Exploration of the effect and mechanism of Shexiang Tongxin Dropping Pill on coronary microvascular dysfunction

Abstract

Coronary microvascular dysfunction(CMVD) refers to a clinical syndrome of myocardial ischemia caused by abnormal microvascular structure or function of coronary arteries with a diameter less than 500µm.It is closely related to adverse cardiovascular events,and its treatment remains a clinical challenge. Shexiang Tongxin Dropping Pill(SXDP) shows the effect of improving coronary microvascular perfusion, but the underlying mechanism remains largely unclear.In this study,we aims to observe the effects of SXDP on enhancing coronary blood flow in coronary artery disease(CAD) patients undergoing percutaneous coronary intervention (PCI) treatment and coronary microvascular embolism(CME) mice model while investigating potential mechanisms linked to oxidative stress and inflammatory responses.Firstly, we selected 62 patients with angina pectoris who were negative for cardiac troponin and randomly divided them into control group and SXDP group, with 31 cases in each group. The control group was given aspirin, statin, ACEI, and β-receptor blocker, the SXDP group added the SXDP on the basis of the above drugs. Both groups took the medicine for three consecutive days, coronary angiography(CAG) and(or) PCI were performed on the the fourth day,two hours before surgery, the control group received 300mg of aspirin and 300mg of clopidogrel, while the SXDP group received 10 pills of SXDP in addition to the aforementioned medication, Subsequently implemented CAG to observe the corrected TIMI frame count(CTFC) value of coronary blood flow, as well as the TC, LDL-C, Lp-PLA2,FIB and hs-CRP in serum. Secondly,we utilized electrocardiogram recordings, laser speckle imaging, and histological examination to assess the enhancement of coronary blood flow in CME mice model induced by autologous blood clot particles following SXDP treatment. Additionally, an in vitro model of oxygen-glucose deprivation (OGD) was established using human umbilical vein endothelial cells(HUVECs) to investigate the impact of SXDP on lncRNA H19 and P66shc DNA methylation. In clinical trials, we observed that SXDP can increase coronary CTFC values and reduce the serum levels of TC, LDL-C, Lp-PLA2, FIB and hs- CRP to varying degrees.And in the CME mice model, SXDP was found to enhance myocardial blood supply, decrease thrombosis and myocardial micro- infarctions, and improve coronary microvascular endothelial function. In vitro experiments, we observed SXDP enhances p66shc DNA methylation through the inhibition of lncRNAH19 expression, leading to a reduction in oxidative stress and inflammatory responses in coronary microvessels. Our findings suggested that SXDP can effectively improve coronary microvascular blood flow in patients with CAD and CME model mice,Simultaneously, lncRNAH19 is a key molecule in SXDP's regulation of P66shc,we should focus on lncRNAH19 as potential values for evaluating CMVD.