulse, suggesting a worse cardiac function. Munhoz et al. suggested that peak O2 pulse, when used as a supplement to peak oxygen uptake, could better reflect cardiovascular functional status and efficiency and assess cardiorespiratory fitness more accurately[29, 30]. They also found that peak O2-pulse correlated with the severity of myocardial ischemia during exercise [30]. Laukkanen et al. followed 2227 middle-aged men for 26 years and found that peak O2-pulse was negatively correlated with the morbidity of cardiovascular disease as well as all-cause mortality[31]. Our study also showed a negative linear correlation between peak O2-pulse and IMR in STEMI patients, which supported the existence of exercise-induced myocardial ischemia in the region innervated by the microcirculation, which in turn leads to a reduction in peak O2-pulse. But further multivariable analysis showed that AccuIMR was not the independent predictor of reduced peak O2-pulse, which may be because that the effect of microvascular function on cardiac function may not yet be at the level of the currently defined reduced peak O2-Pulse, and further studies are needed in the future to determine the quantitative effect of microcirculatory function on O2-pulse.
Ischemia-related indexes and CMD in STEMI patients with complete revascularization after primary PCI
EST specifically detects myocardial ischemia during exercise. However, in practice, a significant proportion of patients with positive results lack significant stenosis in the epicardial coronary arteries, as confirmed by angiography. Previously, with insufficient awareness of CMD and lack of detection of related markers, these positive ECG results were usually considered to be false positives. With the increasing use of coronary microcirculation testing, more studies are focusing on the effects of ischemia on coronary microcirculation. Our study also showed that both positive and equivocal EST results are highly specific to the microcirculatory impairments in patients with STEMI with complete revascularization. In STEMI patients with CMD, the positive rate was significantly high, and logistic regression analysis also showed that AccuIMR was the only significant predictor of abnormal EST results. Currently, coronary CTA is the first-line test in patients with chest pain associated with suspected myocardial ischemia, by global consensus. Therefore, EST can be used as a second-line option for noninvasive testing and may help optimize the diagnostic timing and process of CMD according to our findings. Additionally, our research suggests that, for patients with STEMI who continue to experience chest pain after PCI, or for those in whom conditions for invasive coronary functional tests are inadequate, CPET can be used to assess the presence of CMD specifically based on EST results, which can help avoid readmission and repeat coronary angiography. Moreover, CPET can be used to assess the response to therapy in patients diagnosed with CMD.
Previous studies have reported the diagnostic accuracy of positive EST results for detecting CMD, with reliable specificity but with poor sensitivity [32, 33]. In our study, the negative results in the CMD group, which may be referred to as the false negative rate, also remained high. This phenomenon may be due to that the myocardial consequences of coronary blood flow abnormalities related to CMD differ from those of epicardial flow-limiting stenosis. In the latter, the myocardial perfusion impairment is distributed in the region perfused by the obstructed artery, resulting in segmental impairment of wall contraction. In contrast, myocardial ischemia in CMD may not involve all microvasculature originating from the epicardial artery but may have a patchy distribution. This pathophysiological feature could explain why patients with CMD may have symptoms of ischemia without ECG abnormalities [34] and may be the reason for the poor sensitivity noted in our study. Vandeloo et al. reported in their study that, compared to using quantitative coronary angiography and fractional flow reserve (FFR) as references for determining ischemia, using FFR and IMR as references would have a lower false discovery rate (60.7% vs. 45.8%; p = 0.006) [33], which indicated the importance of microcirculatory dysfunction in contributing to myocardial ischemia. Instead of using 25 as the IMR cutoff value for the diagnosis of CMD in their study, we used a cutoff of 40, which was a widely accepted criterion for patients with STEMI, and has been proven to have a better prognostic value [9, 12, 13]. Additionally, we excluded patients with incomplete revascularization; therefore, the positive EST results in our study were only related to microvascular dysfunction, without being affected by epicardial coronary artery obstruction, which makes our findings more reliable for CMD-related ischemia detection.
The early O2-pulse flattening observed during exercise indicated a limitation in adequately increasing the stroke volume response. This condition often suggests an inability to amplify stroke volume, which is indicative of exercise-induced cardiac dysfunction that may arise from ischemia. This is a firm and sensitive index for assessing and quantifying myocardial ischemia [30, 35, 36]. We found that similar to the EST results, the occurrence rate of early O2-pulse flattening in patients with CMD was much higher than in the Non-CMD group, and IMR was found to be the only significant factor of early O2-pulse flattening. This finding was complementary to EST for detecting myocardial ischemia, particularly caused by CMD.
These results of ischemia-related parameters further proved that patients with CMD had certain myocardial ischemia which is noninvasively detectable, suggesting an ischemia-related mechanism for the effects of CMD on cardiopulmonary fitness.
Study limitations
This study has a few limitations. We only measured the functional indexes of the IRAs in STEMI patients in this study, future analysis of the index of non-IRAs is needed to confirm the results. Furthermore, our study only focused on STEMI patients with primary PCI. Studies of other coronary heart diseases are needed in the future to confirm the results.