COMPREHENSIVE MATHEMATICAL MODEL OF MICROCIRCULATORY DYNAMICS (Ⅰ)——BASIC THEORY

Under the basis of physiological data, a nonlinear and unsteady comprehensive mathematical model of microcirculatory dynamics with distributed parameters is developed. Hemodynamics, interstitium dynamics, lymph dynamics, dynamics of protein transport, oxygen dynamics, dynamics of heat transfer, and myogenic and metabolic regulation procedures are included. The interactions between these factors were comprehensively exhibited. The influences of arteriolar vasomotion and nonlinear viscoelasticity of blood in arteriole are considered. A simplified vessel network consisting of arteriole, open and reserved capillaries, venule, initial lymphatics and arteriole_venule anastomose is adopted as the geometrical model. This kind of comprehensive mathematical model is helpful in analyzing clinical data and developing a “numerical experiment method” in microcirculation research.

Increased index of microcirculatory resistance in older patients with heart failure with preserved ejection fraction

Objective To study the coronary microvascular function in older patients with heart failure with preserved ejection fraction (HFpEF) using an invasive pressure–temperature sensor guidewire. Methods Patients undergoing echocardiography and cardiac catheterization examinations for exertional dyspnea and a positive stress test were retrospectively enrolled from January 2014 to November 2017, and were allocated into the control group or HFpEF group. The HFpEF group was secondary divided into two groups according to the age of 65 years. Comparing the clinical features and values obtained in examinations between the three groups, multivariate regression analysis was used to analyze the predictors of left ventricle end diastolic pressure (LVEDP). Results There were 87 patients enrolled in this study. The older HFpEF patients (n = 32) were more likely to be female;and had the most comorbidities, such as diabetes mellitus, atrial fibrillation, and chronic kidney dysfunction (CKD) with a low estimated glomerular filtration rate (eGFR), and had a similar hypertensive prevalence as the adult HFpEF group (n = 24), whose mean LVEDP and index of microcirculatory resistance (IMR) were highest in comparison to the adult HFpEF patients and controls (n = 31). The coronary flow reserve (CFR) in the older HFpEF and adult HFpEF groups was similarly reduced. In the regression analysis, the IMR linearly correlated to LVEDP, and was the only independent predictor of LVEDP. Conclusions An increased IMR and reduced CFR were characteristics of microvascular dysfunction in older HFpEF patients. The IMR independently had a positive linear correlation with LVEDP. Microvascular rarefaction might be a subsequent pathological progression in the development of HFpEF.

TCM Stage Differentiation Treatment of Diabetic Gangrene——An Observation on Microcirculatory Changes

Microcirculatory changes and therapeutic effects in 39 non-insulin dependent diabetes mellitus (NIDDM) cases were evaluated. Under the same basic treatment in both groups, the treatment group (21 cases) was treated with TCM drugs according to its stages and compared with the control group (18 cases, treated with 654-2). The results showed that the microcirculatory cumulative scores were significantly decreased in both groups (P<0.05), but the decrease in the treatment group was more marked (P<0.05). In the treatment group, 15 cases were cured, 3 markedly effective, 2 effective and 1 ineffective; while in the control group, 13 cases were cured, 1 markedly effective and 4 ineffective. Statistically, there is no significant difference between the 2 groups (P>0.05) in therapeutic effects.

Dynamic microcirculatory changes in liver graft from non-heart-beating donor with warm ischemia injury in rat

