In the last century or so, it has been accepted that obstructive lesions of the epicardial vessels are the main cause of angina pectoris. 1974, Gould KL and Lipscomb K found that blood flow was significantly reduced only when the coronary artery diameter stenosis was >80%, and when coronary blood flow was increased 4-5 times by preemptive use of small artery dilators and then ligated, the coronary artery diameter The blood flow was already significantly reduced when the stenosis was >50%. This experiment gave rise to the concept of coronary flow reserve, which was rapidly translated into clinical concepts: a stenosis of ≥50% of coronary artery diameter is a hemodynamically significant stenosis, and ≥85% is a critical stenosis, which in turn was quickly translated into the concept of ischemic stenosis. Therefore, in the past 40 years, clinical cardiologists have formed a consensus that coronary artery diameter stenosis ≥ 50% is diagnosed as coronary artery disease, and critical stenosis of ≥ 85% can cause myocardial ischemia and therefore should be treated with interventional therapy. However, with the popularization of interventional coronary diagnostic and treatment techniques, it has been found that many patients with evidence of myocardial ischemia have coronary angiography showing nonobstructive lesions of the coronary arteries, i.e., nonobstructive coronary artery disease (CAD).
I. Concept of non-obstructive coronary artery disease
The so-called non-obstructive coronary artery disease is defined as non-obstructive coronary artery disease with 1% to 49% diameter stenosis in one or more vessels, and obstructive coronary artery disease with ≥50% diameter stenosis in one or more vessels. The investigators collected data on coronary heart disease from the U.S. Veterans CART program, which includes coronary angiography and long-term follow-up results. A total of 37,674 patients who underwent elective angiography between 2007 and 2012 were included, and 55.4% were found to have obstructive coronary artery disease and 22.3% had nonobstructive coronary artery disease. the results of the WISE study suggested that 60% of patients with evidence of ischemia due to chest pain or noninvasive findings did not have coronary obstruction affecting blood flow (≥50% stenosis in at least ≥1 main branch).
It has long been assumed that in patients with angina, those with normal or <50% stenosis on coronary angiography are at low risk and have a good prognosis. However, recent long-term follow-up studies of large populations have disproved this traditional view. jespersen L et al. followed 11,223 patients with stable angina who underwent coronary angiography and 5,705 asymptomatic controls for a mean of 4.6 years and found that the rate of cardiovascular events was significantly higher in patients with normal or <50% stenosis on coronary angiography than in controls. lin FY et al. followed 2583 patients who underwent 64-row CT coronary angiography for angina symptoms or cardiovascular risk factors for 3.1 years and found that all-cause mortality was significantly higher in patients with coronary stenosis <50% measured by CT than in patients without coronary stenosis on CT. The US Veterans CART study found that the incidence of myocardial infarction at 1 year was 0.11% in patients without coronary artery disease, 0.24% in patients with non-obstructive coronary artery disease with 1-vessel disease, 0.56% in those with 2-vessel disease, and 0.59% in those with 3-vessel disease. In patients with obstructive coronary artery disease, the risk of myocardial infarction increased as the number of diseased vessel branches (or lmca) increased. Mortality at 1 year was 1.38% in those without coronary artery disease and 2.02%, 1.50%, and 2.72% in patients with nonobstructive coronary artery disease with 1-, 2-, and 3-vessel lesions, respectively. In a multivariate-adjusted model, nonobstructive coronary artery disease with only 3-branch lesions was associated with an increased risk of death at 1 year. These studies suggest that a degree of coronary stenosis <50% cannot be used as an indicator of whether a patient has a good prognosis.
