Applications and research method of coronary artery volume to left ventricular myocardial mass ratio (v / m) in diagnosis of primary microvascular angina (PMVA)

Abstract

APPLICATIONS AND RESEARCH METHOD OF CORONARY ARTERY VOLUME TO LEFT VENTRICULAR MYOCARDIAL MASS RATIO (VfM) IN DIAGNOSIS OF PRIMARY MICROVASCULAR ANGINA (PMVA) The present invention conducts a retrospective case—control analysis on PMVA patients and patients matched for age, gender, body mass index, smoking history, hypertension, diabetes, and dyslipidemia. For each patient, the computed tomography images are three—dimensionally reconstructed to calculate the patient—specific VfM, the vesselspecific VM, and the computed tomography—fractional flow reserve (CT—FFR). The ttest or Mann—Whitney U test is used to compare the results of the two groups. The results show that the left anterior descending artery (LAD) and the left circumflex artery (LCX) in the PMVA group are significantly decreased, and there is no statistically significant difference in the right coronary artery (RCA) between the groups. This indicates that the abnormally decreased V / M value may be a potential biomarker for PMVA in the Chinese population, and this result provides new evidence for the diagnostic value of V / M for PMVA in the context of regional and ethnic backgrounds. (Figure 1)

Description

APPLICATIONS AND RESEARCH METHOD OF CORONARY ARTERY VOLUME TO LEFT VENTRICULAR MYOCARDIAL MASS RATIO (VIM) IN DIAGNOSIS OF PRIMARY MICROVASCULAR ANGINA (PMVA) SPECIFICATION: TECHNICAL FIELD The present invention relates to the technical field of biomedicine, and in particular to applications and a research method of the coronary artery volume to left ventricular myocardial mass ratio (V / M) in the diagnosis of primary microvascular angina (PMVA). BACKGROUND Angina pectoris is a typical symptom of coronary artery disease (CAD), affecting approximately 112 million people worldwide. Up to 70% of angina patients who undergo invasive coronary angiography do not show obstructive CAD (defined as a luminal diameter stenosis Z 50% during coronary angiography), among which coronary microvascular dysfunction (CMD) is the main pathology. Coronary microvessels are blood vessels with a diameter of less than 500 micrometers, accounting for 90% of the total myocardial blood volume and blood ow resistance in the coronary circulation. These invisible coronary microvessels constitute the main site of myocardial metabolism, supplying blood and oxygen, and participating in the removal of metabolic byproducts. CMD without obstructive CAD is known as PMVA, which is characterized by impaired coronary ow reserve (CFR) and diffuse vasodilatory dysfunction, without obvious epicardial coronary artery obstruction. The diagnosis of PMVA usually requires invasive procedures. Currently, the main indicators for evaluating PMVA are CFR and the index of microcirculatory resistance (IMR). IMR is considered the gold standard for evaluating coronary microvessels and detecting PMVA, but this process is highly invasive and lacks an assessment of myocardial function. In clinical practice, CFR is commonly used to evaluate coronary microvessels 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 reects the overall hemodynamic changes at the macro and microvascular levels. The CFR is decreased in patients with epicardial CAD, and the vasodilator reserve is impaired in PMVA patients. Therefore, CFR cannot distinguish between microvascular and epicardial cardiovascular diseases and serves only as an indicator of microvascular function in patients with unobstructed coronary arteries. The fractional ow reserve (FFR) score is currently the gold standard for evaluating myocardial ischemia in patients with obstructive CAD, and its value is inuenced by CMD. As a focal hemodynamic parameter, FFR cannot independently reect CMD, including PMVA. In summary, it is difficult to comprehensively evaluate the impact of large vessel, microvascular, and myocardial abnormalities on coronary hemodynamics. So far, the noninvasive diagnosis of PMVA remains an unsolved challenge. V / M has been proposed as a quantitative indicator of the potential imbalance between coronary blood supply and myocardial demand. A 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 may provide anatomical details of the coronary arteries and myocardium. The CCTA images may be three dimensionally reconstructed to accurately calculate the volume of the coronary arteries and the mass of the left ventricle, thus obtaining the V / M ratio. In addition, based on the three dimensional geometric morphology of the coronary arteries reconstructed from CCTA, computational uid dynamics simulations may be carried out to estimate patientspecific hemodynamic parameters, providing a reference for evaluating the risk of myocardial ischemia in CMD patients. There are racial differences in the incidence, severity, prognosis of CAD, as well as cardiac geometry. In a multiethnic comparative study, the VM ratio of suspected CAD patients of East Asian