Application of Insect Medicines in Treatment of Coronary Microvascular Dysfunction Based on Comorbidity Theory of "Blood-Vessel-Cardiac Collaterals" / 中国实验方剂学杂志

Coronary microvascular dysfunction （CMD） is one of the important causes of myocardial ischemia and non-obstructive coronary artery ischemic symptoms. However， effective diagnostic methods and targeted treatment strategies for CMD are currently lacking. According to traditional Chinese medicine （TCM）， the comorbidity theory of "blood-vessel-cardiac collaterals" plays a central role throughout the entire development process of CMD. It suggests that in the clinical diagnosis and treatment of CMD， the treatment of blood， vessels， and cardiac collaterals should not be neglected. In light of this， insect medicines， known for their efficacy in promoting blood circulation， resolving stasis， and alleviating spasms， hold promise as a potential treatment for CMD. However， there is currently no research or summary on the use of insect medicines for the treatment of CMD. Therefore， this article took the comorbidity theory of "blood-vessel-cardiac collaterals" as the starting point and divided the pathogenesis of CMD into five evolution stages： Beginning in the blood （changes in blood components and hemorheology）， progressing in the vessels （atheromatous plaque formation and unstable plaques）， occurring in the cardiac collaterals （microvascular endothelial damage and microvascular constriction and spasms）， ending in the cardiac collaterals （microvascular remodeling）， and resulting in energy metabolism disorders throughout the process， so as to explore the pathogenesis and evolution of CMD. In addition， based on the modern pharmacological research on insect medicines， this article discussed the clinical application of insect medicines in the treatment of CMD from four aspects： Promoting blood circulation and removing blood stasis to relieve vessels' obstruction， relieving spasms to alleviate pain， combating poison with poison to disperse stagnation， and tonifying cardiac collaterals to nourish the heart， which aims to provide a theoretical basis for the use of TCM in treating CMD， broaden the scope of medication， and improve clinical efficacy.

Construction of a porcine model of ischemia with non-obstructive coronary artery and assessment by CT myocardial perfusion imaging combined with coronary CT angiography / 中华放射学杂志

Objective:To construct a porcine model of ischemia with non-obstructive coronary artery (INOCA) and explore the diagnostic value of a one-stop noninvasive method including CT myocardial perfusion imaging (CT-MPI) and coronary CT angiography (CCTA).Methods:Twelve swines were divided into the experimental group (9) and the normal group (3). Coronary microvascular dysfunction (CMD) porcine model was constructed in the experimental group by inducing diabetes mellitus, chronic kidney disease, and hypercholesterolemia. Invasive coronary angiography (ICA) and functional examination were performed on all 7+3 trial swines to clarify the INOCA diagnosis after completion of the modeling. Then, CT-MPI and CCTA were performed on all individuals to explore the CT-MPI and CCTA characteristics of INOCA porcine models. CT-MPI parameters, including myocardial blood flow (MBF), and myocardial blood volume (MBV) in rest and stress conditions, and CCTA parameters, including severity of stenosis and CAD-RADS, were analyzed.Results:ICA and functional tests showed that all swines in the experimental group met the diagnostic criteria for INOCA, which meant that INOCA porcine model was constructed successfully. CCTA results confirmed that there was no obstructive coronary stenosis in all 10 swines which were examined, which was consistent with ICA findings. CT-MPI results demonstrated that the mean MBF values, as well as the mean MBV values, in the rest and stress condition of each swines in the experimental group were lower than those of the control group. In contrast to the control group, the mean MBF and MBV values of swines in the experimental group in stress condition were generally lower than those in resting condition.Conclusions:In this study, a porcine model of CMD is successfully constructed by inducing hypercholesterolemia+diabetes mellitus+chronic kidney disease. ICA and invasive functional tests show that this CMD model meet the diagnostic criteria for INOCA. It has been confirmed that one-stop CT multimodality examination including CT-MPI and CCTA can be used for the diagnosis of INOCA as a noninvasive diagnostic method.