In recent studies, it has been found that ischemic heart disease can also be caused by nonobstructive coronary artery disease. Lin F et al. performed multi-row coronary CT angiography and SPECT stress test in 163 patients with angina pectoris and found that 105 patients had mild coronary stenosis and 39 had significant coronary stenosis but only 15 had flow-limiting stenosis with normal stress test results, suggesting that the association between stenotic lesions and ischemic heart disease is not consistent. Pathologic studies have confirmed that the onset of acute coronary syndrome (ACS) is not due to oversized plaques obstructing the lumen, but rather to rupture or erosion of vulnerable plaques secondary to intraluminal thrombosis. A pathology study found that 90% of patients with acute or chronic ischemic heart disease were caused by critical coronary stenosis. It found that 30.6% of 212 patients with ACS had normal or near normal coronary angiograms. the GUSTO IIb trial, published in 1999, performed coronary angiograms in 12,142 patients with ACS and found that 6.8% of men and 10.2% of women with ST-segment elevation myocardial infarction, 4.2% of men and 9.1% of women with non-ST-segment elevation myocardial infarction, and 13.9% of men and 30.5% of women with unstable angina with non-obstructive stenosis on coronary angiography. Studies to identify the characteristics of non-obstructive coronary artery infarction (MINOCA) are also ongoing. The investigators used a meta-analysis to assess the prevalence, clinical characteristics and prognosis of MINOCA in 28 relevant papers. The results showed that the prevalence of MINOCA was 6%, with a patient age (median) of 55 years and 40% of women. However, compared with patients with obstructive coronary artery disease-type heart attack (MI-CAD), patients with MINOCA were more likely to be younger and female and less likely to have hyperlipidemia, despite similar other cardiovascular risk factors. 12-month all-cause mortality was lower in patients with MINOCA than in patients with MI-CAD (4.7% versus 6.7%). In addition, quantitative evaluation of 46 papers on the underlying pathophysiological mechanisms of MINOCA showed that cardiac magnetic resonance imaging detected 24%, 33%, and 26% of typical infarcts, myocarditis, and no significant abnormalities, respectively. Coronary artery spasm was induced in 27% of patients with MINOCA, as well as a propensity for thrombosis was detected in 14% of patients.
The underlying causes of nonobstructive coronary artery disease are numerous and in many cases differ from those of obstructive coronary artery disease. Some patients have macrovascular dysfunction with spastic angina, others have coronary microvascular dysfunction. the results of the Fearon et al. study found that occult coronary artery abnormalities could be observed in the majority of patients with non-obstructive coronary artery disease but presenting with angina. In 139 patients (mean age 54 years, 3/4 female), 77% of angina patients had coronary artery disease, 44% had endothelial dysfunction, 21% had microvascular disease, 5% had flow reserve fraction ≤0.8, and 58% had myocardial bridges. the WISE study found that nearly 50% of women without coronary obstructive chest pain presented primarily with coronary microvascular dysfunction (MCD Lee et al. found that although coronary angiography showed <50% stenosis, 44% of patients had endothelial abnormalities, 5% had ffr ≤0.8 suggesting myocardial ischemia, and 21% had a coronary microvascular resistance index ≥25, indicating microvascular dysfunction. < span="">
In 2013, the ESC redefined stable coronary artery disease (SCAD) to include obstructive coronary artery disease (≥50% stenosis of coronary artery diameter) and nonobstructive coronary artery disease including coronary artery spasm and microvascular dysfunction as common mechanisms of SCAD. Microvascular dysfunction has attracted increasing attention from both domestic and international scholars.
Coronary microangiopathy does not present with the overall morphological changes of atherosclerosis, but is closely associated with vascular motility, growth, permeability abnormalities, and inflammation occurrence. Traditional risk factors for coronary artery disease include: hyperlipidemia, hypertension and diabetes mellitus can all lead to coronary microvascular dysfunction, which includes structural changes in the microvasculature that can lead to dysfunction. The following factors can disrupt the microvascular structure and cause microvascular dysfunction: (1) microcirculatory lumen obstruction due to acute coronary syndrome or microembolism after revascularization; (2) increased permeability of the microvascular wall due to infiltrative heart disease; (3) microvascular remodeling due to hypertrophic cardiomyopathy and hypertension; and (4) vascular thinning and perivascular fibrosis due to aortic stenosis and pulmonary hypertension. Postmenopausal women mostly have risk factors such as hypertension, diabetes, metabolic syndrome and obesity, and the coronary small vessel plaque load is heavier than men, which is more likely to cause microvascular dysfunction. Microvascular dysfunction can be caused by smoking, hyperlipidemia, vascular endothelial dysfunction and hypertrophic cardiomyopathy caused by diabetes, smooth muscle cell dysfunction caused by hypertension and vegetative nerve dysfunction after coronary revascularization. Pregnancy-related hypertension and metabolic disorders in women can also cause endothelial dysfunction and increase the risk of coronary heart disease. Extravascular factors such as aortic stenosis, extramural compression due to hypertrophic cardiomyopathy and shortened diastolic perfusion time due to aortic stenosis are causes of microvascular dysfunction.
