In patients with non-obstructive CAD, minor elevation of hs-cTnI was associated with impaired myocardial perfusion as measured by quantitative MCE; both of them independently affect prognosis; low-level hs-cTnI elevation predicts adverse events independent of myocardial ischemia due to microvascular dilation dysfunction.
4.1 Mechanisms affecting hs-cTnI levels
Studies have shown that in an animal experiment in which diabetes, hyperlipidemia and chronic kidney disease were combined with a swine model to simulate ischemia and non-obstructive CAD, even if there was no obvious structural change and overt atherosclerosis, increased coronary blood flow at baseline rather than changes in maximum blood flow after hyperemia resulted in decreased adenosine recruited myocardial perfusion, and in this setting, CMVD is severe enough to produce perturbations in myocardial oxygen balance, resulting in a mismatch between supply and demand. 
Clinical studies  and animal experiments  have shown that the pro-inflammatory environment created by comorbidities such as hypertension, diabetes and dyslipidemia may contribute to CMVD by promoting microvascular inflammation and rarefaction, and ultimately lead to adverse left ventricular remodeling, cardiometabolic dysfunction, and extracellular fibrosis.
All of these may increase coronary microvascular resistance and cardiomyocyte burden,  further aggravate endothelial dysfunction and subendocardial ischemia , leading to mild cardiomyocyte injury.
Our previous studies have shown that comorbidities such as hypertension, diabetes and dyslipidemia are prone to CMVD.  In this study, non-obstructive CAD patients had a relatively high incidence of comorbidities, which may lead to CMVD and reduced myocardial perfusion. The impaired myocardial perfusion further leads to a low level of hs-cTnI elevation.
4.2 Hs-cTnI and cardiovascular events
In the present study, minor myocardial injury in patients with non-obstructive CAD was associated with events independent of impaired myocardial perfusion as measured by quantitative MCE. There was no significant interaction between impaired myocardial perfusion and detectable hs-cTnI on cardiovascular events. These results may suggested that the effect of minor elevated hs-cTnI on cardiovascular events in patients with non-obstructive CAD may have a mechanism other than ischemia.
A slight increase in hs-cTn may exhibit the biochemical characteristics of early subclinical heart disease and is associated with surrogate fibrosis and progressive changes in left ventricular structure, and is therefore strongly associated with an increased risk of heart failure (HF),
Recent studies have shown that in adults without overt cardiovascular disease, a small increase in hs-cTnT at baseline is related to replacement fibrosis and changes in left ventricular structure, and ultimately contributes to HF, a process independent of ischemia-induced subendocardial fibrosis. Hs-cTnI has a worse prognosis in heart failure patients with preserved ejection fraction than in patients with reduced ejection fraction. These findings suggest that increased TnI may reflect cardiomyocyte loss secondary to chronic inflammation or other unknown, ischemia-unrelated pathologies in patients with preserved ejection fraction.
As shown in this study, in patients with non-obstructive CAD, even though hs-cTnI changes are within the normal measurement range, there is a high-risk population for progression to non-fatal myocardial infarction and cardiovascular death. Therefore, we believe that hS-CTNI levels can be used for preventive intervention in high-risk populations. For example, therapeutic trials based on Tn levels, remodeling and fibrosis could be considered as early interventions to prevent symptomatic HF progression.
4.3 Study limitations
This study has a number of limitations. First, this is a single-center retrospective study. Larger multicenter prospective studies are needed to further elucidate the mechanism and prognostic significance of minor elevated hs-cTnI in patients with non-obstructive CAD. Second, the quantitative MCE has not been validated against the gold standard for CMVD in patients. However, many studies have applied quantitative MCE to estimate myocardial blood flow [6,7] and compared it with CFR measured by transthoracic doppler ultrasound, showing that quantitative MCE parameters have good predictive value.  Third, lost to follow-up percentage is slightly higher (11.2%), which may have a certain impact on the follow-up results.