ancestry was higher than that of patients of Caucasian and South Asian ancestry. However, there is currently a lack of a comprehensive assessment of the diagnostic value of VfM for PVMA in the East Asian population. SUMMARY Aiming at the abovementioned existing problems, the present invention aims to provide applications and a research method of the coronary artery volume to left ventricular myocardial mass ratio (V / M) in the diagnosis of PMVA, so as to evaluate the diagnostic value of V / M for PVMA in the East Asian population. In order to achieve the above object, in one aspect, the present invention provides: an application of a tool for detecting coronary artery volume to left ventricular myocardial mass ratio (V / M) in products for the diagnosis of PMVA. Specifically, the PMVA patients are of East Asian ancestry. Specifically, the coronary artery volume to left ventricular myocardial mass ratio (V / M) includes patientspecific V / M and vesselspecific VfM. Specifically, the vesselspecific V / M includes the vesselspecific V / M values of the left anterior descending artery (LAD), the left circumex artery (LCX), and the right coronary artery (RCA). In another aspect, the present invention further provides a research method for the above mentioned application, including the following steps: Sl: collecting the basic clinical data and blood biomarkers of a PMVA group and a control group; S2: comparing and analyzing the coronary artery volume to left ventricular myocardial mass ratio (V / M) between the PMVA group and the control group; and S3: comparing and analyzing the vesselspecific computed tomographyfractional ow reserve (CTFFR) between the PMVA group and the control group. In a further aspect, the present invention provides an application of an agent for increasing the coronary artery volume to left ventricular myocardial mass ratio (V / M) in the preparation of a pharmaceutical composition for treating PMVA. The present invention has the following advantages. The present invention conducts a retrospective casecontrol analysis on PMVA patients and patients matched for age, gender, body mass index, smoking history, hypertension, diabetes, and dyslipidemia. For each patient, the computed tomography images are threedimensionally reconstructed to calculate the patientspecific V / M, the vesselspecific V / M, and computed tomographyderived fractional ow reserve (CTFFR). The ttest or MannWhitney U test is used to compare the results of the two groups. The results show that the total myocardial mass of the PMVA group is significantly higher than that of the control group, and the average V / M is significantly lower than that of the control group. In terms of the vesselspecific VfM, the left anterior descending artery (LAD) and the left circumex artery (LCX) in the PMVA group are significantly decreased, and there is no statistically significant difference in the right coronary artery (RCA) between the groups. This indicates that the abnormally decreased V / M value may be a potential biomarker for PMVA in the Chinese population, and this result provides new evidence for the diagnostic value of V / M for PMVA in the context of regional and ethnic backgrounds. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a research owchart of the present invention; FIG. 2 shows a patient screening and matching process in the present invention; FIG. 3 is a schematic diagram of a calculation method of VfM in the present invention; FIG. 4 is a standardized myocardial segmentation diagram in the present invention; FIG. 5 shows the comparison of the coronary artery lumen volume (V); myocardial mass (M); and V / M ratio between a PMVA group and a control group in the present invention; FIG. 6 is a receiver operating characteristic curve of the patientspecific V / M in the present invention; FIG. 7 shows the comparison of the vesselspecific VfM values of the left anterior descending artery (LAD), left circumex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group in the present invention; and FIG. 8 shows the comparison of the vesselspecific CTFFR values of the left anterior descending artery (LAD), left circumex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group in the present invention. DETAILED DESCRIPTION In order to enable those of ordinary skill in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be further described below in conjunction with the accompanying figures and examples. 