Cardiac syndrome X (CSX) refers to a group of syndromes with typical or atypical angina symptoms (especially exertional angina), ischemic ST-segment depression on exercise stress test, but normal coronary angiography on ergometrine test. CSX is usually noted as Kemp to distinguish metabolic X syndrome. At present, more scholars believe that the main pathophysiological basis of the same chest pain is mainly the resistance vascular dysfunction of small coronary arteries less than 500 μm in diameter and/or increased cardiac pain sensitivity (or abnormal pain perception), so it is also called coronary microangiopathic angina, and recently some scholars even suggest to call it coronary microvascular dysfunction.
1.Pathophysiological mechanism
The pathophysiological mechanism of CSX may be mainly related to the following factors.
1.1. Coronary microvascular endothelial cell dysfunction
Endothelial cells can release nitric oxide and prostacyclin, which are vasodilators, and endothelin-1 and angiotensin-II (ATII), which are vasoconstrictors. The endothelium-dependent vasodilation (EDV) is impaired due to the increased release of endothelin 1 and ATII, decreased nitric oxide synthesis and release, and increased endothelin 1/nitric oxide ratio. , interleukin 1, tumor necrosis factor alpha, low estrogen or deficiency, hyperhomocysteinemia, insulin resistance or diabetes, hypertension, hyperlipidemia or abnormal blood rheology, smoking, atherosclerosis, etc. These factors damage endothelial cells, causing an imbalance in the balance of endothelin 1 and nitric oxide (or prostacyclin) and an increase in the endothelin 1/nitric oxide ratio, leading to EDV disorders.
Lipocalin is a newly discovered cytokine secreted by adipocytes, and endothelial cells can express lipocalin receptors. lipocalin increases heat shock protein 90 to promote endothelial-type nitric oxide synthase activity, resulting in increased nitric oxide production. serum lipocalin is significantly reduced in CSX patients, which can lead to EDV impairment.
Recently, it was found that plasma homocysteine levels were increased in CSX patients and negatively correlated with Duke’s cycling score, suggesting that high levels of homocysteine can also cause EDV disorders.
1.2. Reduced coronary flow reserve capacity
Coronary flow reserve capacity is the ratio of maximum coronary blood flow to basal blood flow. After induced by intravenous vasodilators (pansentin, nitroglycerin, poppies, adenosine, etc.) or cardiac stress tests (e.g. exercise test, dobutamine test, esophageal atrial pacing, etc.), the coronary artery flow reserve capacity is reduced with Doppler ultrasound, nuclear myocardial perfusion such as emission computerizedtomography (ECT), cardiac magnetic resonance ( Patients with CSX commonly have reduced coronary flow reserve capacity due to EDV disorders.
Insufficient coronary flow reserve capacity in CSX patients may also be associated with reduced parasympathetic tone and dysfunction. Transthoracic cardiac ultrasound measurements of coronary flow reserve, heart rate, blood pressure variability, and facial cold stimulation (pressor) tests have shown that more than half of CSX patients have reduced vagal tone and dysfunction.
1.3. Subendocardial myocardial ischemia and abnormal cardiac function
Is there subendocardial myocardial ischemia and abnormal cardiac function in CSX patients? has been the subject of much debate over the years, and the results of the two most recent studies remain contradictory. Gadolinium-enhanced cardiovascular magnetic resonance myocardial perfusion imaging found that 56% of CSX patients induced a reversible myocardial perfusion filling defect at the peak of the dobutamine loading test, leading to the conclusion that the left anterior descending branch of the coronary artery responds to myocardial perfusion during adenosine infusion with reduced coronary blood flow and an EDV impairment. However, magnetic resonance myocardial perfusion imaging showed the opposite, with significant perfusion response to adenosine in both epicardial and subendocardial myocardium of CSX patients, and no evidence of subendocardial myocardial hypoperfusion was found. It is possible that the decrease in mean myocardial transmural blood flow and reduced coronary flow reserve capacity are not due to subendocardial congestive myocardial underperfusion.
The current study did not find significant left ventricular systolic function (left ventricular ejection fraction) abnormalities in patients with early CSX, but asymptomatic ST-segment depression had the same hemodynamic abnormalities as an angina attack, with elevated left ventricular end-diastolic pressure and pulmonary artery end-diastolic pressure. In those with symptoms of chest pain and negative selective coronary angiograms, left ventricular end-diastolic pressure was significantly higher in the group with positive exercise tests than in the negative group. The authors of this paper showed the same results in a study of hemodynamics in CSX patients without gender subgroups and in female CSX patients.
1.4. Abnormal cardiac pain perception
Studies with direct cardiac stimulation by cardiac catheterization found that typical angina could be induced in 94% of CSX patients, and patients had significantly reduced coronary flow reserve in response to poppy bases infusion, so chest pain in CSX patients may be associated with increased cardiac pain sensitivity or reduced pain threshold.
When a dobutamine loading test induces an angina attack in CSX patients, the patient’s right insular cortical activity is enhanced, and pathways that are otherwise inhibited subcortically are readily transmitted to cortical nociceptive areas, causing abnormal perception of pain signals. In CSX patients with refractory angina pectoris, spinal cord stimulation treatment revealed that the patients’ angina pectoris status, exercise tolerance and ST-segment ischemic changes in the ECG during exercise-induced angina pectoris were significantly improved, suggesting that the patients’ cardiac autonomic function was regulated, and its analgesic effect was mainly through stimulation of inhibitory neurons in the posterior horn of the spinal cord, which caused the release of analgesic substances from the central and peripheral nervous system and regulated the central nervous system’s perception of pain The analgesic effect is mainly through stimulating the inhibitory neurons in the posterior horn of the spinal cord, causing the release of analgesic substances from the central and peripheral nervous system, regulating the central nervous system’s abnormal perception of pain, and normalizing cardiac pain sensitivity.