Second, the diagnosis of non-obstructive coronary artery disease
If a patient has angina symptoms and abnormal ECG manifestations, and coronary angiography does not show obstructive disease, non-invasive tests should be performed in patients with non-obstructive coronary artery disease. Non-invasive tests include: electrocardiographic exercise test, echocardiographic stress test, and radionuclide imaging stress test to observe the degree and extent of myocardial ischemia. With the rapid spread of coronary angiography and multi-row CT angiography, the three aforementioned stress tests in many hospitals have almost come to a halt, and this state of affairs must change. The majority of cardiologists must be made aware that the plaque lesion and myocardial ischemia revealed by angiographic techniques are not the same concept, and that speculation of the latter by the former will lead to misdiagnosis and mismanagement.
Among the criteria for diagnosing microvascular dysfunction, endothelial function and coronary flow reserve (CFR) are assessed in patients by intracoronary Doppler flow velocity analysis.CFR is the ratio of the maximal filling state of coronary blood flow in response to adenosine to the basal state of blood flow, and a consistent reduction in intra-myocardial flow reserve (i.e., consistency of microvascular abnormalities) can indirectly reflect impairment of coronary microcirculatory function. It was found that when CFR <2.0 indicates coronary microvascular dysfunction. The flow reserve fraction (FFR) assay is a parameter to evaluate the physiological function of coronary lesions based on intracoronary pressure measurements, and when FFR≤0.8 indicates myocardial ischemia and the presence of microvascular dysfunction. It was shown to correlate well with true microvascular r esistance (TMR) in animal models. Subsequently, a good correlation with TMR was also confirmed in patients with stable coronary artery disease and in STEMI patients undergoing emergency PCI. The presence of microvascular dysfunction was found to be suggested when the coronary microvascular resistance index was ≥25.
Other ancillary tests include: cardiovascular magnetic resonance imaging (CMRI): This provides information on cardiac anatomy, myocardial perfusion and metabolism, ventricular function, and coronary imaging simultaneously, and is a more reliable method for evaluating myocardial perfusion deficits. Other non-invasive tests include positron emission computed tomography (PET), gated scintigraphy, etc.
Progress in the treatment of non-obstructive coronary artery disease
Several studies have pointed out that an aggressive prevention and treatment strategy should be developed for nonobstructive coronary artery disease, thus reducing coronary events and mortality in patients with coronary artery disease is crucial. In addition to aggressive lifestyle improvement, risk factors should be strictly controlled. For those with significant angina symptoms, pharmacological interventions should be actively given to reduce angina attacks. Active pharmacological interventions should also be carried out for the secondary prevention of coronary heart disease.
1.Control of risk factors
1.1 Hypertension: It was found that in patients with non-obstructive CAD combined with hypertension, the application of anti-hypertensive drugs can effectively improve microvascular dysfunction. ACEI and ARB drugs were found to improve endothelium-dependent microvascular dysfunction, while dihydropyridine CCB was not found to have this function. One study showed that non-dihydropyridine CCBs such as verapamil were able to improve microvascular dysfunction.
Beta-blockers: Nebivolol exerts endothelial protection by activating beta3 receptors and has a role in the treatment of non-obstructive coronary artery disease. Carvedilol has a beneficial effect on microvascular lesions due to its alpha-blocking effect. These microangioprotective effects were not seen in metoprolol and atenolol.
The protective effect of antihypertensive treatment on endothelium-dependent microvasculature is less studied. One PET study showed that olmesartan increased CFR and improved microcirculatory dysfunction, whereas amlodipine did not have this effect. Another study showed that although verapamil and enalapril were similar in their antihypertensive effects, the former was able to significantly improve endothelial function, which in turn improved microvascular function. These studies suggest that improved microvascular function is an effect beyond the antihypertensive effect of antihypertensive drugs. Possible mechanisms include direct effects on vascular smooth muscle cells, antioxidant effects, improvement of endothelial function and diastolic function of blood vessels, as well as effects on improving the function of the autonomic nervous system. Notably, recent studies have revealed that the presence of decreased CFR in hypertensive patients is highly correlated with the presence and extent of left ventricular hypertrophy, suggesting that microvascular dysfunction is an inevitable consequence of left ventricular remodeling and altered endothelial and smooth muscle cell function.