BACKGROUND: Since the 1990s, liver grafts from non- heart-beating donor (NHBD) have become an alternative because of the deficiency of grafts from heart-beating-do- nors (HBDs). Warm ischemia injury, however, directly influences the grafts' activity and functional recovery after operation. We investigated the microcirculatory change of liver graft at different warm ischemia time (WIT) in rats and determined the maximum limitation of liver graft to warm ischemia. METHODS: According to WIT, 120 rats were divided ran- domly into 5 groups of 0, 15 , 30 , 45 , 60 minutes respec- tively. The microcirculatory changes of their liver grafts were measured including serum level of hyaluronic acid (HA) and ultrastructural changes. After orthotopic liver transplantation (OLT), the recovery of microcirculation of the liver grafts after 24 hours, 48 hours and 3 days was ob- served. RESULTS: Microcirculatory changes and function of the liver grafts became normal after reperfusion when the WIT was less than 30 minutes. In the 45-minute WI group, part of blood sinusoids was full of cytoplasmic blebs stemming from the microvilli of hepatocytes and hemocytes. The se- rum level of HA in each group after 45 minutes of WI re- covered after reperfusion. CONCLUSIONS: The microcirculatory change of rat liver graft is reversible when the WIT is less than 30 minutes: rat liver graft could be safely subject to warm ischemia within30 minutes. The maximal 45 minutes of WI can be tolera- ted by the microcirculatory function of liver graft. After 60 minutes of WI, irreversible disturbance of microcirculation may appear.

Detection of angiospastic disorders in the microcirculatory bed using laser diagnostics technologies

The evaluation of the microcirculatory bed functional state and the identification of angiospastic disorders with related complications,when the pathological changes are reversible,have an important role in medical practice.The aim of this study was to evaluate the possibility of using optical noninvasive methods and the cold pressor test to solve this problem.A total of 33 patients with rheumatological diseases and 32 healthy volunteers were included in the study.Laser Doppler flowmetry,tissue reflectance oximetry and pulse oximetry were used as optical noninvasive methods.The parameters were recorded before,immediately after and 20 min after the cold pressor test.Based on the measured parameters,the complex parameters of the microcirculatory bed were calculated.A detailed statistical analysis of the parameter changes for each individual in the two groups displayed diverse microcirculatory bed parameter responses upon cold exposure,with differing recovery of parameters after CPT.New diagnostic criteria were proposed for the identification of angiospastic disorders.According to the proposed criteria,27 people of the volunteers group were confirmed to not display any disorders.In the patient group,however,18 people were observed to have a relatively normal functional state of the microcirculatory bed,while 15 people were observed to have a possible tendency to angiospasm.To highlight the diferences between a relatively normal state and presence of angiospastic disorders,statistical analysis of experimental data was carried out,which revealed significant differences.Further analysis of data with angiospastic disorders identified a relationship between their diagnoses and the results of labo-ratory studies.Thus,the evaluation of combined noninvasive optical diagnostic method use,the cold pressor test and proposed diagnostic criteria showed a positive result.This approach can be used to detect the presence of possible angiospastic disorders and related complications,as well as mi-crocirculatory bed disorders against the background of other diseases.

COMPREHENSIVE MATHEMATICAL MODEL OF MICROCIRCULATORY DYNAMICS(Ⅱ)—ALCULATION AND THE RESULTS

The mathematical model described in Part I was solved using “influence line method” combining analytical method and finite element method. Many important aspects of microcirculatory dynamics were analyzed and discussed. It show that interstitial fluid pressure changes its sign twice within one arteriolar vasomotion period and it is therefore not important that interstitial fluid pressure is a little higher or lower than atmospheric pressure; arteriolar vasomotion can periodically result in lymph formation and interstitial total pressure plays an important role in this procedure; local regulation of microcirculation can meet metabolic need some extent in the form of dynamic equilibrium. The property of arteriole as a “resistant vessel” and the efficiency of microvascular network as heat exchanger are also shown. These results show that the comprehensive mathematical model developed in Part I is physiologically reasonable.

Biology and function of pericytes in the vascular microcirculation

Pericytes are the main cellular components of tiny arteries and capillaries.Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines,thus affecting the contraction and relaxation of microvessels and playing an essential role in regulating vascular microcirculation.Moreover,due to the characteristics of stem cells,pericytes can differentiate into a variety of inflammatory cell phenotypes,which then affect the immune function.Additionally,pericytes can also participate in angiogenesis and wound healing by interacting with endothelial cells in vascular microcirculation disorders.Here we review the origin,biological phenotype and function of pericytes,and discuss the potential mechanisms of pericytes in vascular microcirculation disorders,especially in pulmonary hypertension,so as to provide a sound basis and direction for the prevention and treatment of vascular microcirculation diseases.