Short-term prognostic predictive value of deep-learning assisted quantitative myocardial contrast echocardiography in ST-elevated myocardial infarction after primary percutaneous coronary intervention / 中华超声影像学杂志

Objective:To explore the prognostic predictive value of deep neural network (DNN) assisted myocardial contrast echocardiography (MCE) quantitative analysis of ST-elevated myocardial infarction (STEMI) patients after successful percutaneous coronary intervention(PCI).Methods:A retrospective analysis was performed in 97 STEMI patients with thrombolysis in myocardial infarction-3 flow in infarct vessel after primary PCI in Renmin Hospital of Wuhan University from June to November 2021. MCE was performed within 48 h after PCI. Patients were followed up to 120 days. The adverse events were defined as cardiac death, hospitalization for congestive heart failure, reinfarction, stroke and recurrent angina. The framework consisted of the U-net and hierarchical convolutional LSTMs. The plateau myocardial contrast intensity (A), micro-bubble rate constant (β), and microvascular blood flow (MBF) for all myocardial segments were obtained by the framework, and then underwent variability analysis. Patients were divided into low MBF group and high MBF group based on MBF values, the baseline characteristics and adverse events were compared between the two groups. Other variables included biomarkers, ventricular wall motion analysis, MCE qualitative analysis, and left ventricular ejection fraction. The relationship between various variables and prognosis was investigated using Cox regression analysis. The ROC curve was plotted to evaluate the diagnostic efficacy of the models, and the diagnostic efficacy of the models was compared using the integrated discrimination improvement index (IDI).Results:The time-cost for processing all 3 810 frames from 97 patients was 377 s. 92.89% and 7.11% of the frames were evaluated by an experienced echocardiographer as "good segmentation" and "correction needed". The correlation coefficients of A, β, and MBF ranged from 0.97 to 0.99 for intra-observer and inter-observer variability. During follow-up, 20 patients met the adverse events. Multivariate Cox regression analysis showed that for each increase of 1 IU/s in MBF of the infarct-related artery territory, the risk of adverse events decreased by 6% ( HR 0.94, 95% CI =0.91-0.98). There was a 4.5-fold increased risk of adverse events in the low MBF group ( HR 5.50, 95% CI=1.55-19.49). After incorporating DNN-assisted MCE quantitative analysis into qualitative analysis, the IDI for prognostic prediction was 15% (AUC 0.86, sensitivity 0.78, specificity 0.73). Conclusions:MBF of the area supplied by infarct-related artery after STEMI-PCI is an independent protective factor for short-term prognosis. The DNN-assisted MCE quantitative analysis is an objective, efficient, and reproducible method to evaluate microvascular perfusion. Assessment of culprit-MBF after PCI in STEMI patients adds independent short-term prognostic information over qualitative analysis.It has the potential to be a valuable tool for risk stratification and clinical follow-up.

Effect of coronary microvascular dysfunction on cardiac mechanical indices in patients with non-obstructive coronary artery disease / 中华超声影像学杂志

Objective:To investigate the effect and relationship of coronary microvascular dysfunction (CMD) on cardiac mechanical indices in patients with non-obstructive coronary artery disease(NOCAD) in the resting state.Methods:This study was a single-center retrospective study. Seventy-nine NOCAD patients who hospitalized in Qilu Hospital of Shandong University from July 2017 to March 2022 were recruited. All patients underwent conventional echocardiography examination and the examination of coronary flow velocity reserved by transthoracic Doppler echocardiography (TTDE-CFVR). Based on the results of TTDE-CFVR, patients were divided into CMD group (CFVR<2.5, 32 cases) and a control group (CFVR≥2.5, 47 cases). Clinical data, routine echocardiographic parameters, regional mechanical indices including regional myocardial work index(RWI) and regional longitudinal strain(RLS), global mechanical indices including left ventricular global longitudinal strain(GLS), global longitudinal strain in the endocardial layer(GLS-endo), global longitudinal strain in the epicardial layer(GLS-epi), left ventricular global work index(GWI), global contractive work(GCW), global waste work(GWW), global work efficiency(GWE) were compared between two groups. Binary logistic regression was used to analyze the risk factors of CMD. ROC curve was used to construct a prediction model for CMD.Results:There was no significant difference in sex ratio, BMI, smoking history, diabetes, hypertension and dyslipidemia between CMD group and control group. Age was significantly higher in the CMD group than in the control group. RWI, GWI, GCW, GWE and the absolute values of RLS, GLS, GLS-endo and GLS-epi were significantly lower in the CMD group than in the control group. Logistic regression analysis showed that the decrease of absolute value of GLS was an independent risk factor for the CMD( OR=1.335, 95% CI=1.041-1.713, P=0.023). ROC curve showed that myocardial strain-related indexes had a good decrease value for the CMD. Conclusions:For patients with NOCAD, the presence of CMD is associated with the decrease of left ventricular regional and global systolic function.

