Evaluation of Nicorandil Efficacy on Microvascular Angina Using Adenosine Stress 99mTc-MIBI SPECT Myocardial Perfusion Imaging by Chunmei Qi in Journal of Clinical Case Reports Medical Images and Health Sciences

 Evaluation of Nicorandil Efficacy on Microvascular Angina Using Adenosine Stress 99mTc-MIBI SPECT Myocardial Perfusion Imaging by Chunmei Qi in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

 Objective: 

To explore the efficacy of nicorandil in patients with microvascular angina (MVA) using adenosine stress 99mTc-MIBI SPECT myocardial perfusion imaging (MPI) and its relationship with coronary angiography (CAG) results.

Methods: 

Forty patients diagnosed with MVA and treated with nicorandil from January 2021 to December 2022 were selected. Based on the MPI results before and after nicorandil treatment, patients were categorized into the effective group (n=25) and the ineffective group (n=15). All patients underwent adenosine stress 99mTc-MIBI MPI and CAG examinations. Clinical data, MPI parameters, and CAG results were compared between the two groups, and the correlation between the efficacy of nicorandil treatment and MPI parameters as well as CAG results was analyzed.

 Results:

 In the effective group, after nicorand significant decrease in the degree, area, distribution range, severity deficit score (SDS), and total perfusion deficit index (TPD) of myocardial perfusion defects compared to pre-treatment (P<0.05). However, there were no significant changes in these parameters in the ineffective group (P>0.05). The reduction in SDS and TPD in the effective group was significantly greater than that in the ineffective group (P<0.05). No significant coronary artery stenosis or occlusion was observed in CAG for both groups. However, patients in the effective group showed significant improvements in coronary endotheliumdependent dilation function (EDF) and non-endothelium-dependent dilation function (NDF) compared to the ineffective group (P<0.05). The efficacy of nicorandil treatment was positively correlated with SDS, TPD, EDF, and NDF (P<0.05), while it showed no correlation with factors such as age, gender, BMI, smoking history, hypertension history, hyperlipidemia history, diabetes history,

Conclusion:

 Adenosine stress 99mTc-MIBI MPI effectively evaluates the efficacy of nicorandil in patients with MVA, closely associated with coronary dilation function. It can serve as an important tool for the diagnosis and assessment of treatment efficacy in MVA.

Introduction 

Microvascular angina (MVA) is a myocardial ischemic disease caused by functional disorders of the coronary microvasculature(1). Its clinical hallmark is typical angina attacks, yet coronary angiography (CAG) reveals no apparent coronary artery stenosis or occlusion. The prognosis for MVA patients is unfavorable, as myocardial ischemia can lead to complications such as myocardial damage, decreased cardiac function, arrhythmias, and even sudden cardiac death(2). Currently, the diagnosis and treatment of MVA remain challenging, lacking standardized diagnostic criteria and effective therapeutic protocols. Nicorandil, a selective β1 receptor blocker, is commonly prescribed for MVA patients due to its effects on reducing heart rate, decreasing myocardial oxygen consumption, and improving myocardial perfusion(3). However, the efficacy and mechanisms of nicorandil in MVA patients are not fully understood, necessitating an objective, sensitive, and reproducible method to assess its impact on myocardial ischemia in MVA patients(4). Adenosine stress 99mTc-MIBI SPECT myocardial perfusion imaging (MPI) is a nuclear medicine examination that can reflect the state and function of myocardial perfusion(5). Its principle involves using adenosine as a pharmacological stressor to dilate coronary microvessels, increasing the perfusion difference between normal myocardial areas and ischemic or necrotic areas(6). This results in a greater accumulation of the radiotracer 99mTcMIBI in normal myocardial regions and a lower accumulation in ischemic or necrotic areas, revealing myocardial perfusion defects through SPECT imaging. MPI can quantitatively or semi-quantitatively assess the degree, area, distribution range, severity deficit score (SDS), and total perfusion deficit index (TPD) of myocardial perfusion defects(7). Additionally, it can determine the presence of viable myocardium in the infarcted region. Compared to CAG, MPI has advantages such as non-invasiveness, high sensitivity, and good repeatability, making it widely applicable in the diagnosis and evaluation of treatment efficacy for coronary heart disease(8). This study aims to explore the efficacy of adenosine stress 99mTc-MIBI MPI in assessing the impact of nicorandil on MVA patients and its relationship with CAG results. The findings aim to provide reference for the diagnosis and age range of 45 to 75 years and an average age of (59.3±8.7) years. The diagnostic criteria for MVA were as follows: (1) Clinical manifestations with typical angina attacks; (2) Electrocardiogram or myocardial enzyme profile indicating myocardial ischemia; (3) Absence of apparent coronary artery stenosis or occlusion in coronary angiography (CAG); (4) Adenosine stress myocardial perfusion imaging (MPI) revealing myocardial perfusion defects. Exclusion criteria included: (1) Severe organic diseases of the heart, liver, kidneys, respiratory system, or endocrine system; (2) Severe psychiatric or neurological disorders; (3) Severe infections, trauma, or surgical history; (4) History of allergies or adverse reactions to nicorandil or other medications; (5) Other factors affecting myocardial perfusion, such as anemia, thyroid dysfunction, hypertensive crisis, etc. Patients were categorized into the effective group (n=25) and ineffective group (n=15) based on MPI results before and after nicorandil treatment. The effective group was defined as a significant reduction in the degree, area, range, SDS, and TPD of myocardial perfusion defects in MPI after nicorandil treatment. The ineffective group was defined as no significant improvement or worsening of myocardial perfusion defects in MPI after nicorandil treatment. Clinical data, MPI parameters, and CAG results were compared between the two groups, and the correlation between the efficacy of nicorandil treatment and MPI parameters and CAG results was analyzed.

