With the widespread use of coronary angiography, patients and physicians are often faced with typical angina attacks with normal coronary angiograms, posing many doubts and challenges. Recently, a study of 400,000 coronary angiograms performed for suspected coronary artery disease reported that while about 70% of patients had typical angina attacks, only 37.6% had obstructive coronary artery disease, meaning that nearly 50% had angina attacks without coronary artery stenosis.
It has also been shown that in patients with angina with normal coronary angiograms, even when coronary artery malformations are excluded, a significant proportion of patients have recurrent and prolonged attacks of angina, even complicated by serious cardiovascular events such as myocardial infarction and sudden death. Coronary angina attacks with normal coronary angiogram mainly involve seven types of diseases: microvascular angina, coronary artery spasm, myocardial bridge, myocardial pericardial disease, aortic (valve) disease, extracardiac disease, etc.
1.Microvascular angina pectoris
Also known as cardiac X syndrome, it is a group of clinical syndromes with typical exertional angina symptoms accompanied by objective evidence of myocardial ischemia, but no significant stenosis on coronary angiography. Large coronary arteries (>500 μm diameter) are called conduit vessels because they contribute <5% to coronary resistance, whereas small anterior arteries (100-500 μm diameter) and small arteries (<100 μm) are the main contributors to flow resistance. Resistance vessel dysfunction that cannot be demonstrated on coronary angiography is the main pathophysiological basis for microvascular angina:.
(i) microvascular endothelial dysfunction leading to spasm;
(ii) microvascular atherosclerosis;
(iii) inflammation;
④Neurological dysfunction: including plant nerve dysfunction and somatic nerve abnormalities reflex pain mechanism.
Diagnostic criteria for microvascular angina pectoris.
① with typical exertional angina symptoms;
② Ischemic changes in ECG or cardiac stress test during angina attack;
③ negative excitation test, that is, to exclude coronary artery spasm;
④Coronary angiography showed no significant stenosis of epicardial vessels.
The main treatment strategies for microvascular angina include the following.
①relief of symptoms: non-dihydropyridine calcium antagonists and new anti-myocardial ischemic drugs such as ranolazine and nicorandil are preferred; traditional nitrates are ineffective or have little effect;
② drugs that improve endothelial cell function such as statins;
③Anti-platelet drugs;
④Extracorporeal counterpulsation therapy: relieves angina symptoms by increasing microvascular perfusion and improving endothelial cell function;
⑤ Chinese patent medicine: Musk Tongxin Dripping Pill, etc.
2.Coronary artery spasm
Also known as vasospastic angina, variant angina, typically manifests as angina at rest with transient ST-segment elevation on ECG. The degree of ST elevation may depend mainly on the degree of coronary artery spasm. Non-completely occluded spasm often manifests as ST-segment depression or T-wave changes, and ST-segment elevation only manifests when severe spasm makes the vessel close to complete occlusion or complete occlusion. In addition, the collateral circulation established by long-term repeated spasm and the short duration of occlusive spasm may also be the reason why the ST segment is not elevated or no ST segment elevation is detected. Coronary artery spasm involves three main pathophysiological mechanisms.
①Core mechanism: reactivity of vascular smooth muscle cells and increased ROCK activity are related;
(ii) pathogenesis basis: structural and functional disorders of vascular endothelial cells; (iii) predisposing factors: endogenous and exogenous factors.
Invasive diagnostic criteria for coronary artery spasm.
①Consistent with the clinical features of resting chest pain;
② significant stenosis without ischemic significance on coronary angiography; ③ coronary artery stenosis of 90% or more after intracoronary injection of acetylcholine, along with an episode of chest pain or chest tightness similar to usual chest pain or chest tightness, with or without ischemic changes on ECG, and chest pain or chest tightness subsequently relieved after the coronary artery spasm is released.
Noninvasive diagnostic criteria for coronary artery spasm (missing one).
① Clinical features of resting chest pain;
② negative ECG exercise test or ischemic changes during the recovery period after exercise, including ST-segment elevation or depression meeting ischemic diagnostic criteria;
(③Nuclear perfusion myocardial imaging load test showed reverse redistribution, i.e. good myocardial perfusion in the load state but perfusion deficit in the resting state.
The main treatment strategies for vasospastic angina are.