1 Research Methods 1.1 Research Design This study was a retrospective casecontrol analysis based on the matching of the PMVA group and the control group. PMVA patients were identified and collected according to medical records and diagnostic criteria. The control group was matched with PMVA patients according to demographic and clinical characteristics. The patientspecific V / M, vesselspecific VM, and CTFFR values were compared between the two groups, as shown in FIG. 1. The PMVA group included patients diagnosed with PMVA at the First Peoples Hospital of Hangzhou, China from August 2021 to August 2024. Two experienced cardiologists independently evaluated each patient according to the diagnostic criteria for PMVA proposed by the Coronary Vasomotor Disorders International Study Group (COVADIS). In case of inconsistent evaluation conclusions, a third physician was introduced as an arbitrator. The control group included patients who received CCTA for angina pectoris during the same period and were not diagnosed with CMD. Inclusion Criteria: patients who underwent CCTA scanning and IMR measurement and were diagnosed with PMVA or without CMD. PMVA Diagnostic Criteria: ( 1) the presence of symptoms suggesting myocardial ischemia; (2) objective evidence of myocardial ischemia based on existing techniques; (3) no obstructive CAD (coronary artery diameter narrowing > 50% and / or fractional ow reserve (FFR) < 0.75); (4) confirmation of reduced coronary ow reserve and / or induced microvascular ischemia. Exclusion Criteria: ( 1) patients with contrast agent allergy; (2) special populations such as lactating or pregnant women who are not suitable for the examination; (3) patients who have received stent implantation, other surgical treatments, or systemic treatments; (4) severe arrhythmia, decompensated heart failure; (5) BMI > 35; (6) patients with severe liver and kidney insufficiency, systemic or immune diseases, or concurrent malignant tumors that significantly affect the cardiac circulation; (7) patients who cannot meet the requirements of the trial. This study reviewed the imaging data of the initially selected subjects, and 7 patients were further excluded due to low image quality, as shown in FIG. 2. In the final included cohort, there were 23 patients in the PMVA group and 25 patients in the control group. Notably, all patients in the control group had angina pectoris symptoms, and 11 of them were diagnosed with CAD. 1.2 CCTA Acquisition The CCTA examination was performed using a Siemens dualsource 128slice computed tomography (CT) scanner. The scanning range was from 1.0 cm below the tracheal bifurcation to the level of the diaphragm of the heart / 1.5 cm below the lower edge of the heart. Scanning parameters: dual Vectron tubes, rotation speed 0.25 s / rotation; collimator width 2 mm >< 96 mm >< 0.6 mm; maximum temporal resolution 66 ms; ying focal spot technology: 0.4 mm >< 0.5 mm. Patients were trained in advance to hold their breath, and the heart rate was controlled below 75 beats per minute. If the patients resting heart rate was > 75 beats per minute, metoprolol tablets were orally administered before the examination at a dose of 2575 mg, and the examination was started after the standard heart rate was achieved. The scans of all patients were completed within one cardiac cycle using prospective electrocardiogram gating technology. The optimal phase (usually the late diastole) was selected on the postprocessing workstation (Siemens Syngo.via) for image reconstruction. 1.3 Calculation of PatientSpecific V / M, VesselSpecific VM, and VesselSpecific CT FFR The VfM measurement was carried out on the PHIgo research platform (GE Pharmaceutical Co., Ltd, Massachusetts, United States). FIG. 3 shows the workow of the V / M measurement. The CCTA images were automatically segmented to obtain the regions of interest of the coronary arteries and the left ventricular myocardium. Calculation of PatientSpecific VfM: for each patient, the total coronary artery volume (V) and the left ventricular myocardial volume were determined according to the threedimensional reconstructed structure 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 patientspecific V / M ratio was derived. Calculation of VesselSpecific V / M: the left anterior descending artery (LAD), left circumex artery (LCX), and right coronary artery (RCA) are the main coronary artery vessels. At the microcirculation level, these three main vessels supply blood to specific myocardial regions. Therefore, the vesselspecific V / M was calculated using the PHIgo research platform. The coronary artery tree was segmented to obtain the vessel volumes of the three epicardial arteries (VLAD, Vch, VRCA). The CQK software of PHIgo automatically obtained the perfusion regions of the 17 segments of the American Heart Association (AHA) (as shown in FIG. 4), in which myocardial segments 1, 2, 7, 8, 13, 14, and 17 were defined as the supply region of the LAD, myocardial segments 5, 6, 11, 12, and 16 were defined as the supply region of the LCX, and myocardial segments 3, 4, 9, 10, and 15 were defined as the supply region of the RCA20. Then, the myocardial mass of these 3 regions was calculated. Finally, the coronary artery volume of each epicardial coronary artery was divided by the corresponding myocardial mass to calculate the vesselspecific VfM ratio. Some contour lines were excluded, especially in some cases of right dominance. Analysis and Calculation of VesselSpecific CTFFR: for each coronary artery, a deep learningbased CTFFR analysis was performed using the DEEPVESSELFFR software (Koya Medical Technology Co., Ltd, Beijing, China). The DEEPVESSEL FFR software automatically measured the severity of coronary artery stenosis and calculated the FFR of each vessel as the transverse pressure ratio, that is, the ratio of the pressure value at the distal end of the stenosis to that at the proximal end. A unique deep bidirectional longterm recurrent neural network (DBL RNN) algorithm was used to rapidly calculate the CTFFR value. 