Effect of ulinastatin on hepatic ischemia-reperfusion injury in rats

Objective To investigate the effect of ulinastatin(UTI)on hepatic ischemia-reperfusion injury in rats.Methods Totally 24 adult Sprague-Dawley rats were randomly divided into 3 groups:sham-operated control group(SO group),ischemia-reperfusion group(I/R group)and ulinastatin group(UTI group).Liver in I/R group underwent 1 h of reperfusion after 30 min of ischemia.In UTI group,UTI(2×104 U/kg)was administered to rats 30 min before modeling.The levels of alanine aminotransferase,aspartate aminotransferase and tumor necrosis factor-alpha(TNF-α)in serum were measured and the levels of nitric oxide and malondialdehyde in liver were determined.The histological changes of liver were observed.Results The levels of alanine aminotransferase,aspartate aminotransferase and TNF-α in serum were significantly increased in I/R group compared with those in UTI group(P<0.05).The levels of nitric oxide and malondialdehyde in liver were significantly higher in I/R group than in UTI group(P<0.05).Histological examination of liver indicated that the damages were more severe in I/R group than in UTI group.Conclusion UTI has the ability to inhibit the production of TNF-α and oxyradical,and ameliorate microcirculatory dysfunction in rats with hepatic ischemia-reperfusion injury.

Effect of Shenfu injection on microcirculation effect index in early-and middle-stage of cardiogenic shock rats

OBJECTIVE Shenfu injection(SFI)is an effective treatment of cardiogenic shock,the pathology of the central link was microcirculation disturbance.However,whether the microcirculation status of the early-and mid-stage of cardiogenic shock has any difference is unclear.This study aimed to observe the effect of SFI on the microcirculatory disturbance in mesentery for early-and mid-stage of cardiogenic shock rat.METHODS The early-and mid-stage model of cardiogenic shock was established by ligating the ending or root of left anterior descending coronary arteries(LADCA).The rats were randomly divided into 9 groups,ie control group,early-stage model group,mid-stage model group,3 early medicated groups and 3 mid medicated groups(the dosage was 1,3.33,10 mL·kg^(-1) SFI for cardiogenic shock rats of early-and mid-stage,respectively).Parameters in mesenteric microcirculation,such as velocity of RBCs in venules,diameters of venules,the count of leukocyte adhesion and vascular permeability which calculated by FITC-dextran leakage were observed through an GeneandiM2 inverted intravital microscope and high-speed video camera system.RESULTS The cardiogenic shock induced by ligating the LADCA resulted in a number of responses in microcirculation,including a significant increase in the counts of adhesive leukocytes,narrowing of the vascular diameter,decrease in the velocity of RBCs and dextran efflux.All of the above parameters for early-stage cardiogenic shock rats were attenuated by the treatment with SFI,especially the dosage of 10 mL·kg^(-1).While SFI had no apparent time-effect on the vascular diameter and vascular permeability in mesentery for mid-stage cardiogenic shock rats.CONCLUSION The microcirculation status of the early-and mid-stage of cardiogenic shock rats were quite different.The efficacy of early treatment with SFI was more obvious than the mid administration,which could provide experimental and theoretical basis for the patients with cardiogenic shock in an earlier time.