① Relieve symptoms: mainly calcium antagonists, nitrates, nicorandil, etc.; unless combined with exertional angina, β-blockers are prohibited;
② Improve prognosis: lipid regulation, antithrombotic and improve endothelial cell function such as statins, ADP receptor antagonists and other drug therapy;
③Strictly quit smoking and remove triggering factors;
④Interventional treatment or ICD implantation can be considered for severe cases.
3.Myocardial bridge
The coronary artery and its branches usually travel in the subepicardial fat on the surface of the heart or in the deep epicardial surface. When a section of the coronary artery is surrounded by myocardium, the section of myocardium is called myocardial bridge and the section of coronary artery is called wall coronary artery. A myocardial bridge is a coronary artery that is supposed to travel in the epicardium and penetrates the myocardial layer. The clinical diagnosis is mainly confirmed by the “systolic stenosis or milking effect” seen in coronary CTA or angiography, and its clinical significance is controversial.
Myocardial bridges are seen almost exclusively in the left anterior descending branch. Myocardial fibers are oriented at nearly right angles to the long axis of the vessel in the anterior and posterior descending branches and at smaller angles in the anterior right and anterior left ventricular branches. When the heart contracts, the myocardial bridge compresses the wall coronary artery to further narrow its lumen. The longer and thicker the myocardial bridge, the greater the angle between the myocardial fibers and the vessel, and the more severe the narrowing of the wall coronary artery, the more severe the distal myocardial ischemia, and even myocardial infarction. Because coronary arteries are diastolic blood supply and myocardial bridges cause “systolic compression”, they were previously thought to have a limited effect on myocardial blood supply. With advances in intracoronary function and imaging, particularly intracoronary Doppler techniques, the clinical significance of myocardial bridges has been increasingly understood.
Recent studies have shown that systolic compression caused by myocardial bridges may lead to a severe decrease in diastolic storage function of the patient’s coronary arteries, triggering serious cardiovascular events such as myocardial ischemia, myocardial infarction or sudden death. Some hypertrophic cardiomyopathies and Tako-Tsubo cardiomyopathies may be associated with myocardial bridges. The determination of the treatment strategy requires a comprehensive evaluation based on the patient’s clinical symptoms, systolic compression length, and myocardial bridge index (the product of myocardial bridge depth and length). Such patients should not be treated with vasodilators, and β-blockers are preferable, and surgical treatment if necessary.
4.Myocardial pericardial disease
A variety of myocardial pericardial diseases including myocarditis, hypertensive heart disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial amyloidosis, athlete’s heart, Tako-Tsubo cardiomyopathy, and pericarditis can cause angina attacks due to structural and functional abnormalities of the myocardial pericardium and microvasculature. Microvascular structural and functional abnormalities involve endothelial dysfunction, myocardial interstitial and perivascular fibrosis, capillary thinning, and increased arterial stiffness. Of these, small artery occlusion and capillary thinning are independent factors affecting microcirculatory hemodynamics.
The main mechanisms involved are.
(i) Impaired microvascular function.
② Mismatch between hypertrophy and hyperplasia of the myocardium and increased blood supply;
(iii) Combined myocardial bridges;
④Left ventricular outflow tract obstruction with increased myocardial oxygen consumption;
⑤ Decreased diastolic reserve function of coronary arteries. The diagnostic and differential diagnostic values of cardiac magnetic resonance and nuclear perfusion imaging stress tests are most prominent.
5.Aortic (valve) disease
Aortic stenosis or insufficiency of the aortic valve causes angina pectoris associated with inadequate coronary perfusion and increased oxygen consumption by myocardial hypertrophy, especially in elderly patients with degenerative heart disease. Aortic coarctation tears accumulate coronary artery openings, resulting in obstruction of blood flow through the openings, which can also trigger significant myocardial ischemia and even myocardial infarction or sudden death to occur. In addition, mitral valve prolapse, aortic valve malformation, and aortic sinus aneurysm rupture can be combined with angina attacks. Aortic and its valve diseases have a higher risk of sudden death and mostly require active clinical intervention.
6.Early repolarization syndrome and arrhythmia
Early repolarization syndrome, rapid or slow arrhythmias can trigger or exacerbate angina attacks. Treatment strategies need to be determined according to clinical risk stratification.
7. Extracardiac diseases
A variety of gastrointestinal, respiratory, skin soft tissue diseases and systemic diseases including reflux esophagitis, costochondritis, pneumonia, severe anemia, cardiac neuropathy, etc. can lead to chest pain attacks.