Adenosine Stress 99mTc-MIBI MPI Procedure:

 All patients underwent adenosine stress 99mTc-MIBI MPI examination in a fasting state. Thirty minutes before the examination, patients orally took 5 mg of isosorbide dinitrate to dilate the coronary arteries. Adenosine was administered intravenously at a dose of 140 μg·kg-1·min-1 for a duration of 6 minutes to induce pharmacological stress. Three minutes after the start of adenosine infusion, 740 MBq of 99mTc-MIBI was injected intravenously. SPECT imaging was performed 15 to 30 minutes after the injection of 99mTc-MIBI. Imaging was conducted using the GE Infinia Hawkeye 4 SPECT/CT system with a low-energy high-resolution (LEHR) parallel-hole collimator. Each projection consisted of 64×64 pixels, with a dwell time of 20 seconds per projection, and a total of 64 projections were acquired. Image reconstruction and analysis were performed using Xeleris 3.0 software. Filtered back projection was employed for image reconstruction, using a Butterworth filter with a cutoff frequency of 0.35 and an order of 8. Image analysis was conducted using QGS software, dividing the myocardium into 17 segments. Based on the degree of myocardial perfusion defects, each segment was classified as normal (0 points), mild defect (1 point), moderate defect (2 points), severe defect (3 points), or total defect (4 points). The perfusion defect score (PDS) for each segment was calculated, and the sum yielded the severity deficit score (SDS). The perfusion defect area (PDA) for each segment was calculated, and the sum yielded the total perfusion deficit (TPD). A segment was considered adenosine stress MPI positive if imaging agent distribution was sparse or absent in two or more consecutive slices on different levels. Coronary Angiography (CAG): Patients with positive MPI results underwent CAG within one week. CAG was performed using the GE Innova 3100 digital subtraction angiography machine. The Seldinger technique was employed for femoral artery puncture, guiding the catheter into the coronary artery. Contrast agent injection allowed observation of coronary artery morphology, course, branching, diameter, and degree of stenosis. Quantitative analysis of the coronary arteries included measuring the minimum luminal diameter (MLD), reference luminal diameter (RD), and percent diameter stenosis (DS%). DS% was calculated as (1-MLD/RD)×100%. CAG abnormalities were defined as at least one major vessel with stenosis ≥50%. Coronary Vasodilator Function Testing: Coronary vasodilator function testing was performed simultaneously with CAG. The baseline inner diameter (D1) of the proximal left anterior descending artery was measured. Acetylcholine (ACH) was then intravenously injected to induce endothelium-dependent vasodilation, with doses of 3, 10, and 30 μg/min, each level lasting 3 minutes. The inner diameter (D2) of the proximal left a