1.4 Statistical Analysis Data analysis was performed using SPSS software (Version 28.0, IBM Corp.; Armonk, NY, USA). Propensity score matching (PSM) was used to handle the differences in outcome variables between the two groups. Pearsons chisquare test was used for the analysis of categorical data, and the results were reported as frequencies and percentages. The normality and homogeneity of variance of continuous data were initially evaluated. Continuous data with a normal distribution were described as mean i standard deviation, and an independent samples t-test was used for comparison between groups. Data with a nonnormal distribution were described as median (P25, P75), and the MannWhitney U test was used for comparison. Violin plots were used for comparison between groups and vesselspecific V / M analysis, and the receiver operating characteristic (ROC) curve was used to evaluate the ability of V / M to identify PMVA patients. 2 Research Results 2.1 General Information The comparison of the general clinical data between the two groups is shown in Table 1 below. There were no statistically significant differences in the basic clinical data and blood biomarkers between the PMVA group and the control group (P > 0.05). Table 1 Comparison of General Clinical Data between the Two Groups Control Group PME-151 'IJzffv'alue P-ïalue W Male [Number of cases (%)] [:(-18} 12 (:'-2} 0.083 0.113 Body mass, index 3.30: 3.03 33.00: 3.31 .1 .455 0.515 Smoking 0 (24) 5 (22) 0.035 0.332 Hypertension [Number efcases (%)] H (561 15 (051 0.420 0.514 Diabetes [Number ef cases (%)] 010) 2 (0; 2.203 0.132 Dyslipidemia [Number ofcases (%)] 1 (12) 2 (01 0.140 0.100 HbAlc DîHÆlmol-l] 5.5 (51,05) 5.5 (31,33) -0.133 0.055 URBAIEMem de SD, mmc-DL) 3.00: 1.11 5.10: 1.33 0.310 0.003 eGFR (Mean :l: 5Dm1nol-'L) 013931333 13.520 10.150 -1.130 0.254 LDL-C (Mw Ì SD: MOLD 2 30:0 32 2.22: 0.30 0.551 0.150 HDLC (Mami 5D, mel.-L) 1.1-330.31 1.10: 0.30 .0010 0.002 Ham-rem :l: sn, mel.-L) 532.400 01.02 555.115 002.10 -0.101 0.420 CI[M(P25.P?53mmoLL] 10.5 (12.11.0001 34.0 (14.0.1000)- -0.301 0.011 P25 and P75 : 25th and 75th percentiles; SD: standard deviation; HbAlc: glycated hemoglobin; UREA: urea; eGFR: estimated glomerular filtration rate; HDLC: highdensity lipoprotein cholesterol; LDLC: lowdensity lipoprotein cholesterol; UA: uric acid; Cr: creatinine. 2.2 PatientSpecific Parameters: Myocardial Mass, Coronary Artery Lumen Volume, V / M Ratio The comparison results 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 FIG. 5. Among them, (A) is the distribution of the coronary artery lumen volume of the two groups. (B) is the distribution of the myocardial mass of the two groups. (C) is the distribution of the myocardial V / M ratio of 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 i standard deviation. ns indicates no significant difference, and * and ** indicate significant differences (P < 0.05, P < 0.01). PMVA: Primary microvascular angina. As may be seen from FIG. 5, compared with the control group, the total myocardial mass of the PMVA group was significantly higher, and the V / M ratio was significantly lower (P < 0.05). However, there was no significant difference in the coronary artery lumen volume between the two groups. The receiver operating characteristic (ROC) curve of the patientspecific V / M is shown in FIG. 6. As may be seen from FIG. 6, the patientspecific VfM may effectively predict PMVA, with an area under the curve of 0.753 (95% CI: 0.6160.890, P < 0.01). 2.3 VesselSpecific Parameters: VM and CTFFR The comparison results of the vesselspecific V / M values of the left anterior descending artery (LAD), left circumex artery (LCX), and right coronary artery (RCA) between the PMVA group and the control group are shown in FIG. 7. Among them, 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 i standard deviation. ns indicates no significant difference, and * indicates a significant difference (P < 0.05). As may be seen from FIG. 7, compared with the control group, the vesselspecific V / M values of the LAD and LCX in the PMVA group were significantly lower (P < 0.05), while there was no significant decrease in the RCA group (P > 0.05). In terms of the vesselspecific CTFFR values, there were no statistically significant differences between the PMVA group and the control group in the LAD (0.88 i 0.04 vs. 0.87 i 0.04, P > 0.05), LCX (0.93 i 0.02 vs. 0.91 i 0.03, P > 0.05), and RCA (0.90 i 0.04 vs. 0.89 i 0.05, P > 0.05), as shown in FIG. 8. In conclusion, through this study, it may be observed that the patientspecific V / M ratio of PMVA patients is significantly decreased. In addition, it was also