Application of ratio V / M of coronary artery volume to left ventricular myocardial mass in PMVA diagnosis and research method

Abstract

The invention discloses application of the ratio V / M of coronary artery volume to left ventricular myocardial mass in PMVA diagnosis and a research method, and relates to the technical field of biomedicine. Retrospective case contrast analysis is carried out on PMVA patients and age, gender, body weight index, smoking history, hypertension, diabetes and dyslipidemia patients. For each patient, the computed tomography images are three-dimensionally reconstructed to calculate patient-specific V / M and vascular-specific V / M, and CT-FFR. And comparing the two groups of results by adopting t test or Mann-Whitney U test. The result shows that the total myocardial mass of the PMVA group is obviously higher than that of the control group, and the average V / M is obviously lower than that of the control group. In the aspect of blood vessel specificity V / M, the left anterior descending branch and the levorotatory branch of the PMVA group are obviously reduced, and the difference between the right coronary artery groups has no statistical significance. The result shows that the abnormally reduced V / M value may be a potential biomarker of PMVA of Chinese population, and the result provides new evidence for the V / M diagnostic value of PMVA in regional and national backgrounds.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to the application and research method of the ratio of coronary artery volume to left ventricular myocardial mass V / M in PMVA diagnosis. Background Art

[0002] Angina pectoris is the classic symptom of coronary artery disease (CAD), which affects approximately 112 million people worldwide. Up to 70% of patients with angina who undergo invasive coronary angiography do not have obstructive CAD (defined as ≥50% narrowing of the luminal diameter on coronary angiography), in which coronary microvascular dysfunction (CMD) is the main pathology. Coronary microvessels are vessels with a diameter of <500 μm that account for 90% of the total blood volume and blood flow resistance of the coronary circulation myocardium. These invisible coronary microvessels constitute the main site of myocardial metabolism, supplying blood and oxygen and participating in the clearance of metabolic byproducts. CMD without obstructive CAD is called primary microvascular angina (PMVA) and is characterized by impaired coronary flow reserve (CFR) and diffuse vasodilation dysfunction without obvious epicardial coronary artery obstruction.

[0003] Diagnosis of PMVA usually requires invasive procedures. The main indicators for evaluating PMVA are CFR and the microcirculatory resistance index (IMR). IMR is considered the gold standard for evaluating coronary microvasculature and detecting PMVA, but the procedure is highly invasive and lacks assessment of myocardial function. In clinical practice, CFR is often used to evaluate coronary microvascular and myocardial function. CFR is usually measured using advanced cardiac imaging, such as positron emission tomography, which is expensive and relies on complex operations. CFR reflects global hemodynamic changes at the macro and microvascular levels. Patients with epicardial CAD have reduced CFR, and patients with PMVA have impaired vasodilator reserve. Therefore, CFR cannot distinguish between microvascular and epicardial cardiovascular disease and is only used as an indicator of microvascular function in patients with patent coronary arteries. FFR score is currently the gold standard for evaluating myocardial ischemia in patients with obstructive CAD, and its value is affected by CMD9. FFR, as a focal hemodynamic parameter, cannot independently reflect CMD, including PMVA. In summary, it is difficult to comprehensively evaluate the impact of macrovascular, microvascular, and myocardial abnormalities on coronary hemodynamics. To date, non-invasive diagnosis of PMVA is an unsolved challenge.

[0004] The ratio of coronary artery volume to myocardial mass (V / M) has been proposed as a quantitative indicator of potential imbalance between coronary blood supply and myocardial demand. Low V / M is an independent predictor of ischemia and may serve as a potential indicator of diffuse atherosclerosis. Coronary computed tomography angiography (CCTA) is a common noninvasive examination that provides anatomical details of the coronary arteries and myocardium. CCTA images can be reconstructed in three dimensions to accurately calculate the volume of the coronary arteries and the mass of the left ventricle, thereby obtaining the V / M ratio. In addition, based on the three-dimensional geometry of the coronary arteries reconstructed by CCTA, computational fluid dynamics simulations can be performed to estimate patient-specific hemodynamic parameters, providing a reference for assessing the risk of myocardial ischemia in patients with CMD.