1.5. Autonomic cardiac dysfunction
Cardiac autonomic dysfunction is a manifestation of the imbalance between the sympathetic and parasympathetic nervous systems.The clinical manifestation of CSX is an over-activation of sympathetic nervous system function and is not a direct result. Because of the impaired function of the vagus nervous system, the vagal tone is reduced and dysfunctional, allowing the sympathetic nervous system to dominate. The sympathetic dominance leads to increased production of endogenous sympathetic neurotransmitters (catecholamines), resulting in sustained microvascular constriction, resulting in endothelial cell damage and increased adenosine release. Adenosine directly stimulates adenosine receptors in the myocardium and vascular endothelium, causing chest pain through spinal nerve reflexes, and coronary blood flow reserve is also reduced due to microvascular endothelial cell dysfunction.
1.6.Inflammatory response
The relationship between the inflammatory response and CSX has received significant attention and general agreement from more studies, including studies on the mechanisms of inflammatory response substances such as highsensitivityCreactiveproteinhs-CRP, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukin-1, and tumor necrosis factor alpha, whose The main effect may still be to damage endothelial cells, such as CRP inhibits nitric oxide production and vascular regeneration, upregulates vascular smooth muscle angiotensin receptor 1 expression and inhibits prostacyclin release from endothelial cells, leading to EDV impairment. Pathomorphological evidence for the involvement of inflammation in the pathogenesis of CSX has been obtained from endomyocardial biopsy specimens from CSX patients with elevated serum hs-CRP levels. Studies on the possible association of Helicobacter pylori infection with the pathogenesis of CSX, among others, have also been reported. hs-CRP patients with high levels of CSX not only have a high frequency of chest pain but also a long duration. Serum hs-CRP can be used as an independent variable to predict plate motion test and Holter positivity.
1.7. Estrogen depression or deficiency
The prevalence of CSX in menopausal women is high, and it is speculated that its onset may be related to estrogen, and the correlation and possible causal relationship between the two have been established. In perimenopausal and postmenopausal women, estrogen depression or deficiency reduces the ability to inhibit the formation and development of atherosclerotic plaques, and reduces the ability to inhibit endothelin 1, leading to increased vascular tone and EDV impairment. After short-term administration of estrogen to CSX patients, acetylcholine not only failed to induce vasoconstriction, but also increased coronary blood flow, further suggesting that short-term application of estrogen can improve EDV disorders in CSX patients.
1.8. Insulin resistance
Early glucose tolerance test found that CSX patients had hyperinsulinemia, while their glucose absorption was 40% less than that of healthy subjects, suggesting that CSX patients may have insulin resistance. Subsequent studies further found that fasting insulin levels and insulin sensitivity index were positively correlated with plasma endothelin 1 levels, and insulin sensitivity was negatively correlated with endothelin 1 and not with nitric oxide levels, suggesting that the role of insulin resistance in the pathogenesis may lead to endothelial dysfunction in CSX patients.
1.9. Coronary atherosclerosis
Although no small vessel pathological changes were found in the coronary small vessel tissue of CSX patients under electron microscopy, electron beam CT in recent years found that 63%-73% of female CSX patients had coronary artery calcification, and the calcification score was lower than that of those with angiographically confirmed coronary artery lesions, and coronary artery calcification is an important sign of coronary atherosclerosis. Exercise can constrict atherosclerotic arteries and dilate normal arteries, which may help explain why exercise can induce angina attacks in CSX patients.
1.10. Abnormal blood rheology and/or lipid metabolism
Patients with CSX have increased blood rheological parameters such as erythrocyte aggregation and aggregation force, low-shear plasma viscosity, white blood cell count, and hs-CRP, which reduce coronary blood flow velocity and lead to coronary microcirculatory dysfunction. Abnormal lipid metabolism can lead to abnormal blood rheology, and increased plasma viscosity can also directly damage endothelial cells and cause subendothelial lipid deposition, especially elevated LDL cholesterol and lipoprotein a. The negative correlation between LDL cholesterol and lipoprotein a and coronary blood flow reserve may be due to endothelial cell dysfunction.
1.11, Mental and/or psychological factors
Compared with patients with coronary artery disease and healthy individuals, female CSX patients have more psychological influences, such as more life disturbing factors and high values of anxiety and depression scores; while those with wide social networks have less life disturbing factors and health anxiety, and low values of depression scores. The vast majority of CSX patients had negative anxiety and depression, and their depression and anxiety scores were significantly higher. Supportive psychological interventions to correct inappropriate cognitions can reduce anxiety and depression scores, improve somatic symptoms, and reduce chest pain episodes.
2. The intrinsic link between cardiac X syndrome and metabolic syndrome
Obesity, type 2 diabetes, hyperlipidemia, hypertension, and hyperinsulinemia often occur together in patients, and the combination of two or more of these factors is called metabolic syndrome. These factors are all risk factors for atherosclerosis, thus, CSX and metabolic syndrome are two different concepts from different perspectives, but the common point in etiology of both is endothelial cell dysfunction, resulting in reduced diastolic function of microvessels, and both can be seen as the same disease process.
The prognosis of cardiac X syndrome is mostly good, and it usually does not develop further into serious adverse consequences such as myocardial infarction or sudden cardiac death, but angina-like chest pain symptoms often bring a lot of pain to patients, and even seriously affect their normal work and quality of life. When chest pain attacks, the effect of treatment with conventional anti-anginal drugs is not very satisfactory, and patients have varying effects on nitroglycerin, betalactam and cardiac pain.