found that the vesselspecific V / M of the LCX and LAD in the PMVA group was decreased. There was no significant difference in the CTFFR 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 such an observation has been made in the East Asian population. The coronary microvascular function declines with age and is related to 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, which indicates that other as yet undetermined factors are involved in the occurrence and progression of CMD. There were no significant differences in the basic clinical information between the PMVA group and the control group, allowing us to focus on V / M without involving the traditional risk factors of CMD. V / M may be combined with other risk factors as an indicator for comprehensively evaluating the coronary microvascular function and predicting the risk of PMVA. The potential pathogenic mechanisms of CMD are divided into two major categories: structural microcirculatory changes and functional arteriolar disorders, and the two may coexist. Structural microcirculatory changes may reduce myocardial blood ow and / or impair the maximum microvascular vasodilation ability, leading to myocardial ischemia. To alleviate ischemia, the heart may undergo remodeling, characterized by myocardial hypertrophy and changes in ventricular wall pressure, ultimately resulting in an increase in myocardial mass. Therefore, we observed that the myocardial mass of the PMVA group was larger than that of the control group. In addition, structural changes may lead to an increase in the sensitivity of smooth muscle cells to vasoconstrictor stimuli (such as endothelinl, acetylcholine, serotonin). Functional arteriolar disorders are caused by endothelial dysfunction, weakened owmediated dilation, a weakened response to increased shear stress of nitric oxide, and impaired smooth muscle cell relaxation, thus affecting the coronary artery lumen volume. Therefore, V / M reects the changes in function and structure and indicates many cardiovascular risk factors (such as smoking status). In the absence of obstructive CAD, V / M may help to reveal the driving factors behind the decrease in blood pressure in hypertension and angina pectoris. Patients with MVA secondary to CMD may present with typical angina pectoris, atypical symptoms, or anginal equivalent symptoms, usually manifested as retrostemal exertional pressure, chest pain or discomfort, and / or dyspnea. These symptoms may occur during or after exercise, or they may occur at rest, and their duration varies. The symptoms of MVA are similar to those of other cardiovascular diseases, and its diagnosis poses significant clinical challenges. Invasive examinations have a high risk, many complications, a long recovery time, and high costs. In addition, it is difficult to directly and comprehensively observe the hemodynamic effects of large vessel, microvascular, and myocardial abnormalities. In contrast, VfM may be noninvasively derived through CCTA examination and comprehensively reect the hemodynamic alterations from the macro to the microvascular level. Therefore, based on the research results in the present invention, it is known that the ratio of the coronary artery lumen volume to the myocardial mass in Chinese PMVA patients is lower than that in other angina pectoris patients without CMD. The CCTAbased V / M may provide a noninvasive method for the diagnosis of PMVA in the East Asian population. The above has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art will understand that the present invention is not limited by the abovementioned examples. The abovementioned examples and the descriptions in the specification only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, various changes and improvements will be made to the present invention, and these changes and improvements fall within the scope of the present invention claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. Application of a tool for measuring the ratio between the coronary artery volume and left ventricular myocardial mass V / M in diagnostic products for PMVA.

2. The use according to claim 1, characterized in that the PMVA relates has on patients from East Asia with PMVA.

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

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

5. Research procedure for the application according to any one of claims 1 to 18 4, metals feature that it includes the following steps: Sl: Collection of basic clinical data and blood biomarkers from both the PMVA group as the control group; SZ: Comparative analysis of the relationship between coronary arterial volume and left ventricular myocardial mass V / M in the PMVA group and the control group; S3: Comparative analysis of vessel-specific CT-FFR between the PMVA group and the control group.

6. Application of a reagent that determines the ratio between the coronary artery volume and left ventricular myocardial mass VfM increases, in the production of a drug combination for the treatment of PMVA. 11 / 4 FIG.1 FIG.2