Disorders of cerebrovascular angioarchitectonics and microcirculation in the etiology and pathogenesis of Alzheimer’s disease

There have recently appeared many reports dedicated to cerebral hemodynamics disorders in AD. However, certain specific aspects of cerebral blood flow and microcirculation during this disease are not fully understood. This research focuses on the identification of particular features of cerebral angioarchitectonics and microcirculation at preclinical and clinical AD stages and on the determination of their importance in AD etiology and pathogenesis. 164 patients participated in the research: Test Group—81 patients with different AD stages;Control Group— 83 patients with etiologically different neurodegenerative brain lesions with manifestations of dementia and cognitive impairment but without AD. All patients underwent: assessment of cognitive function (MMSE), severity of dementia (CDR) and AD stages (TDR), laboratory examination, computed tomography (CT), magnetic resonance imaging (MRI), brain scintigraphy (SG), rheoencephalography (REG) and cerebral multigated angiography (MUGA). All Test Group patients, irrespective of their AD stage, had abnormalities of the cerebral microcirculation manifested in dyscirculatory angiopathy of Alzheimer’s type (DAAT), namely: reduction of the capillary bed in the hippocampus and frontal-parietal regions;development of multiple arteriovenous shunts in the same regions;early venous dumping of arterial blood through these shunts with simultaneous filling of arteries and veins;development of abnormally enlarged lateral venous trunks that receive blood from the arterio-venous shunts;anomalous venous congestion at the border of frontal and parietal region;increased loop formation of distal intracranial arterial branches. Control group patients did not have combinations of such changes. These abnormalities are specific for AD and can affect amyloid beta metabolism contributing to its accumulation in the brain tissue and thereby stimulating AD progression.

Coronary physiology assessment in the catheterization laboratory

Physicians cannot rely solely on the angiographic appearance of epicardial coronary artery stenosis when evaluating patients with myocardial ischemia. Instead, sound knowledge of coronary vascular physiology and of the methods currently available for its characterization can improve the diagnostic and prognostic accuracy of invasive assessment of the coronary circulation, and help improve clinical decision-making. In this article we summarize the current methods available for a thorough assessment of coronary physiology.

褐藻淀粉硫酸酯对家兔心肌梗塞样损害的影响

本文通过心电图观察。血清磷酸肌酸激酶(SCPK)活性测定、心肌切片病理学研究、球结膜微循环显微电视观察和照相,比较了褐藻淀粉硫酸脂(LS)和肝素对78只由异丙基肾上腺素所致的家兔实验性心肌梗塞的影响。LS50mg/kg 腹腔注射和肝素4mg/kg 腹腔注射虽不能予防心电图异常 T 波的出现,但能促进其恢复,予防 SCPK 异常升高,微循环障碍恢复加快,心肌坏死程度按 Rona 分级减轻,经 H 检验有显著差异(P<0.05)。

Shexiang Tongxin dropping pill(麝香通心滴丸)protects against sodium laurate-induced coronary microcirculatory dysfunction in rats

OBJECTIVE:To investigate the protective effects of Shexiang Tongxin dropping pill(麝香通心滴丸,STDP)in a rat model of coronary microcirculatory dysfunction(CMD).METHODS:Sprague-Dawley rats were allocated randomly into four groups:sham,CMD model,STDP,and nicorandil.After 4 weeks of treatment,CMD was induced by injection of sodium laurate(0.2 m L,2 g/L)into the left ventricle while obstructing the ascending aorta.Rats in the sham group underwent an identical surgical procedure but were administered physiological(0.9%)saline(0.2 m L).Twenty-four hours after surgery,blood samples were collected for biochemical analyses and enzyme-linked immunosorbent assays.Heart tissues were removed for histopathology staining;apoptosis and inflammatory cytokines were examined by Western blotting.RESULTS:The STDP group had a lower level of creatine kinase-myocardial band,lactate dehydrogenase,and cardiac troponin-I than that in the CMD model group.Infiltration of inflammatory cells,myocardial ischaemia,and microthrombosis were relieved in the STDP group compared with CMD model group.Levels of endothelin-1,nuclear factor-kappa B,tumour necrosis factor-α,interleukin-6,interleukin-1β,malondialdehyde,B-cell lymphoma(Bcl)-2-associated X protein,and caspase-3 were lower,and levels of nitric oxide,Bcl-2,and superoxide dismutase were higher,in the STDP group in comparison with the CMD model group.CONCLUSION:STDP pretreatment improved the CMD induced by sodium laurate via anti-inflammatory,anti-apoptosis,and anti-oxidant mechanisms.

