Flow competition between hepatic arterial and portal venous flow during hypothermic machine perfusion preservation of porcine livers

Hypothermic machine perfusion (HMP) is regarded as a better preservation method for donor livers than cold storage. During HMP, livers are perfused through the inlet blood vessels, namely the hepatic artery (HA) and the portal vein (PV). In previous HMP feasibility studies of porcine and human livers, we observed that the PV flow decreased while the HA flow increased. This flow competition restored either spontaneously or by lowering the HA pressure (PHA). Since this phenomenon had never been observed before and because it affects the HMP stability, it is essential to gain more insight into the determinants of flow competition. To this end, we investigated the influence of the HMP boundary conditions on liver flows during controlled experiments. This paper presents the flow effects induced by increasing PHA and by obstructing the outlet blood vessel, which is the vena cava inferior (VCI). Flow competition was evoked by increasing PHA to 55-70 mmHg, as well as by obstructing the VCI. Remarkably, a severe obstruction resulted in a repetitive and alternating tradeoff between the HA and PV flows. These phenomena could be related to intra-sinusoidal pressure alterations. Consequently, a higher PHA is most likely transmitted to the sinusoidal level. This increased sinusoidal pressure reduces the pressure drop between the PV and the sinusoids, leading to a decreased PV perfusion. Flow competition has not been encountered or evoked under physiological conditions and should be taken into account for the design of liver HMP protocols. Nevertheless, more research is necessary to determine the optimal parameters for stable HMP.     

Hydrodynamic characterisation of ventricular assist devices

A new mock circulatory system (MCS) was designed to evaluate and characterise the hydraulic performance of ventricular assist devices (VADs). The MCS consists of a preload section and a multipurpose afterload section, with an adjustable compliance chamber (C) and peripheral resistor (Rp) as principal components. The MCS was connected to a pulse duplicator system for validation, simulating a wide range of afterload conditions. Both pressure and flow were measured, and the values of the different components calculated. The data perfectly fits a 4-element electrical analogon (EA). The MCS was further used to assess the hydrodynamic characteristics of the Medos VAD as an example of a displacement pump. Data was measured for various MCS settings and at different pump rates, yielding device specific pump function graphs for water and pig blood. Our data demonstrate (i) flow sensitivity to preload and afterload and (ii) the effect of test fluid on hemodynamic performance.     

Oxidized low-density lipoprotein cholesterol is associated with decreases in cardiac function independent of vascular alterations

In contrast to the plethora of vasculopathies to which oxidized low-density lipoprotein cholesterol (ox-LDL) can be linked, there are no data linking ox-LDL to myocardial (dys)function in the community. We tested whether ox-LDL, a marker of oxidative stress, was linked to early cardiac structural and functional damage in the general population. The Asklepios Study is a random sample of 2524 male and female volunteers, comparable to the Belgian population between 35 and 55 years free from overt cardiovascular disease. Cardiac morphology, systolic, and early and late diastolic tissue Doppler mitral annulus velocities were recorded during an echocardiography, followed by a vascular examination (carotid and femoral arteries). Serum ox-LDL was measured by sandwich ELISA using the mAb-4E6 monoclonal antibody. Effects of ox-LDL were assessed after adjustment for age, gender, lipid fractions, blood pressure, heart rate, height, weight, glycemia, smoking, and drug treatment. Mean ox-LDL was 96.0+/-38.9 U/L. After adjustment, increasing ox-LDL levels were associated with a more spherical left ventricular cavity (minor/major axis dimensions; P<0.001) and decreasing diastolic (early diastolic tissue Doppler mitral annulus velocity; P<0.001, more pronounced in women) and systolic function (amplitude of systolic tissue Doppler mitral annulus velocity; P=0.008, more pronounced in men). These results remained unaffected when further adjustments were made for inflammatory markers, lifestyle, or vascular damage (atherosclerosis and arterial stiffening). These results are the first "proof of concept" that ox-LDL impacts cardiac structure and function at a community level, independent of classic risk factors, lifestyle, inflammation, and prevalent vascular damage. Our data suggest that ox-LDL is a risk marker for early ventricular remodelling. However, the effect size in the general population is small.     

Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population

BACKGROUND: The relationship between aortic (carotid-femoral) pulse wave velocity and stiffness measures based on local diameter and pressure readings is not yet fully understood. METHODS: We compared the relationship with age and gender of aortic pulse wave velocity to stiffness indices (compliance and distensibility coefficient) evaluated at the common carotid and femoral arteries in 2195 (1131 women) apparently healthy subjects, aged 35-55 years participating in the Asklepios study. Aortic pulse wave velocity was further compared with previously reported central arterial stiffness parameters on the same population. Subjects were divided into four age groups for analysis. RESULTS: Femoral arterial stiffness was higher in men than in women (P < 0.001) but did not change with age and no age-gender interaction was evident. Carotid arterial stiffness increased with age (P < 0.001) and showed a significant (P < 0.001) age-gender interaction, with carotid stiffness increasing more rapidly in women than in men, crossing over around the age of 45. Aortic pulse wave velocity did not differ between men and women, but did increase with age (P < 0.001). No age-gender interaction was evident. CONCLUSION: The relation with age and gender of local and central stiffness measures is not the same over the age range 35-55 in apparently healthy men and women. Depending on the central stiffness parameter used, age-gender effects evident at the carotid artery are or are not found centrally. Though the relevance of these differences requires further evaluation in a longitudinal study with outcome data, they need to be kept in mind when designing or interpreting results from arterial stiffness evaluation studies.     

Renal targeting of kinase inhibitors

Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tubular cells and reduced unwanted systemic effects. In our approach kinase inhibitors are linked to the renal carrier lysozyme using a platinum-based linker that binds drugs via a coordinative linkage. Many kinase inhibitors contain aromatic nitrogen atoms able to bind to this linker without the need of prior derivatization. The resulting drug-lysozyme conjugates are rapidly filtered in the glomerulus into the tubular lumen and subsequently reabsorbed via the endocytic pathway for clearance of low-molecular weight proteins. An important property of the formed conjugates is their in vivo stability and the sustained drug release profile within target cells. This review summarizes the state-of-the-art of drug targeting to the kidney. Furthermore, we will highlight recent results obtained with kinase inhibitor-lysozyme conjugates targeted to different kinases, i.e. the transforming growth factor (TGF)-beta-receptor kinase, p38 MAPkinase and Rho-associated kinase. Both in vitro and in vivo results demonstrated their efficient tubular uptake and beneficial therapeutic effects, superior to treatment with free kinase inhibitors. These proof-of-concept studies clearly indicate the feasibility of drug targeting for improving the renal specificity of kinase inhibitors.