Aspirin plus verapamil relieves angina and perfusion abnormalities in patients with coronary microvascular dysfunction and Chagas disease: a pilot non-randomized study

Abstract INTRODUCTION: Most patients with chronic cardiomyopathy of Chagas disease (CCCD) harbor a secondary cause of coronary microvascular dysfunction (CMD), for which there is no evidence-based therapy. We evaluated the impact of verapamil plus aspirin on symptoms and perfusion abnormalities in patients with CCCD and CMD. METHODS: Consecutive patients with angina pectoris, who had neither coronary artery obstructions nor moderate-severe left ventricular dysfunction (left ventricular ejection fraction > 40%) despite showing wall motion abnormalities on ventriculography, were referred for invasive angiography and tested for Chagas disease. Thirty-two patients with confirmed CCCD and ischemia on stress-rest SPECT myocardial perfusion scintigraphy (MPS) were included. Clinical evaluation, quality of life (EQ-5D/ Seattle Angina Questionnaire), and MPS were assessed before and after 3 months of treatment with oral verapamil plus aspirin (n=26) or placebo (n=6). RESULTS: The mean patient age was 64 years, and 18 (56%) were female. The ischemic index summed difference score (SDS) in MPS was significantly reduced by 55.6% after aspirin+verapamil treatment. A decrease in SDS was observed in 20 (77%) participants, and in 10 participants, no more ischemia could be detected. Enhancements in quality of life were also detected. No change in symptoms or MPS was observed in the placebo group. CONCLUSIONS: This low-cost 3-month treatment for patients diagnosed with CCCD and CMD was safe and resulted in a 55.6% reduction in ischemic burden, symptomatic improvement, and better quality of life.

Effect of Shuangshen Ningxin Capsules on Cardiac Function and Hemodynamics in Rats with Coronary Microvascular Dysfunction / 中国实验方剂学杂志

