Effectiveness and safety of Shexiang Baoxin Pill(MUSKARDIA)in patients with stable coronary artery disease and concomitant diabetes mellitus:a subgroup analysis of a randomized clinical trial

Background:Preliminary studies have indicated that Shexiang Baoxin Pill(MUSKARDIA)has a coronary artery dilation effect and increases the coronary blood flow,relieving the symptoms of angina.This study aimed to evaluate the benefit of MUSKARDIA on patients with stable coronary artery disease(CAD)and diabetes mellitus(DM).Methods:This was a subgroup analysis of a multicenter,randomized,placebo-controlled phase IV trial.CAD patients with a medical history of DM or baseline fasting blood glucose(FBG)≥7.0 mmol/L were grouped according to the treatment(standard therapy plus MUSKARDIA or placebo).The primary outcome was major adverse cardiovascular events(MACEs),which was the composite outcome of cardiovascular death,non-fatal myocardial infarction,and non-fatal stroke.The secondary outcome was the composite outcome of all-cause death,non-fatal myocardial infarction,non-fatal stroke,hospitalization for unstable angina or heart failure,and coronary angioplasty.Results:MACEs occurred in 2.6%(9/340)and 4.8%(18/376)of patients in the MUSKARDIA and placebo groups,respectively(P=0.192).Secondary composite outcome was significantly less frequent with MUSKARDIA than with placebo(15.3%[52/340]vs.22.6%[85/376],P=0.017).Risk of MACEs(hazard ratio[HR]=0.69,95%confidence interval[CI]:0.31-1.57)was comparable between two groups.In patients with uncontrolled DM(≥4 measurements of FBG≥7 mmol/L in five times of follow-up),the risk of secondary outcome was significantly lower with MUSKARDIA(5/83,6.0%)than with placebo(15/91,16.5%)(HR=0.35,95%CI:0.13-0.95).Conclusion:As an add-on to standard therapy,MUSKARDIA shows a trend of reduced MACEs in patients with stable CAD and DM.Furthermore,MUSKARDIA may reduce the frequency of all-cause death,hospitalization,and coronary angioplasty in this population,especially in those with uncontrolled DM.Trial Registration:ChiCTR.org.cn,ChiCTR-TRC-12003513.

Layers of interstitial fluid flow along a“slit-shaped”vascular adventitia

Interstitial fluid(ISF)flow through vascular adventitia has been discovered recently.However,its kinetic pattern was unclear.We used histological and topographical identification to observe ISF flow along venous vessels in rabbits.By magnetic resonance imaging(MRI)in live subjects,the inherent pathways of ISF flow from the ankle dermis through the legs,abdomen,and thorax were enhanced by paramagnetic contrast.By fluorescence stereomicroscopy and layer-by-layer dissection after the rabbits were sacrificed,the perivascular and adventitial connective tissues(PACTs)along the saphenous veins and inferior vena cava were found to be stained by sodium fluorescein from the ankle dermis,which coincided with the findings by MRI.The direction of ISF transport in a venous PACT pathway was the same as that of venous blood flow.By confocal microscopy and histological analysis,the stained PACT pathways were verified to be the fibrous connective tissues,consisting of longitudinally assembled fibers.Real-time observations by fluorescence stereomicroscopy revealed at least two types of spaces for ISF flow:one along adventitial fibers and another one between the vascular adventitia and its covering fascia.Using nanoparticles and surfactants,a PACT pathway was found to be accessible by a nanoparticle of<100 nm and contained two parts:a transport channel and an absorptive part.The calculated velocity of continuous ISF flow along fibers of the PACT pathway was 3.6-15.6 mm/s.These data revealed that a PACT pathway was a"slit-shaped"porous biomaterial,comprising a longitudinal transport channel and an absorptive part for imbibition.The use of surfactants suggested that interfacial tension might play an essential role in layers of continuous ISF flow along vascular vessels.A hypothetical"gel pump"is proposed based on interfacial tension and interactions to regulate ISF flow.These experimental findings may inspire future studies to explore the physiological and pathophysiological functions of vascular ISF or interfacial fluid flow among interstitial connective tissues throughout the body.