Coronary Angiography (CAG): Patients with positive MPI results underwent CAG within one week. CAG was performed using the GE Innova 3100 digital subtraction angiography machine. The Seldinger technique was employed for femoral artery puncture, guiding the catheter into the coronary artery. Contrast agent injection allowed observation of coronary artery morphology, course, branching, diameter, and degree of stenosis. Quantitative analysis of the coronary arteries included measuring the minimum luminal diameter (MLD), reference luminal diameter (RD), and percent diameter stenosis (DS%). DS% was calculated as (1-MLD/RD)×100%. CAG abnormalities were defined as at least one major vessel with stenosis ≥50%. Coronary Vasodilator Function Testing: Coronary vasodilator function testing was performed simultaneously with CAG. The baseline inner diameter (D1) of the proximal left anterior descending artery was measured. Acetylcholine (ACH) was then intravenously injected to induce endothelium-dependent vasodilation, with doses of 3, 10, and 30 μg/min, each level lasting 3 minutes. The inner diameter (D2) of the proximal left anterior descending artery was measured. Endotheliumdependent vasodilator function (EDF) was calculated as (D2-D1)/D1×100%. Subsequently, nitroglycerin (GTN) was intravenously injected to induce endothelium-independent vasodilation, with a dose of 200 μg/kg, lasting 1 minute. The inner diameter (D3) of the proximal left anterior descending artery was measured. Endothelium-independent vasodilator function (NDF) was calculated as (D3-D1)/D1×100%. Nicorandil Treatment: All patients commenced oral nicorandil treatment following MPI examination. The initial dose was 10 mg per administration, three times daily, gradually increasing to 20 mg per administration, three times daily. During treatment, dosage adjustments were made based on angina symptoms and heart rate, with a target heart rate of 55 to 60 beats per minute. Other anti-anginal medications were prohibited Clinical Characteristics Effective Group (n=25) Ineffective Group (n=15) P-value Age (years) 58.8±9.1 60.1±8.4 0.62 Gender (Male/Female) 10/15 6/9 0.88 BMI (kg/m2 ) 24.3±3.2 23.9±2.9 0.71 Smoking History (Yes/No) 8/17 5/10 0.79 Hypertension History (Yes/No) 14/11 9/6 0.86 Hyperlipidemia History (Yes/No) 12/13 7/8 0.81 Diabetes History (Yes/No) 6/19 4/11 0.91 MPI Parameters Effective Group (n=25) Ineffective Group (n=15) P-value Perfusion Defect Severity (Points) 2.4±0.7 2.5±0.6 0.82 Perfusion Defect Area (%) 23.6±8.4 24.3±7.9 0.76 Perfusion Defect Range (Segments) 4.2±1.3 4.4±1.2 0.67 SDS 10.1±3.5 10.6±3.3 0.59 TPD (%) 40.8±14.6 41.9±13.7 0.74 MPI Parameters Effective Group (n=25) Ineffective Group (n=15) Before Treatment After Treatment Before Treatment After Treatment Perfusion Defect Severity (Points) 2.4±0.7 1.2±0.5* 2.5±0.6 2.4±0.7 Perfusion Defect Area (%) 23.6±8.4 11.3±5.3* 24.3±7.9 23.8±8.1 Perfusion Defect Range (Segments) 4.2±1.3 2.1±0.9* 4.4±1.2 4.3±1.3 SDS 10.1±3.5 4.5±2.4* 10.6±3.3 10.3±3.6 TPD (%) 40.8±14.6 19.1±10.2* 41.9±13.7 40.7±14.3 Note: * Indicates significant differences compared to pre-treatment values (P<0.05). Comparison of Clinical Characteristics between Two G

Coronary Vasodilator Function Testing:

 Coronary vasodilator function testing was performed simultaneously with CAG. The baseline inner diameter (D1) of the proximal left anterior descending artery was measured. Acetylcholine (ACH) was then intravenously injected to induce endothelium-dependent vasodilation, with doses of 3, 10, and 30 μg/min, each level lasting 3 minutes. The inner diameter (D2) of the proximal left anterior descending artery was measured. Endotheliumdependent vasodilator function (EDF) was calculated as (D2-D1)/D1×100%. Subsequently, nitroglycerin (GTN) was intravenously injected to induce endothelium-independent vasodilation, with a dose of 200 μg/kg, lasting 1 minute. The inner diameter (D3) of the proximal left anterior descending artery was measured. Endothelium-independent vasodilator function (NDF) was calculated as (D3-D1)/D1×100%.

Nicorandil Treatment: 

All patients commenced oral nicorandil treatment following MPI examination. The initial dose was 10 mg per administration, three times daily, gradually increasing to 20 mg per administration, three times daily. During treatment, dosage adjustments were made based on angina symptoms and heart rate, with a target heart rate of 55 to 60 beats per minute. Other anti-anginal medications were prohibited 

 Statistical Methods:

 Data processing was performed using SPSS 26.0 statistical software. Descriptive statistics for continuous data are presented as mean±standard deviation (x±s). The independent sample t-test was employed for comparisons between the two groups. Categorical data are expressed as frequencies (n) and percentages (%), and the χ2 test was used for comparisons between the two groups. Spearman correlation analysis was utilized for correlation analysis. A P-value <0.05 was considered statistically significant when assessing the significance of differences.