[0005] There are racial differences in the incidence, severity, and prognosis of CAD and cardiac geometry. In a multiethnic comparative study, patients with suspected CAD of East Asian descent had a higher V / M than those of Caucasian and South Asian descent. However, a comprehensive evaluation of the diagnostic value of V / M of PVMA in East Asian populations is lacking. Summary of the invention

[0006] In view of the above-mentioned problems, the present invention aims to provide an application and research method of the ratio of coronary artery volume to left ventricular myocardial mass V / M in the diagnosis of PMVA, so as to evaluate the diagnostic value of V / M of PVMA in East Asian population.

[0007] In order to achieve the above object, the present invention provides:

[0008] Application of tools for detecting the ratio of coronary artery volume to left ventricular myocardial mass V / M in PMVA diagnostic products.

[0009] Specifically, the PMVA is a PMVA patient in East Asia.

[0010] Specifically, the ratio of coronary artery volume to left ventricular myocardial mass V / M includes patient-specific V / M and vessel-specific V / M.

[0011] Specifically, the vessel-specific V / M includes vessel-specific V / M values ​​of the left anterior descending artery LAD, the left circumflex artery LCX, and the right coronary artery RCA.

[0012] On the other hand, the present invention also provides a research method for the application as described above, comprising the following steps:

[0013] S1: Collect basic clinical data and blood biomarkers of PMVA group and control group;

[0014] S2: Comparative analysis of the ratio of coronary artery volume to left ventricular myocardial mass V / M between the PMVA group and the control group;

[0015] S3: Comparative analysis of vessel-specific CT-FFR between the PMVA group and the control group.

[0016] On the other hand, the present invention also provides the use of an agent for increasing the ratio V / M of coronary artery volume to left ventricular myocardial mass in the preparation of a pharmaceutical composition for treating PMVA.

[0017] The beneficial effects of the present invention are:

[0018] The present invention conducts a retrospective case-control analysis of PMVA patients and patients with age, gender, body mass index, smoking history, hypertension, diabetes and dyslipidemia. For each patient, the computed tomography images were three-dimensionally reconstructed to calculate patient-specific V / M and vessel-specific V / M, as well as CT-derived fractional blood flow reserve CT-FFR. The results of the two groups were compared using t-test or Mann-Whitney U test. The results showed that the total myocardial mass in the PMVA group was significantly higher than that in the control group, and the average V / M was significantly lower than that in the control group. In terms of vessel-specific V / M, the left anterior descending and left circumflex arteries in the PMVA group were significantly reduced, and there was no statistically significant difference between the right coronary artery groups. This suggests that abnormally reduced V / M values ​​may be a potential biomarker for PMVA in the Chinese population, and the results provide new evidence for the diagnostic value of V / M of PMVA in regional and ethnic contexts. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The figure is a research flow chart of the present invention.

[0020] Figure 2 This is the patient screening and matching process in the present invention.

[0021] Figure 3 Schematic diagram of the V / M calculation method in the present invention.

[0022] Figure 4 This is the standardized myocardial segmentation map in the present invention.

[0023] Figure 5 This is a comparison of the coronary artery lumen volume (V), myocardial mass (M), and V / M ratio between the PMVA group and the control group in the present invention.

[0024] Figure 6 This is the receiver operating characteristic curve of patient-specific V / M in the present invention.

[0025] Figure 7 Graph depicts a comparison of vessel-specific V / M values ​​of the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group in the present invention.

[0026] Figure 8This is a comparison of vessel-specific CT-FFR values ​​of the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group in the present invention. DETAILED DESCRIPTION

[0027] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0028] 1 Research Methods

[0029] 1.1 Study design

[0030] This study was a retrospective case-control analysis based on matched PMVA and control groups. PMVA patients were identified and collected based on medical records and diagnostic criteria. The control group was matched with PMVA patients based on demographic and clinical characteristics. Patient-specific V / M and vessel-specific V / M as well as CT-FFR values ​​were compared between the two groups, as shown in the attached Figure 1 shown.

[0031] The PMVA group included patients diagnosed with PMVA at the First People's Hospital of Hangzhou, China, from August 2021 to August 2024. Two experienced cardiologists independently evaluated each patient according to the PMVA diagnostic criteria proposed by the Coronary Artery Vascular Disturbance International Study Group (COVADIS). In case of inconsistent evaluation conclusions, a third physician was introduced as an arbitrator. The control group included patients who underwent CCTA for angina pectoris during the same period and were not diagnosed with CMD.