Objective:To investigate the effect of Shuangshen Ningxin capsules （SSNX） on cardiac hemodynamics and cardiac function in rats with coronary microvascular dysfunction. Method:Rats were randomly divided into a sham operation group， a model group， a nicorandil group （5 mg·kg^-1）， and high- （180 mg·kg^-1）， medium- （90 mg·kg^-1）， and low-dose （45 mg·kg^-1） SSNX groups. Rats received corresponding drugs for 7 days. Two hours after the last administration， the model of coronary microvascular dysfunction was induced by left ventricular injection of embolic microspheres （40-120 μm， about 1 000 microspheres）. Twenty-four hours after modeling， left ventricular internal dimension in diastole （LVIDd）， left ventricular internal dimension in systole （LVIDs） left ventricular end-diastolic volume （LVEDV）， left ventricular end-systolic volume （LVESV）， stroke volume （SV）， cardiac output （CO）， left ventricular ejection fraction （EF）， and left ventricular shortening rate （FS） were detected by echocardiography. Cardiac catheterization was used to observe the arterial systolic blood pressure （SBP）， diastolic blood pressure （DBP）， left ventricular systolic pressure （LVSP）， left ventricular end-diastolic pressure （LVEDP）， maximum rate of increase in left ventricular pressure （LV+dp/dt_max）， and maximum rate of decrease in left ventricular pressure （LV-dp/dt_max）， and the mean arterial pressure （MAP） was calculated. Heart rate （HR） was calculated according to Ⅱ lead ECG. Biochemical analysis was carried out to detect the activities of creatine kinase （CK）， creatine kinase-MB （CK-MB）， and lactate dehydrogenase （LDH）. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum cardiac troponin T （cTnT）. Western blot was used to detect the protein expression of Caspase-3， Bcl-2， and Bax， and 2，3，5-triphenyltetrazolium chloride （TTC） staining to observe the area of myocardial infarction. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of the myocardium. Result:As revealed by echocardiography， compared with the sham operation group， the model group showed reduced SV， CO， EF， and FS （<italic>P</italic><0.01）， and increased LVIDs and LVEDV （<italic>P</italic><0.01）. Compared with the model group， the SSNX groups showed increased EF （<italic>P</italic><0.05， <italic>P</italic><0.01） and FS （<italic>P</italic><0.01）， and the high- and medium-dose SSNX groups displayed reduced LVIDs and LVESV， and increased LVEDV， SV， and CO （<italic>P</italic><0.05， <italic>P</italic><0.01）. SBP， DBP， MAP， LVSP， LV+dp/dt_max， and LV-dp/dt_max in the model group were lower than those in the sham operation group （<italic>P</italic><0.01）， while there was no significant difference in HR. SSNX improved hemodynamics of rats， and increased SBP， DBP， MAP， LVSP， LV+dp/dt_max， LV-dp/dt_max， and HR as compared with the model group （<italic>P</italic><0.05， <italic>P</italic><0.01）. The serum CK， LDH， CK-MB， and cTnT levels in the model group were higher than those in the sham operation group （<italic>P</italic><0.01）. Compared with the model group， SSNX groups reduced serum CK， LDH， CK-MB， and cTnT （<italic>P</italic><0.05，<italic> P</italic><0.01）. Compared with the sham operation group， the model group displayed increased expression of Caspase-3 protein in the myocardium （<italic>P</italic><0.01） and reduced expression of Bcl-2 protein （<italic>P</italic><0.05）. The expression of Caspase-3 protein in the myocardium of SSNX groups was lower than that in the model group， and statistical difference was observed between the low-dose SSNX group and the model group （<italic>P</italic><0.05）. Compared with the model group， the SSNX groups exhibited increased expression of Bcl-2 in the rat myocardium， and the statistical difference was observed in the high-dose SSNX group <italic>（P</italic><0.01）. As demonstrated by the TTC staining， compared with the model group， SSNX groups showed reduced areas of myocardial infarction （<italic>P</italic><0.01）. The HE staining indicated that the pathological injury in myocardial tissues of the SSNX groups was relieved as compared with that in the model group. Conclusion:SSNX can significantly enhance the cardiac function after coronary microvascular dysfunction caused by embolic microspheres， improve cardiac hemodynamics， reduce the area of myocardial infarction， and decrease CK， LDH， CK-MB， and cTnT levels. The mechanism may be related to the inhibition of cardiomyocyte apoptosis to protect the myocardium.

Estudo Comparativo da Doença Coronariana Microvascular Causada por Doença de Chagas e por Outras Etiologias / Chagas Cardiomyopathy as the Etiology of Suspected Coronary Microvascular Disease. A Comparison Study with Suspected Coronary Microvascular Disease of Other Etiologies

Resumo Fundamento A doença de Chagas (DC) constitui uma causa potencial negligenciada de doença microvascular coronariana (DMC). Objetivos Comparar pacientes com DMC relacionada à DC (DMC-DC) com pacientes com DMC ligada a outras etiologias (DMC-OE). Métodos De 1292 pacientes estáveis, encaminhados para angiografia coronária invasiva para elucidar o padrão hemodinâmico e a causa de angina, 247 apresentaram coronárias subepicárdicas normais, e 101 foram incluídos após aplicação dos critérios de exclusão. Desses, 15 compuseram o grupo de DMC-DC e suas características clínicas, hemodinâmicas, angiográficas, e cintilográficas foram comparadas às do grupo de 86 pacientes com DMC-OE. O nível de significância estatística para todas as comparações adotado foi de 0,05. Resultados Pacientes com suspeita de DMC-DC apresentaram características antropométricas, clínicas e angiográficas, além de alterações hemodinâmicas e de perfusão miocárdica estatisticamente comparáveis às detectadas nos 86 pacientes com DMC-OE. Disfunção ventricular diastólica, expressa por elevada pressão telediastólica do ventrículo esquerdo, foi igualmente encontrada nos dois grupos. Entretanto, em comparação a esse grupo com DMC-OE, o grupo com DMC-DC exibiu fração de ejeção ventricular esquerda mais baixa (61,1 ± 11,9 vs 54,8 ± 15,9; p= 0,049) e mais elevado escore de mobilidade da parede ventricular (1,77 ± 0,35 vs 1,18 ± 0,26; p= 0,02). Conclusão A cardiomiopatia crônica da doença de Chagas esteve associada à etiologia de possível doença microvascular coronariana em 15% de amostra de 101 pacientes estáveis, cujo sintoma principal era angina requerendo elucidação por angiografia invasiva. Embora os grupos DMC-DC e DMC-OE apresentassem características clínicas, hemodinâmicas, e de perfusão miocárdica em comum, a disfunção global e segmentar do ventrículo esquerdo foi mais grave nos pacientes com DMC associada à DC em comparação à DMC por outras etiologias. (Arq Bras Cardiol. 2020; 115(6):1094-1101)