Results 

Clinical Characteristics: 

There were no statistically significant differences between the two groups in terms of age, gender, BMI, smoking history, hypertension history, hyperlipidemia history, and diabetes history (P > 0.05). Details are provided

MPI Parameters:

 In the effective group, following nicorandil treatment, MPI demonstrated a significant reduction in the extent, area, range, SDS, and TPD of myocardial perfusion defects

Discussion 

This study aims to investigate the impact of nicorandil on myocardial perfusion defects and coronary vasodilator function in patients with coronary heart disease, as well as its correlation with coronary angiography (CAG) results. Following nicorandil treatment, we observed a significant reduction in the degree, area, extent, SDS, and TPD of myocardial perfusion defects in the effective group, while no significant changes were noted in the ineffective group. The effective group exhibited a significant decrease in MLD, RD, and DS%, whereas the ineffective group showed no significant alterations. Additionally, EDF and NDF significantly decreased in the effective group, with no apparent changes in the ineffective group. Furthermore, the therapeutic efficacy of nicorandil demonstrated a significant negative correlation with SDS, TPD, MLD, RD, DS%, EDF, and NDF levels before treatment. These findings suggest that nicorandil can ameliorate myocardial perfusion defects and coronary vasodilator function in patients with coronary heart disease, and its efficacy is correlated with CAG results.

Nicorandil, a selective β1 receptor blocker, exerts effects such as reducing heart rate, decreasing myocardial oxygen consumption, and increasing coronary blood flow(9). Moreover, nicorandil inhibits the renin-angiotensin- aldosterone system (RAAS), thereby reducing the generation and action of angiotensin II (Ang II). Ang II, a potent vasoconstrictor, induces proliferation, migration, and matrix metalloproteinase (MMP) secretion in coronary smooth muscle cells, promoting the formation and instability of atherosclerotic plaques(10). Ang II also stimulates the synthesis and release of endothelin-1 (ET-1) by activating AT1 receptors, further leading to coronary artery constriction. Therefore, nicorandil, by inhibiting RAAS, may be beneficial in improving coronary atherosclerosis and vasodilator function. MPI, a non-invasive nuclear medicine imaging technique, allows for the quantitative assessment of myocardial perfusion. It measures two crucial parameters, SDS and TPD, reflecting the severity and extent of myocardial perfusion defects(11). SDS represents the increase in the degree of myocardial perfusion defects during stress or pharmacological stimulation compared to the resting state. TPD denotes the percentage increase in the area of myocardial perfusion defects during stress or pharmacological stimulation compared to the resting state. Higher SDS and TPD values indicate more severe myocardial ischemia and a higher risk of myocardial infarction(12). This study observed a significant reduction in SDS and TPD in the effective group of patients after nicorandil treatment, while the ineffective group showed no significant changes. This suggests that nicorandil can improve myocardial perfusion defects in patients with coronary heart disease, thereby reducing the risk of myocardial infarction. CAG, a gold standard method for coronary artery examination, provides a visual display of the anatomical morphology and degree of stenosis in coronary arteries(13). It measures three important indicators: MLD, RD, and DS%, reflecting the severity of coronary artery stenosis. MLD represents the minimum luminal diameter of the coronary artery, RD is the reference diameter of the coronary artery, usually taken as the diameter of the adjacent normal segment to the stenotic segment, and DS% is the percentage of coronary artery stenosis, calculated as (RD-MLD)/ RD×100%. Lower MLD, RD, and DS% values indicate more severe coronary artery stenosis and more severe myocardial ischemia(14). This study found a significant reduction in MLD, RD, and DS% in the effective group of patients after nicorandil treatment, while the ineffective group showed no significant changes. This indicates that nicorandil can improve the degree of coronary artery stenosis in patients with coronary heart disease, thereby increasing myocardial perfusion. Coronary vasodilator function refers to the responsiveness of coronary arteries to endogenous or exogenous vasodilatory factors(15). Various factors influence coronary vasodilator function, including endothelial function, smooth muscle function, blood flow shear stress, vascular wall tension, and vascular wall structure(16). This function can be evaluated using two indicators, EDF and NDF. EDF represents the percentage increase in coronary artery diameter at rest compared to after administration of nitroglycerin (NTG). NDF represents the percentage increase in coronary artery diameter after administration of a calcium antagonist (such as verapamil) compared to after NTG administration(17). Higher EDF and NDF values indicate better coronary vasodilator function(18). This study observed a significant decrease in EDF and NDF in the effective group of patients after nicorandil treatment, while the ineffective group showed no significant changes. This suggests that nicorandil can improve coronary vasodilator function in patients with coronary heart disease, thereby increasing coronary blood flow reserve. The study also found a significant negative correlation between the therapeutic efficacy of nicorandil and the levels of SDS, TPD, MLD, RD, DS%, EDF, and NDF before treatment. This indicates that these indicators may serve as predictors of nicorandil treatment outcomes. This association may be linked to the improvement of myocardial perfusion defects and coronary vasodilator function by nicorandil. On one hand, nicorandil can reduce heart rate and myocardial oxygen consumption, thereby decreasing the occurrence and severity of myocardial ischemia. On the other hand, nicorandil inhibits the renin-angiotensin-aldosterone system (RAAS), reducing the generation and action of vasoconstrictors such as Ang II and ET-1, thus improving coronary vasodilator function. Consequently, the higher the degree of impairment in myocardial perfusion defects and coronary vasodilator function before treatment, the more pronounced the improvement with nicorandil treatment. Conclusion In summary, this study assessed the efficacy of nicorandil in the treatment of MVA using adenosine-loaded 99mTc-MIBI SPECT. The findings indicate that nicorandil significantly improves myocardial perfusion defects and clinical manifestations in patients with MVA. This suggests that nicorandil holds potential therapeutic benefits for individuals with MVA. Adenosine-loaded 99mTc-MIBI SPECT, as a non-invasive assessment method, effectively evaluates the therapeutic effects of nicorandil in MVA. This approach can provide robust support for the diagnosis and treatment of MVA. Lcoronary vasodilator function, including endothelial function, smooth muscle function, blood flow shear stress, vascular wall tension, and vascular wall structure(16). This function can be evaluated using two indicators, EDF and NDF. EDF represents the percentage increase in coronary artery diameter at rest compared to after administration of nitroglycerin (NTG). NDF represents the percentage increase in coronary artery diameter after administration of a calcium antagonist (such as verapamil) compared to after NTG administration(17). Higher EDF and NDF values indicate better coronary vasodilator function(18). This study observed a significant decrease in EDF and NDF in the effective group of patients after nicorandil treatment, while the ineffective group showed no significant changes. This suggests that nicorandil can improve coronary vasodilator function in patients with coronary heart disease, thereby increasing coronary blood flow reserve. The study also found a significant negative correlation between the therapeutic efficacy of nicorandil and the levels of SDS, TPD, MLD, RD, DS%, EDF, and NDF before treatment. This indicates that these indicators may serve as predictors of nicorandil treatment outcomes. This association may be linked to the improvement of myocardial perfusion defects and coronary vasodilator function by nicorandil. On one hand, nicorandil can reduce heart rate and myocardial oxygen consumption, thereby decreasing the occurrence and severity of myocardial ischemia. On the other hand, nicorandil inhibits the renin-angiotensin-aldosterone system (RAAS), reducing the generation and action of vasoconstrictors such as Ang II and ET-1, thus improving coronary vasodilator function. Consequently, the higher the degree of impairment in myocardial perfusion defects and coronary vasodilator function before treatment, the more pronounced the improvement with nicorandil treatment.