[0032] Inclusion criteria: Patients who underwent CCTA scan and IMR measurement and were diagnosed with PMVA or no CMD.

[0033] PMVA diagnostic criteria: (1) the presence of symptoms suggestive of myocardial ischemia; (2) objective evidence of myocardial ischemia based on existing technology; (3) non-obstructive CAD (coronary artery diameter narrowing >50% and / or blood flow reserve fraction (FFR) <0.75); (4) confirmed reduced coronary blood flow reserve and / or induced microvascular ischemia.

[0034] Exclusion criteria: (1) patients allergic to contrast agents; (2) special populations such as breastfeeding women or pregnant women who are not suitable for examination; (3) patients who have undergone stent implantation, other surgical treatments or systemic treatments; (4) patients with severe arrhythmias or decompensated heart failure; (5) BMI>35; (6) patients with severe liver and kidney dysfunction, systemic or immune diseases, or concomitant malignant tumors that significantly affect cardiac circulation; (7) patients who cannot meet the trial requirements.

[0035] This study reviewed the imaging data of the initially selected subjects and further excluded 7 patients due to poor image quality. Figure 2 As shown in Figure 4, there were 23 patients in the PMVA group and 25 patients in the control group. It is worth noting that all patients in the control group had angina symptoms, and 11 of them were diagnosed with CAD.

[0036] 1.2CCTA acquisition

[0037] CCTA examination used a Siemens dual-source 128-row computed tomography (CT) scanner, and the scanning range was from 1.0 cm below the tracheal bifurcation to the level of the cardiac diaphragm / 1.5 cm below the lower edge of the heart.

[0038] Scanning parameters: dual Vectron tubes, rotation speed 0.25s / rev; collimator width 2mm×96mm×0.6mm; maximum time resolution 66ms; flying focal spot technology: 0.4mm×0.5mm. Patients were trained in advance to hold their breath and control their heart rate below 75 beats / min. If the patient's resting heart rate was >75 beats / min, oral metoprolol tablets were taken before the examination, with a dose of 25-75mg, and the examination was started after reaching the standard heart rate. All patients were scanned within one cardiac cycle using prospective electrocardiogram gating technology. The optimal phase (usually the late diastole) was selected for image reconstruction on the post-processing workstation (Siemens Syngo.via).

[0039] 1.3 Calculation of patient-specific V / M, vessel-specific V / M, and vessel-specific CT-FFRV / M measurements were performed on the PHIgo research platform (GE Pharmaceutical Co., Ltd, Massachusetts, United States). Figure 3 The workflow of V / M measurement is shown. The CCTA images are automatically segmented to obtain the regions of interest of the coronary arteries and left ventricular myocardium.

[0040] Patient-specific V / M calculation: For each patient, the total coronary volume (V) and left ventricular myocardial volume were determined based on the three-dimensional reconstruction of the region of interest. The left ventricular myocardial mass (M) was calculated by multiplying the left ventricular myocardial volume by the average density of myocardial tissue (1.05 g / ml), and finally the patient-specific V / M ratio was derived.

[0041] Vessel-specific V / M calculation: The left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) are the main coronary arteries. At the microcirculatory level, these three main vessels supply blood to specific myocardial regions. Therefore, vessel-specific V / M was calculated using the PHIgo research platform. The coronary artery tree was segmented to obtain three epicardial arteries (V LAD , V, V RCALCX) vascular volume. PHIgo's CQK software automatically obtains the American Heart Association 17-segment (AHA) perfusion area (see attached Figure 4 The myocardial mass of these three regions was then calculated. Finally, the coronary volume of each epicardial coronary artery was divided by the corresponding myocardial mass to calculate the vessel-specific V / M ratio. Some contour lines were excluded, especially some right-dominant cases.