1.2 Hyperlipidemia: Recent studies have shown that the application of atorvastatin can significantly improve CFR in patients with hyperlipidemia, suggesting that statins can improve endothelium-dependent microvascular function in patients. Although some studies have found that statins can significantly improve endothelium-dependent diastolic function in large coronary and peripheral vessels, there is a lack of systematic and larger studies to confirm whether statins can improve microvascular function. For the mechanism of action of statins to improve microvascular dysfunction, in addition to their lipid-regulating effects, effects other than lipid-regulating effects such as anti-inflammatory and antioxidant effects may play a role.
1.3 Diabetes mellitus: Compared with studies on hypertension and hyperlipidemia, there are relatively few studies on glycemic control and improvement of microvascular dysfunction in patients with diabetes mellitus. The application of euglycemia or glimepiride combined with metformin in type 2 diabetic patients was found to significantly improve their endothelial function and increase coronary CFR. insulin application in type 1 diabetic patients was able to increase CFR, and its long-term efficacy remains to be seen.
1.4 Other risk factor control: Late studies have found that weight loss in obese patients leads to an increase in coronary flow induced by dipyridamole and that this improvement is associated with an increase in adipocytokines. Coronary flow reserve was significantly decreased in smokers, and vitamin C resulted in a significant improvement in CFR in smokers.
2. Control of angina symptoms
For patients with non-obstructive stable coronary artery disease with angina symptoms, pharmacological treatment should be considered to reduce angina symptoms and improve patients’ quality of life.
2.1 Beta-blockers: Since beta-blockers can inhibit sympathetic excitation, slow down heart rate, reduce myocardial oxygen consumption and increase coronary perfusion, they play an important role in anti-angina, especially for patients with increased sympathetic activity or faster heart rate. Some studies have found that beta-blockers reduce angina symptoms and decrease the duration and number of ST depressions on 24-hour ambulatory electrocardiograms in patients with non-obstructive coronary artery disease combined with microvascular lesions compared with placebo or other drugs. Some studies have also found that the beta-blocker atenolol is effective in reducing the frequency of angina attacks in patients with cardiac X syndrome.
2.2 Calcium channel blockers: Calcium channel blockers are recommended in large-vessel spasm angina. A study of patients with vasospastic angina, which began in 1988, showed that calcium channel blockers improved the quality of patient survival and that patients did not develop infarction.Ohba K et al. found that calcium channel blockers significantly reduced angina symptoms in patients with microvascular spastic angina and that there were no adverse cardiovascular events during the 47.8±27.5 months of follow-up. In patients with non-obstructive coronary artery disease combined with microangiopathy, non-dihydropyridine drugs such as diltiazem are currently recommended for anti-anginal therapy. The combination L- and T-type calcium channel blocker, miradil, may reduce the frequency of angina in patients with coronary artery flow slowing syndrome.
2.3 Nitrates: Nitrates are widely used in the treatment of angina pectoris in coronary artery disease because of their ability to dilate veins to reduce cardiac preload and dilate coronary arteries. However, in patients with non-obstructive coronary artery disease combined with microangiopathy and coronary spasm, sublingual administration of short-acting nitrates has limited effect. In a Japanese observational study of 1429 patients with vasospastic angina, no difference was found in the effect of nitrate administration with or without nitrate on major adverse cardiovascular events (HR = 1.28; 95% CI, 0.72-2.28). The application of nitrates in combined microangiopathy is sometimes less effective, mainly because nitrates have a limited and sometimes counterproductive effect on microvascular dilatation, mainly because nitrates sometimes lead to the development of hypotension, while activating the sympathetic nervous system and increasing the heart rate. Intravenous or intracoronary nitrate injections have been reported to reduce CRF.
2.4 Nicorandil: With its role as an ATP-sensitive potassium channel opener and nitrate-like effects, it can effectively dilate coronary resistance vessels and is effective in the treatment of angina pectoris in patients with non-obstructive coronary artery disease combined with microangiopathy. The JCAD study found that nicorandil significantly reduced all-cause mortality in stable angina by 35% and reduced cardiovascular mortality by 56%. The study found that intracoronary nicorandil reduced the incidence of no-reflow in ACS and non-ACS patients, and that nicorandil improved microvascular function in patients with stable coronary artery disease.Yamabe et al. found that oral or intravenous administration of nicorandil for 2 weeks significantly reduced the duration and number of ST depressions on 24-hour ambulatory electrocardiograms and reduced the duration of angina symptoms.
