Abstract
KL1 Endothelium-dependent hyperpolarization (EDH) and endothelial dysfunction in hypertension: The role of endothelial ion channels
Kenichi Goto
Kyushu University
Vascular endothelial cells regulate arterial tone through the release of diffusible factors, including nitric oxide, prostaglandins and endothelium-derived constricting factors. In addition, contact-mediated electrical propagation from endothelial cells to smooth muscle cells via myoendothelial gap junctions termed endothelium-dependent hyperpolarization (EDH) plays a critical role in endothelium-dependent vasodilation in resistance size arteries that regulate peripheral resistance and hence blood pressure. There is a general consensus that the opening of endothelial small- and intermediate-conductance Ca2+ activated K+ channels (SKCa and IKCa) is the initial mechanistic step for the generation of EDH and emerging evidence reveal that Ca2+ influx through endothelial transient receptor potential vanilloid 4 (TRPV4) ion channels, nonselective cation channels of the TRP family, plays a critical role in this process. In animal models and humans, EDH and EDH-mediated vasorelaxation are impaired in long-term hypertension and antihypertensive treatments restore such impairments. However, the underlying mechanisms of impaired EDH and its improvement by antihypertensive treatments during hypertension remain elusive. A number of studies including ours suggest that changes in endothelial ion channels such as SKCa and TRPV4 channels contribute to the impaired EDH during hypertension. In this lecture, we present the current knowledge about EDH. We then explore the changes in EDH during hypertension, focusing on underlying mechanisms and potential therapeutic approaches aimed at the prevention and restoration of impaired EDH during hypertension, with special reference to the role of endothelial SKCa and TRPV4 channels.
KL2 Clinical management of adverse complications in patients with left ventricular assist devices
Michinari Hieda
Kyushu University
Left ventricular assist devices (LVAD) (or left ventricular assist systems (LVAS)), are an essential therapeutic option for the treatment of patients with end-stage advanced heart failure. LVAD is used worldwide as a “bridge to heart transplant (BTT)”, “bridge to recovery (BTR)”, or a “destination therapy (DT)”. Indeed, compared with optimal medical therapy, LVAD can reduce cardiovascular death and improve the quality of life in patients with advanced heart failure. However, with the increasing usage of LVAD and longer survival, a substantial number of patients experience adverse events and critical complications. Major adverse complications with the LVAD include ischemic and hemorrhagic strokes, bleeding complications, device thrombosis, right heart failure, and LVAD related infections, which lead to the primary causes of death in patients with LVAD. Especially, cerebrovascular events and gastrointestinal bleeding are among the most serious complications. This key-note lecture discusses clinical management and prevention of those complications for patients with LVAD. Based on blood rheology, fundamental causes of complications related to LVAD and its countermeasures will be presented.
KL3 Coagulation of blood: A possible triggering mechanism of the intrinsic coagulation pathway, and assessment of the anticoagulant effect of DOACs using a seesaw-type device
Makoto Kaibara1 and Hiroshi Ujiie2
1Past affiliation: RIKEN (The Inst. Phys. Chem. Res.), 2Ujiie Neurosurgical & Medical Clinic
Rheological and biochemical studies on blood coagulation, focusing on a possible triggering mechanism in the intrinsic coagulation pathway, are summarized. Also, it will be shown that a developed seesaw-type device may be useful for assessing the anticoagulant effect of direct oral anticoagulants (DOACs) as well as for determining the coagulation time of blood.
A markedly reduced blood flow and an elevation of hematocrit are risk factors for venous thrombus formation. However, these risk factors alone seem to be insufficient to stimulate the coagulation cascade in the absence of a primary triggering mechanism. It will be shown that the initiation of intrinsic coagulation pathway may be caused by the activation of factor IX by an enzyme in erythrocyte membranes. The activation of factor IX by the enzyme was enhanced by a decrease in flow shear rate and an elevation of hematocrit. The results suggest one route to venous thrombus formation that occurs in a stagnant flow condition.
A seesaw-type method using a sphere-shaped capsule as a blood container was developed. In the present version, a total of five blood samples can be run concurrently. We show some fundamental data, and discuss the potential of the present technique for assessing the procoagulant activity of blood and treatment effect with anticoagulants.
KL4 Computational fluid dynamics (CFD) analysis to optimize the design of rotary blood pumps
Masahiro Nishida
National Institute of Advanced Industrial Science and Technology
Computational fluid dynamics (CFD) analysis is an important tool to optimize the design of rotary blood pumps. Shear stress analysis is especially important for the rotary blood pump whereas pressure analysis is important for general industrial pumps to enhance the pump head. This is because high-shear stress causes hemolysis, and low-shear stress causes thrombogenesis after platelet activation which is exposed by certain level of high-shear stress. Therefore, the design of the rotary blood pump can be evaluated by the result of CFD analysis whose pressure distribution relating to the pump head and whose shear stress distribution relating to hemolysis and thrombogenesis, namely hemocompatibility of the pump. High shear stress causes hemolysis because the repeated high-shear loading causes fatigue destruction of erythrocyte membrane. The hemolysis level is approximately proportional to the square of the shear stress and the exposure time. Our group determined approximate threshold level of high-shear stress causing hemolysis as 300 Pa in a rotary blood pump based on the correlation study results of CFD analysis, flow visualization analysis and hemolysis test. Low-shear stress causes thrombogenesis although the mechanism is very complicated. Our group also determined approximate threshold level of low-shear stress causing thrombogenesis as 5 Pa in a monopivot centrifugal blood pump. The design of the monopivot centrifugal pump has been optimized by CFD analysis. In the future, the relationship between shear stress and hemocompatibility should be further clarified and the evaluation technology should be better established.
KL5 Dynamics of blood fluidity under various pathologic conditions: The roles of endothelial anticoagulant activities and their pathophysiologic conditions
Ikuro Maruyama
Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
Endothelial monolayers play crucial roles for blood fluidity in the circulation and maintain continuous fluent circulations. The fluent circulations are mainly accomplished by endothelial antithrombogenic activity. The antithrombogenic activity of endothelial cells are accomplished by several factors. They include prostacyclin (PGI2) and nitric oxide (NO) production with accomplishing inhibition in platelets functions, including adhesions and aggregations. Moreover, endothelial cells express anticoagulant activities via thrombomodulin (TM), a heparin-like molecule. TM is an endothelial glycoprotein and acts as a regulator of thrombin, typical procoagulant protein generated by the endothelial damages. TM binds thrombin and converts thrombin from a procoagulant to an anticoagulant protease. Thrombin bound to TM fails its procoagulant activity with enhancing protein C (PC) activation by thrombin. Activated PC (APC) degrades the activated coagulation factors Va and VIIIa and negatively regulates the coagulation cascade in the vessels. Thus, endothelial TM converts thrombin from a procoagulant protease to an anticoagulant. Moreover, one of the typical damage associated molecular patterns (DAMPs), High Mobility Grope Box-1 (HMGB1) and histones, both released from damaged tissues and cells, act as prothrombotic factors. We confirmed that these DAMPs are also quenched by TM. Thus endothelial TM acts as a “guardian” of the closed circulatory system. Previously we succeeded in the cloning of human TM cDNA and produced the recombinant TM (rTM). Now this rTM is available for the treatment of DIC in Japan.