[0042] Vessel-specific CT-FFR analysis and calculation: For each coronary artery, a deep learning-based CT-FFR analysis was performed using the DEEPVESSELFFR software (Koya Medical Technology Co., Ltd, Beijing, China). The DEEPVESSELFFR software automatically measures the severity of coronary artery stenosis and calculates the FFR of each vessel as the transverse pressure ratio, which is the ratio of the distal to proximal pressure values ​​of the stenosis. The unique deep bidirectional long-term recurrent neural network (DBL-RNN) algorithm is used to quickly calculate the CT-FFR value.

[0043] 1.4 Statistical analysis

[0044] Data were analyzed using SPSS software (Version 28.0, IBM Corp.; Armonk, NY, USA). Propensity score matching (PSM) was used to address differences in outcome variables between the two groups. Categorical data were analyzed using the Pearson chi-square test, and the results are reported as frequencies and percentages. A preliminary assessment of normality and homogeneity of variance was performed for continuous data. Normally distributed continuous data were described as mean ± standard deviation and compared between groups using independent sample t-test. Non-normally distributed data were described as medians (P25, P75) and compared using the Mann-Whitney U test. Violin plots were used for inter-group comparisons and vessel-specific V / M analysis, and the receiver operating characteristic (ROC) curve was used to evaluate the ability of V / M to identify patients with PMVA.

[0045] 2 Research results

[0046] 2.1 General Information

[0047] The comparison of general clinical data between the two groups is shown in Table 1. There were no statistically significant differences in basic clinical data and blood biomarkers between the PMVA group and the control group (P>0.05).

[0048] Table 1 Comparison of general clinical data between the two groups

[0049]

[0050] P25 and P75: 25th and 75th percentiles; SD: standard deviation; HbA1c: glycated hemoglobin; UREA: urea; eGFR: estimated glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; UA: uric acid; Cr: creatinine.

[0051] 2.2 Patient-specific parameters: myocardial mass, coronary artery lumen volume, V / M ratio

[0052] The results of the comparison of the coronary artery lumen volume (V), myocardial mass (M), and V / M ratio between the PMVA group and the control group are shown in the attached figure. Figure 5 As shown, (A) is the distribution of coronary artery lumen volume in the two groups. (B) is the distribution of myocardial mass in the two groups. (C) is the distribution of myocardial V / M ratio in the two groups. The internal box plot depicts the median and quartiles, the bold horizontal line represents the median, and the upper and lower limits correspond to the upper and lower quartiles. The three long horizontal lines represent the mean ± standard deviation. "ns" indicates that the difference is not significant, and "*" and "**" indicate significant differences (P<0.05, P<0.01). PMVA: primary microvascular angina.

[0053] From the attached Figure 5 As can be seen from the data, compared with the control group, the total myocardial mass in the PMVA group was significantly increased, and the V / M ratio was significantly decreased (P<0.05). However, there was no significant difference in the coronary artery lumen volume between the two groups.

[0054] The receiver operating characteristic (ROC) curve of patient-specific V / M is shown in the attached figure. Figure 6 As shown. Figure 6 It can be seen that patient-specific V / M can effectively predict PMVA, with an area under the curve of 0.753 (95% CI: 0.616-0.890, P<0.01).

[0055] 2.3 Vascular-specific parameters: V / M and CT-FFR

[0056] The results of comparison of the vessel-specific V / M values ​​of the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group are shown in the attached figure. Figure 7 As shown, the inner box plot depicts the median and quartiles, the bold horizontal line represents the median, and the upper and lower limits correspond to the upper and lower quartiles. The three long horizontal lines represent the mean ± standard deviation. "ns" indicates no significant difference, and "*" indicates a significant difference (P<0.05).

[0057] From the attached Figure 7 It can be seen that compared with the control group, the vascular-specific V / M values ​​of LAD and LCX in the PMVA group were significantly decreased (P<0.05), while there was no significant decrease in the RCA group (P>0.05).

[0058] In terms of vessel-specific CT-FFR values, there were no significant differences in LAD (0.88±0.04 vs. 0.87±0.04, P>0.05), LCX (0.93±0.02 vs. 0.91±0.03, P>0.05), and RCA (0.90±0.04 vs. 0.89±0.05, P>0.05) between the PMVA group and the control group. Figure 8 shown.