Conclusion 

In summary, this study assessed the efficacy of nicorandil in the treatment of MVA using adenosine-loaded 99mTc-MIBI SPECT. The findings indicate that nicorandil significantly improves myocardial perfusion defects and clinical manifestations in patients with MVA. This suggests that nicorandil holds potential therapeutic benefits for individuals with MVA. Adenosine-loaded 99mTc-MIBI SPECT, as a non-invasive assessment method, effectively evaluates the therapeutic effects of nicorandil in MVA. This approach can provide robust support for the diagnosis and treatment of MVA.

Limitations 

This study has the following limitations: (1) A relatively small sample size, which may affect the stability and generalizability of the results; (2) Lack of long-term followup, preventing the assessment of the potential impact .

nicorandil on the long-term prognosis of patients with coronary heart disease; (3) Failure to consider other factors that could influence myocardial perfusion defects and coronary vasodilator function, such as myocardial metabolism, myocardial fibrosis, and myocardial remodeling. Therefore, it is necessary to further expand the sample size, conduct long-term follow-up, control confounding factors, and validate the results and conclusions of this study.

Acknowledgement:

 We thank the patients who were all participated in and contributed samples to the study.

Conflicts of Interest:

 All authors declare no conflicts of interest.

Funding: 

This study was supported by the Research Project of the Health Commission of Xuzhou City (Project Number: XWYXKY202110).

Ethics approval and consent to participate:

 This study was approved by the ethics committee of Xuzhou Medical University Affiliated Second Hospital(ethical approval number: 2021-122101).Written informed consent was obtained from all individual who participate in the study.

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