Patients with chest pain undergoing invasive coronary angiography are found to have normal-appearing coronary arteries (defined as lesions < 50%) up to 60% of cases5. In a substantial proportion of these patients, angina symptoms are due to other underlying mechanisms, different from coronary artery narrowing, including CMD6,7.
CMD can be detected by non-invasive tools, such as PET imaging, dipyridamole stress echocardiography, and other emerging imaging modalities in this field, like cardiac magnetic resonance and computed tomography1. In the present study, the non-invasive parameter chosen to identify CMD was the reduced CFR evaluated by dipyridamole stress echocardiography. The use of dipyridamole allowed to obtain good quality images at peak hyperemia, avoiding an excessive increase in heart rate, which would have affected speckle tracking analysis.
CFR is dependent on the combined effects of epicardial coronary stenosis and CMD. In the absence of obstructive coronary artery narrowing, impaired CFR reflects the presence of microvascular dysfunction. Therefore, CFR can be useful to assess CMD in patients with chest pain but no obstructive CAD8. According to both 2019 European guidelines for diagnosis and management of chronic coronary syndromes9 and 2021 American guidelines for the evaluation and diagnosis of chest pain10, a non-invasive measurement of CFR by means of transthoracic echocardiography and vasodilatory stress is advised in patients with suspected ischemia and no obstructive coronary artery disease (INOCA), with class of recommendation IIb.
Patients with CMD have traditionally been considered at “low-risk”. However, this issue remains controversial. This population is heterogeneous, including truly normal, smooth coronary arteries, and mild or moderate, isolated or multiple, single or multivessel non-significant coronary stenosis. It is reasonable to expect a less benign prognosis for patients with coronary disease, even if non-significant. Moreover, it has been shown that patients with chest pain and non-obstructive CAD are predominantly women, and their risk of cardiac events is higher when compared to asymptomatic subjects11,12. Supporting this finding, the WISE study demonstrated that women with reduced CFR assessed by adenosine, had increased risk of major adverse outcomes (including cardiac death, stroke, and new onset of heart failure) over a 5.4-year follow-up period13.
In the absence of obstructive CAD, CMD do not normally give rise to regional wall motion abnormalities during stress, even when ST-segment changes and positive perfusion scan are present14–19. However, it has been proven that impaired CFR in the LAD evaluated by dipyridamole stress echocardiography is associated with a less benign long-term outcome and a higher risk of hard events in patients with known or suspected CAD and negative stress echocardiography by wall motion criteria20,21.
CMD may contribute to subtle changes in myocardial contractile function, non-detectable with the traditional indices of LV systolic function. LV contractile dysfunction becomes more apparent using GLS, a parameter of myocardial deformation which is able to detect subclinical systolic impairment when LVEF is still normal.
The overall population of this study shows a negative stress echocardiography by traditional wall motion criteria; however, GLS at baseline is significantly lower in patients with impaired CFR if compared to controls, reflecting the presence of a LV subtle contractile dysfunction in case of CMD. A previous study by Michelsen et al.22 found no association between baseline GLS and CFR in women with angina and non-obstructive CAD. Similarly, Rodriguez-Zanella et al.23 recently found no significant difference in rest GLS between patients with and without CFR. However, the hypothesis of subclinical contractile dysfunction in patients with CMD cannot be excluded, since that microvascular dysfunction is one of the known mechanisms of myocardial ischemia, and that these patients show a poorer prognosis.
A novel finding emerging from the present study it the opposite response to dipyridamole stress echocardiography observed between the two groups. In particular, patients without CMD exhibit a certain contractile response to hyperemic stress evaluated by STE (mean improvement in GLS, % -1.18 ± 0.84). Conversely, a significant impairment in GLS from rest to peak dose is observed among patients with CMD (Δ GLS, % +1.04 ± 0.82), which could be explained by a supply/demand mismatch of myocardial perfusion during stress22,24. The linear correlation analysis between CFR and Δ GLS confirms these data: as the CFR increases, the LV contractile reserve improves, and viceversa (Fig. 3).
The results of the present study are in agreement with the data emerging from a recent study by Jovanovic et al25., who demonstrated that CFR, resting, peak, and Δ GLS were all markedly impaired in a population of 70 women with cardiac syndrome X compared to controls.
In conclusion, rest GLS and GLS response to dipyridamole stress are impaired among patients with chest pain syndrome, non-obstructive CAD and CMD, reflecting subclinical LV systolic dysfunction and lack of LV contractile reserve due to underlying myocardial ischemia.
The main limitation of this study is that it has been carried out in a single center, and the sample size is too small to drive definitive general conclusions. Further and larger studies are needed to clarify the association between baseline GLS and CFR, and to explain the mechanisms underlying the association between GLS reserve and CMD.
Moreover, it would be interesting to follow the study population over time in order to establish if GLS at rest and after dipyridamole stress echocardiography may be further useful tools to stratify the cardiovascular risk and choose the best therapy in patients with CMD.