Effects of Danhong Injection (丹红注射液) on Peri-Procedural Myocardial Injury and Microcirculatory Resistance in Patients with Unstable Angina Undergoing Elective Percutaneous Coronary Intervention: A Pilot Randomized Study

Objective To evaluate the effect of Danhong Injection(丹红注射液,DH)on the index of microcirculatory resistance(IMR)and myocardial injury in patients with unstable angina undergoing elective percutaneous coronary intervention(PCI).Methods Seventy-eight patients with unstable angina were randomly divided into DH group(39 cases)and the control group(39 cases)during elective PCI.Randomization was performed using a random-number table.The DH group received DH at a dosage of 40 mL(mixed with 250 mL saline,covered by a light-proof bag,intravenous drip)during PCI and daily for 7 consecutive days,while the control group only received the same dosage of saline.Both groups received standardized treatment.The IMR and fractional flow reserve(FFR)were measured at maximal hyperemia before and after PCI.Myocardial markers,including myoglobin,creatine kinase(CK),creatine kinase MB(CK-MB),and coronary troponin T(cTnT)values were measured at baseline and 24 h after PCI.Results Among the 78 patients enrolled,the baseline and procedural characteristics were similar between the two groups.There was no significant difference in pre-PCI myocardial markers and coronary physiological indexes between the two groups.However,post-PCI CK and CK-MB levels in the DH group were significantly lower than those in the control group(111.97±80.97 vs.165.47±102.99,P=0.013;13.08±6.90 vs.19.75±15.49,P=0.016).Post-PCI myoglobin and cTNT-positive tend to be lower in the DH group than in the control group but did not reach statistical significance(88.07±52.36 vs.108.13±90.94,P=0.52;2.56%vs.7.69%,P=0.065).Compared with the control group,the post-IMR levels of the DH group tended to decrease,but there was no statistical difference(20.73±13.15 vs.26.37±12.31,P=0.05).There were no statistical differences in post-FFR in both groups.The peri-procedural myocardial injury of the DH group was significantly lower than that of the control group(2.56%vs.15.38%,P=0.025).During the 30-d follow-up period,no major adverse cardiovascular events occurred in either group.Conclusion This study demonstrated benefit of DH in reducing myocardial injury and potential preserving microvascular function in patients with unstable angina undergoing elective PCI.

Index of microcirculatory resistance: state-of-the-art and potential applications in computational simulation of coronary artery disease

The dysfunction of coronary microcirculation is an important cause of coronary artery disease(CAD).The index of microcirculatory resistance(IMR)is a quantitative evaluation of coronary microcirculatory function,which provides a significant reference for the prediction,diagnosis,treatment,and prognosis of CAD.IMR also plays a key role in investigating the interaction between epicardial and microcirculatory dysfunctions,and is closely associated with coronary hemodynamic parameters such as flow rate,distal coronary pressure,and aortic pressure,which have been widely applied in computational studies of CAD.However,there is currently a lack of consensus across studies on the normal and pathological ranges of IMR.The relationships between IMR and coronary hemodynamic parameters have not been accurately quantified,which limits the application of IMR in computational CAD studies.In this paper,we discuss the research gaps between IMR and its potential applications in the computational simulation of CAD.Computational simulation based on the combination of IMR and other hemodynamic parameters is a promising technology to improve the diagnosis and guide clinical trials of CAD.