2.5 Ivabradine: Ivabradine (ivabradine) is the first selective and specific cardiac pacing current (If) inhibitor with specific heart rate lowering effects. Clinical studies have demonstrated its efficacy and safety in the treatment of stable angina pectoris. Ivabradine improved angina symptoms and changes in ECG ischemia in patients with obstructive coronary artery disease, while in patients with non-obstructive coronary artery disease, only one study showed that ivabradine was able to improve angina symptoms in patients with non-obstructive coronary artery disease combined with microangiopathy compared to placebo.
2.6 Trimetazidine: Trimetazidine inhibits β-oxidation of free fatty acids, resulting in a reduction in free fatty acid metabolism, thus allowing the myocardium to produce energy primarily from glucose metabolism, which in turn improves angina symptoms by producing more ATP and inhibiting acidosis and calcium overload. In a double-blind controlled study, trimetazidine was able to significantly increase exercise tolerance and reduce the duration of ST depression in patients with non-obstructive coronary artery disease combined with microangiopathy.
2.7 Ranolazine: A fatty acid partial oxidase inhibitor that reduces angina pectoris by altering cardiac metabolism to reduce cardiac oxygen demand. It also has the effect of inhibiting Na+ inward flow and promoting Ca+ outward flow, thus reducing intracellular calcium overload, dilating coronary arteries and improving diastolic function of the heart. Oral administration of Ranolazine did not cause slowing of heart rate or decrease in blood pressure. In a stressful exercise trial in stable angina, it was shown that ranolazine significantly prolonged the duration of exercise trials, reduced the number and frequency of weekly episodes of angina, and prolonged the time to the appearance of ST-segment depression compared to the placebo group. In a small randomized controlled study, 20 female patients with non-obstructive coronary artery disease combined with microangiopathy were able to significantly reduce angina symptoms and increase CRF after 4 weeks of treatment with ranolazine compared to placebo or ivabradine in another controlled study in 45 patients with microangiopathy, which significantly reduced angina symptoms and increased exercise tolerance.
2.8 Theophyllines: theophyllines are adenosine receptor antagonists that increase coronary CRF by antagonizing the secretion of adenosine at the site of microangiopathy. picano et al. found that aminophylline improved angina symptoms and improved exercise tolerance in patients with microangiopathy, especially in patients with comorbid COPD. In one study, it was observed that intravenous aminophylline significantly reduced microvascular angina symptoms and ECG ST depression. radice et al. observed that oral administration of 400 mg of aminophylline reduced exercise-induced microvascular angina symptoms and ECG ST depression.
2.9 α-blockers: The constriction of coronary resistance vessels exacerbates microvascular dysfunction, and α-blockers can theoretically play a beneficial role in microvascular angina due to their ability to dilate the coronary arteries. Rosen et al. found that the α-blocker doxazosin increased coronary flow reserve, while another study, Botker et al. found that doxazosin did not reduce the symptoms of angina and improved ST depression. The role of α-blockers in microangiopathy still needs to be confirmed.
3. Secondary prevention of non-obstructive coronary artery disease
The 2013 ESC guidelines state that secondary prevention of coronary artery disease is still applicable to patients with non-obstructive coronary artery disease. However, secondary prevention in patients with non-obstructive coronary artery disease is not promising, and Dasari TW et al. found that in secondary prevention of coronary artery disease, the use of aspirin was similar in patients with non-obstructive coronary artery disease compared with patients with obstructive coronary artery disease, while the use of statins was less. At 1 year follow-up, the rates of aspirin, statin, ACEI, and β-blocker drug applications were significantly lower in patients with nonobstructive coronary artery disease than in patients with obstructive coronary artery disease. The LDL-C attainment rate was better in patients with non-obstructive coronary artery disease than in patients with obstructive coronary artery disease at the beginning and after 1 year. manfrini O et al. found a higher rate of beta-blocker use of 77.8% and a lower rate of ACEI drug use of 57.7% in patients with non-obstructive coronary artery disease. dasari TW et al. retrospectively analyzed the results of a study of 148 patients with non-obstructive coronary artery disease from 2004 to 2007 in Dasari TW et al. retrospectively analyzed the secondary prevention of coronary artery disease in 1489745 patients with coronary angiography at 786 US study centers from 2004 to 2007 and found that aspirin, statins, β-blockers, and ACEIARBs were significantly less used in 15.9% of patients with nonobstructive coronary artery disease compared with patients with obstructive coronary artery disease (72.7% vs 90.9%, 60.0% vs 80.3%, 57.9% vs 79.4%, and 45.9% vs 58.6%, respectively; all P < 0.0001). Multivariate analysis revealed that the drugs that patients with non-obstructive coronary artery disease were more reluctant to apply in the order of ACEIARB (OR 0.83, CI 0.80-0.86), β-blockers (OR 0.46, CI 0.44-0.47), statins (OR 0.45, CI 0.43-0.48) and aspirin (OR 0.37, CI 0.35 -0.39).
