For this patient, the latter two can be excluded from the three major causes of congenital, traumatic, or iatrogenic diseases.

Coronary artery atherosclerosis, Kawasaki disease, coronary artery dysplasia and trauma can lead to coronary artery aneurysm (9). However, the above reasons cannot explain the coronary artery dilation and CAA formation in this CAF patient. In diastole, LV pressure drops significantly to 0–10 mmHg, which leads to the rapid flow of blood from the main branch of RCA on the surface of the heart into the LV through the orificium fistula. The long-term impact of this rapid blood flow on the coronary artery wall may be the pathological reason for the dilation of the RCA. The patient's RCA dilated to 7.56 mm, 6.37 mm, and 19.12 mm in the proximal, middle, and distal parts (Figures 2B,C), respectively. A huge aneurysm had already formed in the distal end of the RCA. Preoperative TTE showed that there was bidirectional blood flow at the orificium fistulae. On both sides of the orificium fistula, the systolic PG_max and V_max were greater than those in diastole. This results in a stronger impact of systolic blood flow from LV on the distal end of RCA compared to diastolic blood flow from the coronary artery. Therefore, the formation of a distal CAA in this patient's RCA is more closely related to the systolic blood flow impact, which disappeared with surgical treatment, possibly resulting in a reduction in the diameter of the CAA to 13.5 mm five years after surgery (Figure 2D; Table 1).

In the diastole of the heart, due to the obvious pressure difference between the RCA orifice and the LV chamber, the blood in the RCA of this patient rapidly and directly flows into the LV chamber through the fistula. As the RCA gradually expands, it becomes easier for the blood in the lumen to flow into the LV chamber, so that the decrease of myocardial blood perfusion in the RCA distribution area gradually intensifies. This can be referred to as “stealing blood”. Under certain inducing factors of increased myocardial oxygen consumption, myocardial ischemia and hypoxia suddenly worsen, leading to myocardial ischemia symptoms.

The common symptoms of CAF include dyspnea, palpitations, and chest pain (6, 8). This patient complained of persistent chest pain during his first visit to the doctor. The ECG, TTE, and CTP all indicate myocardial ischemia, therefore we conclude that the patient has persistent ischemic chest pain. The cause of myocardial ischemia is “stealing blood” caused by CAF, and the increased demand for blood in the myocardium due to work pressure may be a trigger for symptoms of myocardial ischemia. The increased pressure can lead to sympathetic nerve activity. It remains to be further clarified whether this patient has an increase in sympathetic amine substances that induce endothelial dysfunction or spasms in small coronary arteries.

However, persistent ischemic chest pain did not result in an increase of TNI, a marker of myocardial injury. This may be related to the insufficient degree of ischemia and the absence of stenotic lesions in the branches of RCA.

The patient underwent surgical treatment and the fistula was sealed with a patch. Although the fistula recurred again after surgery, there was no persistent chest pain within the next 5 years, the inverted T wave in the ECG disappeared (Figure 1B), and CTP did not detect myocardial hypoperfusion (Figure 1F). This indicates that the patient's myocardial ischemia has been significantly improved. Although the patient's CAF reappeared after being occluded, the orificium fistula became smaller, and the patch to some extent blocked blood flow and changed the direction of blood flow and reduced blood flow velocity, resulting in a decrease in total blood volume entering the LV, ultimately reducing “stealing blood”. In addition, in the sixth year after operation, the orificium fistula was further reduced to 2.5 mm, and the V_max was further reduced to 145 cm/s in diastole (Table 1). This indicates that the CAF is gradually decreasing and “stealing blood” is gradually decreasing.

After COVID-19 infection, this patient experienced persistent chest pain accompanied by referred pain, tachycardia, and T-wave inversion again, but did not show insufficient myocardial blood flow perfusion (Figure 1G) as indicated by CTP. Additionally, the depth of the inverted T-wave was not as significant as before surgery under the premise of similar heart rate (Figures 1A,D), and TTE indicated that the patient's CAF blood stealing phenomenon did not worsen. All of these manifestations suggest that the patient experienced mild myocardial ischemia. Undoubtedly, the “stealing blood” caused by recurrent RCAF makes the myocardium more prone to suffer from symptomatic myocardial ischemia under the influence of other triggers, which may include increased sympathetic nervous activity and elevated serum ET-1 titer after COVID-19 infection. Previous studies have suggested that some COVID-19 patients experience chest pain (10), chest tightness, fatigue, anxiety and high heart rate in the following months (11, 12). Some cases of chest pain resemble angina pectoris, while others present as persistent chest pain (13). This ischemic symptom may be related to coronary microvascular perfusion defects (13), which can last for one to six month (11, 14) and may be related to angiotensin converting enzyme 2 mediated endothelial damage, microvascular inflammation, thrombosis, and endothelial dysfunction (15, 16). There are also studies showing an increase in serum ET-1 titer in COVID-19 patients (17, 18), which is related to coronary microvascular endothelial dysfunction (19, 20).

The patient had chest symptoms after virus infection, so we need to differentiate it from viral myocarditis. However, this patient did not exhibit elevated biomarkers of myocardial injury or heart failure, as well as symptoms of heart failure or severe arrhythmia. Therefore, we excluded the diagnosis of myocarditis. In addition, pulmonary embolism should be differentiated. However, the patient had no evidence of venous thrombosis, no elevated titer of D-dimer, no S_IQ_IIIT_III and elevated pulmonary artery pressure. Therefore, we also excluded this disease.

At the patient's first visit, oral metoprolol can alleviate chest pain. Later, when the patient experiences COVID-19 infection, chest pain can also be alleviated by increasing the dosage of metoprolol. This suggests that metoprolol can alleviate ischemic chest pain in this CAF patient. We know that metoprolol can be used to treat coronary artery disease by reducing the blood demand of the myocardium by reducing heart rate and myocardial contractility, and this mechanism can also alleviate the degree of myocardial ischemia caused by “stealing blood” in CAF patients.

In addition, we know that the diastole is divided into isovolumic relaxation, rapid filling and slow filling phases. Metoprolol can prolong diastole by reducing the heart rate, thereby prolonging the slow filling phase. During the slow filling phase, the increase in blood volume in the LV leads to an increase in pressure, resulting in a decrease in the velocity of blood flowing into the LV through the RCAF of this patient. Therefore, metoprolol can reduce the “stealing blood” from CAF by reducing heart rate and prolonging the slow filling phase, thereby improving the blood perfusion of microvessels in the RCA branch.