[0059] In conclusion, this study observed a significant decrease in the patient-specific V / M ratio in patients with PMVA. In addition, the vessel-specific V / M was found to be decreased in the LCX and LAD in the PMVA group. There was no significant difference in CT-FFR values ​​between the PMVA group and the control group. These results generally highlight the potential diagnostic value of V / M for PMVA. Moreover, this is the first time that this has been observed in an East Asian population.

[0060] Coronary microvascular function declines with age and is associated with factors such as smoking, advanced age, obesity, hypertension, dyslipidemia, and hyperglycemia. Although the clinical manifestations of CMD patients are similar between men and women, studies have consistently shown an increased prevalence in women, especially postmenopausal women, suggesting that other yet-to-be-determined factors are involved in the occurrence and progression of CMD. There was no significant difference in basic clinical information between the PMVA group and the control group, allowing us to focus on V / M without involving traditional risk factors for CMD. V / M can be combined with other risk factors as an indicator for comprehensive evaluation of coronary microvascular function and prediction of PMVA risk.

[0061] Potential pathogenic mechanisms of CMD fall into two broad categories: structural microcirculatory alterations and functional arteriolar dysregulation, which can coexist. Structural microcirculatory alterations can reduce myocardial blood flow and / or impair maximal microvascular vasodilation, leading to myocardial ischemia. To mitigate ischemia, the heart may undergo remodeling characterized by myocardial hypertrophy and altered ventricular wall pressures, ultimately resulting in an increase in myocardial mass. Thus, we observed a greater myocardial mass in the PMVA group compared with the control group. In addition, structural changes may result in increased sensitivity of smooth muscle cells to vasoconstrictor stimulation (e.g., endothelin-1, acetylcholine, serotonin). Functional arteriolar dysregulation is caused by endothelial dysfunction, diminished flow-mediated relaxation, reduced response to increased nitric oxide shear stress, and impaired smooth muscle cell relaxation, thus affecting coronary artery luminal volume. Therefore, V / M reflects both functional and structural changes, indicating many cardiovascular risk factors (e.g., smoking status). In the absence of obstructive CAD, V / M may help to reveal the drivers behind the decrease in BP and angina in hypertension.

[0062] Patients with MVA secondary to CMD may present with typical angina, atypical symptoms, or angina-equivalent symptoms, usually manifested by pressure behind the sternum, chest pain or discomfort, and / or dyspnea. These symptoms may occur during or after exercise or at rest, and their duration varies. MVA has similar symptoms to other cardiovascular diseases, and diagnosis is challenging. Invasive examinations are high-risk, have many complications, and require a long recovery time and high costs. In addition, it is difficult to directly and comprehensively observe the effects of macrovascular, microvascular, and myocardial abnormalities on hemodynamics. In contrast, V / M can be noninvasively derived through CCTA examinations, and comprehensively reflect hemodynamic changes from the macro to microvascular levels.

[0063] Therefore, based on the research results in the present invention, it can be seen that the ratio of coronary artery lumen volume to myocardial mass in Chinese PMVA patients is lower than that in other angina patients without CMD. V / M based on CCTA may provide a non-invasive method for the diagnosis of PMVA in East Asian populations.

[0064] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. Application of tools for detecting the ratio of coronary artery volume to left ventricular myocardial mass V / M in PMVA diagnostic products.

2. The use according to claim 1, characterized in that: The PMVA described is a PMVA patient in East Asia.

3. The use according to claim 1, characterized in that: The ratio of coronary artery volume to left ventricular myocardial mass V / M includes patient-specific V / M and vessel-specific V / M.

4. The use according to claim 3, characterized in that: The vessel-specific V / M includes the vessel-specific V / M values ​​of the left anterior descending artery LAD, the left circumflex artery LCX, and the right coronary artery RCA.

5. The research method of application according to any one of claims 1 to 4, characterized in that: The following steps are included: S1: Collect basic clinical data and blood biomarkers of PMVA group and control group; S2: Comparative analysis of the ratio of coronary artery volume to left ventricular myocardial mass V / M between the PMVA group and the control group; S3: Comparative analysis of vessel-specific CT-FFR between the PMVA group and the control group.

6. Use of an agent for increasing the ratio of coronary artery volume to left ventricular myocardial mass V / M in the preparation of a pharmaceutical composition for treating PMVA.

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