3.1 Aspirin: In the CONFIRM study, a total of 27125 patients with CT-confirmed non-obstructive coronary artery disease (diameter stenosis 1 to 49%) were observed for the effect of aspirin on the clinical prognosis of non-obstructive coronary artery disease, and the relationship between aspirin and all-cause mortality was observed over 27.2 months of follow-up, and it was found that aspirin was not necessarily associated with reduced mortality. Despite this, experts still believe that according to the consensus on secondary prevention of coronary heart disease, almost all patients should take aspirin long-term if there are no contraindications, but they should be informed of the dose and precautions to improve the effect and reduce the risk of bleeding. The recommended dose of aspirin is 75-150 mg/day, and prophylaxis such as PPI is used when necessary for elderly patients and patients with gastric disease. Avoid alcohol abuse while taking the drug. clopidogrel should be used in combination in patients with ACS and post-PCI patients.
3.2 Statins: In addition to their lipid-regulating effects, statins have endothelial protective, anti-inflammatory and antioxidant effects and play an important role in the secondary prevention of coronary heart disease. A large amount of evidence-based medicine has demonstrated that the use of statins can reduce cardiovascular reoccurrence events and lower mortality. Also in the CONFIRM study, the clinical prognosis of 27125 patients with non-obstructive coronary artery disease (diameter stenosis 1 to 49%) was observed with statins, and after 27.2 months of follow-up, it was found that the risk of death in non-obstructive coronary artery disease was increased by 6% compared to normal controls, and that statin use significantly reduced mortality by 56% (HR 0.44, 95% confidence interval 0.28-0.68, P=0.0003), but there was no benefit for those without coronary artery disease without plaque. Therefore, statins should be used routinely to try to achieve lipid targets, generally lowering LDL-C by 2.6 mmol/L (100 mg/dl) and to 70 mg/dl in patients with ACS.
3.3 β-blockers: β-blockers have a definite role in the secondary prevention treatment of cardiovascular disease. The use of β-blockers in patients with coronary angina and myocardial infarction is supported by Class I evidence. If β-blockers are used in post-infarction patients without contraindications, they can significantly reduce the rate of infarction recurrence, improve cardiac function and reduce the incidence of sudden death. The use of β-blockers in patients with coronary artery disease with or without diabetes can reduce mortality and improve survival. β-blockers can not only reduce angina attacks and improve quality of life, but more importantly, can reduce the reinfarction rate and sudden death rate in patients after myocardial infarction, therefore, β-blockers are the basic medication for the treatment of coronary artery disease. In addition to avoiding contraindications, the heart rate and blood pressure should be paid attention to and the appropriate dose should be selected.
3.4 Angiotensin-converting enzyme inhibitors (ACEI): For patients with coronary artery disease, angiotensin-converting enzyme inhibitors (ACEI) should be used. ACEI can help improve endothelium, protect cardiac function, and prevent ventricular remodeling, etc. For patients with coronary artery disease combined with cardiac insufficiency, ACEI should be used for a long time, and the appropriate drug and dose should also be selected according to blood pressure. Manfrini O et al. found that ACEI drug therapy in patients with non-obstructive coronary artery disease significantly reduced mortality at 6 months (OR 0.31).
IV. Conclusion
Cardiovascular events are significantly increased in non-obstructive coronary artery disease compared with non-coronary artery disease; therefore, non-obstructive coronary artery disease should be given adequate attention. Proper diagnosis and active prevention and treatment are crucial.