Abstract Background Chagas disease (CD) as neglected secondary form of suspected coronary microvascular dysfunction (CMD). Objectives Comparison of patients with CMD related to CD (CMD-CE) versus patients with CMD caused by other etiologies (CMD-OE). Methods Of 1292 stable patients referred for invasive coronary angiography to elucidate the hemodynamic pattern and the cause of angina as a cardinal symptom in their medical history, 247 presented normal epicardial coronary arteries and 101 were included after strict exclusion criteria. Of those, 15 had suspected CMD-CE, and their clinical, hemodynamic, angiographic and scintigraphic characteristics were compared to those of the other 86 patients with suspected CDM-OE. Level of significance for all comparisons was p < 0.05. Results Patients with suspected CMD-CE showed most anthropometric, clinical, angiographic hemodynamic and myocardial perfusion abnormalities that were statistically similar to those detected in the remaining 86 patients with suspected CMD-OE. LV diastolic dysfunction, expressed by elevated LV end-diastolic pressure was equally found in both groups. However, as compared to the group of CMD-OE the group with CMD-CE exhibited lower left ventricular ejection fraction (54.8 ± 15.9 vs 61.1 ± 11.9, p= 0.049) and a more severely impaired index of regional wall motion abnormalities (1.77 ± 0.35 vs 1.18 ± 0.26, p= 0.02) respectively for the CMD-OE and CMD-CE groups. Conclusion Chronic Chagas cardiomyopathy was a secondary cause of suspected coronary microvascular disease in 15% of 101 stable patients whose cardinal symptom was anginal pain warranting coronary angiography. Although sharing several clinical, hemodynamic, and myocardial perfusion characteristics with patients whose suspected CMD was due to other etiologies, impairment of LV segmental and global systolic function was significantly more severe in the patients with suspected CMD related to Chagas cardiomyopathy. (Arq Bras Cardiol. 2020; 115(6):1094-1101)

Cancer therapy-related cardiovascular dysfunction and coronary microvascular dysfunction: Research progress / 第二军医大学学报

The risk of cardiovascular diseases is significantly increased in cancer patients receiving chemotherapy or radiotherapy. Recent evidences suggested that cardiac dysfunction and subsequent heart failure are mainly caused by vascular toxicity rather than myocardial toxicity. However, not all of the vascular toxicity of cancer therapies can be explained by obstructive coronary artery disease. In the past few decades, it has been found that myocardial ischemia may be caused by structural or functional disorders of the complex vascular network that cannot be seen by coronary angiography, known as coronary microvascular dysfunction (CMD). There is growing evidences that cancer therapy-related cardiovascular dysfunction (CTRCD) and CMD have many common pathophysiological mechanisms. This paper elucidates the relationship between CTRCD and CMD from the pathophysiological perspective, providing reference for exploring new diagnostic methods and treatment strategies of cardiovascular diseases.

Advances in animal model and traditional Chinese medicine prevention in coronary microvascular dysfunction / 中国中药杂志

Coronary microvascular dysfunction (CMD) is a common mechanism for some heart disease like cardiac X syndrome and no-reflow phenomenon after percutaneous coronary intervention(PCI). With the development of medical imageology, CMD has received increased attention. Animal model of CMD is indispensable tool for the research of pathogenesis and treatment evaluation, therefor choose an appropriate animal model is the first issue to carry out CMD research. Experimental and clinical studies have shown unique effectiveness of traditional Chinese medicine(TCM) in CMD therapy. Clarifying of the TCM therapeutic effect mechanisms and seeking an optimal solution of combination of traditional Chinese and western medicine will be the focus of future research. This paper reviewed the establishment and evaluation of CMD animal model, as well as the intervention study of TCM on CMD. The article aims to provide reference for the basic research of CMD and the TCM experimental study on CMD.