AMELIORATING EFFECTS OF CARDIOTONIC PILLS,A COMPOUND CHINESE MEDICINE ON MYOCARDIAL MICROCIRCULATORY DISTURBANCE AND MYOCARDIAL INJURY AFTER ISCHEMIA-REPERFUSION

Cardiotonic Pills(CP)is a compound preparation of Chinese medicine consisting of Salvia miltiorrhiza,Panax notoginseng and Borneol,and it has been approved in 1994by the China State Food and Drug Administration for treating ischemic angina pectoris.It has passed the Phase II clinical trials by the US Food and Drug Administration in2009,December,demonstrating its potential to prolong

Predictive value and impact analysis for the index of microcirculatory resistance in MI patients with elective percutaneous coronary intervention

Objective To evaluate the predictive value and impact for the index of microcirculatory resistance(IMR)in myocardial infarction(MI)patients with elective percutaneous coronary intervention(PCI)for treating coronary artery occlusion.Methods A total of 34 patients with STEMI or non-STEMI treated after 12h time window

Effects of modified Wenjing decoction on microcirculation in reproductive organs in rats with symptom patterns of cold coagulation and blood stasis

OBJECTIVE: To investigate the relationship between symptom patterns of cold coagulation and blood stasis(CCBS) and microcirculation disturbance. In addition, we determined the efficacy of modified Wenjing decoction(WJD) for the treatment of CCBS.METHODS: CCBS was induced in rats with an icewater bath treatment. The ovarian function, microvascular and circulatory status of reproductive organs, and function of local microvascular endothelial cells(VECs) and vascular smooth muscle cells(VSMCs) were evaluated.RESULTS: Ovarian dysfunction was observed in the rats with CCBS. It was characterized by the presence of an estrous cycle disorder and a decrease in reproductive hormone levels. Microvascular circulation disorders were associated with an imbalance in vasoconstriction, relaxation substances, nitric oxide, abnormal blood flow in whole blood, and decreased blood flow in the auricle and uterus. VECs were damaged, and VSMCs contracted and proliferated in ovarian and uterine tissues.CONCLUSION: Our findings suggest that the dysfunctional reproductive organs observed in gynecological CCBS may be closely related to the microcirculation disturbance of local tissues, microvascular contraction, and vascular remodeling. Modified WJD can be used to treat CCBS by improving microcirculation in reproductive organs.

The venous ulcer continues to be a clinical challenge: an update

Venous ulcers are a common chronic problem in many countries especially in Northern Europe and USA. The overall prevalence of this condition is 1% rising to 3% in the over 65 years of age. Over the last 25 years, there have been many developments applicable to its diagnosis and treatment. These advances, notwithstanding healing response and recurrence, are variable, and the venous ulcer continues to be a clinical challenge. The pathogenesis of venous ulcers is unrelieved or ambulatory venous hypertension resulting mostly from deep venous thrombosis leading to venous incompetence, lipodermatosclerosis, leucocyte plugging of the capillaries, tissue hypoxia and microvascular dysfunction. It is not known what initiates venous ulcers. Triggers vary from trauma of the lower extremity to scratching to relieve itchy skin over the ankle region. Venous ulcers can be painful, and this condition presents an increasing burden of care. A systematic analysis of the role of technology used for diagnosis and management strongly supports the use of compression as a mainstay of standardised care. It further shows good evidence for the potential of some treatment procedures to accelerate healing. This article reviews the pathogenetic mechanisms, current diagnostic methods and standard care and its limitations.

Changes in microglia activity of rat brain induced by Macrovipera lebetina obtusa venom

Aims: The microglia activity of rat brain following exposure of theMacrovipera lebetina obtusa venom was investi-gated. Methods: Histochemical analysis of brain microcirculatory bed staining by Ca2+ ATPase method for variable doses after intraperitoneal injections given for different time periods was used. The hemorrhagic activity of snake venom metalloproteinases was tested. Toxicological data were calculated using Behrens and Miller-Tainter methods. Surface, size of brain microglial cells (MGCs) and staining intensity were quantified using ImageJ software. Results: The vasodestructive action of the venom resulted in changes in ATPase activity. The intensity of staining of rat brain microcirculatory bed was venom dose-, and time-dependent. Increased activity of MGCs in hemorrhagic loci of different regions of venom affected brain was also demonstrated. Conclusion: The activation of microglia and changes of its form, size, and position strongly correlates with hemorrhage-induced cerebrovascular damage.