Alexander M. Seifalian

The effect of short-term treatment with simvastatin on renal function in patients with peripheral arterial disease

The objective of this study was to investigate the effects of lipid-lowering treatment on renal function in patients with peripheral arterial disease (PAD). This was a retrospective study of hyperlipidemic claudicants referred to a vascular surgery and risk modification clinic. Serum creatinine and urate concentrations and the fasting lipid profile were measured pretreatment and after 3-4 months of treatment with 20 mg/day simvastatin. In 103 consecutive patients with PAD (57 men; 46 women), median age 67 years (range: 51 to 83) there was a significant decrease in serum creatinine from a mean (SD) of 87 (12) μmol/L pretreatment to 84 (12) μmol/L post-treatment (p<0.0001). This difference was more marked in the tertile of patients with the highest baseline creatinine levels. There was also a significant reduction in serum urate from 0.37 (0.07) mmol/L to 0.35 (0.07) mmol/L (p<0.0001). Both these effects were independent of the degree of total cholesterol (TC) or low-density lipoprotein (LDL) cholesterol reduction. There was a significant reduction in TC from 6.6 (1.0) to 5.2 (0.8) mmol/L and LDL cholesterol from 4.3 (1.0) to 2.8 (0.7) mmol/L; both p<0.0001. Significant improvement also occurred in the high-density lipoprotein cholesterol and triglyceride levels. Cholesterol lowering with simvas tatin 20 mg/day improved indices of renal function after 3-4 months of treatment in hyper lipidemic patients with PAD. Further studies are needed to establish and define the clinical relevance of these findings, especially in patients with different degrees of renal failure.

In vivo femoropopliteal arterial wall compliance in subjects with and without lower limb vascular disease

OBJECTIVE The purpose of this study was to further the development of a compliant vascular graft with a preliminary assessment of the elastic properties of the femoropopliteal artery in subjects with and without lower limb peripheral vascular disease. METHODS This prospective controlled study was set in a university department of surgery. Using an ultrasound scan wall tracking system with the simultaneous measurement of brachial blood pressure, measurements of femoropopliteal artery wall motion were undertaken in 11 patients with peripheral vascular disease (group 1), in 11 older control subjects who were matched for blood pressure, age, and sex (group 2), and in 12 younger control subjects (group 3). Diametrical compliance and stiffness index were determined for the common femoral artery, the proximal superficial femoral artery, the distal superficial femoral artery (DSFA), and the midgenicular popliteal artery. RESULTS All the arterial segments in group 1 showed a trend towards increased stiffness and less compliance than the group 2, age-matched control vessels, with significantly lower distensibility noted at the common femoral artery (mean compliance of 6.2% vs 14.1% mm Hg(-1) x 10(-2), respectively; P <.05) and the DSFA (mean compliance of 2.2% vs 1.9% mm Hg(-1) x 10(-2), respectively; P <.05). The popliteal artery segment in group 3 proved to be more compliant and less stiff than did the same vessel in group 2 (8.5% vs 4.7% mm Hg(-1) x 10(-2), respectively; P <.01). In all three study groups, the DSFA was consistently noted to be the least distensible vessel segment. CONCLUSION Lower limb peripheral vascular disease is associated with a reduction in femoropopliteal artery elasticity. Age alone appears to have a minimal effect on the compliance of the proximal half of the femoropopliteal segment. The elastic properties of the femoropopliteal vessel are subject to marked variation along its course. To minimize compliance mismatch, the degree of elasticity engineered into a vascular graft must reflect that observed in vivo.

EFFECT OF PROLONGED PULSATILE SHEAR STRESS IN VITRO ON ENDOTHELIAL CELL SEEDED PTFE AND COMPLIANT POLYURETHANE VASCULAR GRAFTS

OBJECTIVES Compliance mismatch between graft and native artery, and failure of the graft to develop an endothelial lining are the two main factors in graft failure. The objective of this study was to assess a new compliant graft for effective cell attachment and cell retention at physiological levels of pulsatile shear stress over a 6-hour period of physiological pulsatile flow. DESIGN Laboratory haemodynamic study. MATERIALS AND METHODS Human umbilical vein endothelial cells labelled with 111In-oxine were seeded on compliant polyurethane (CPU) and polytetrafluoroethylene (PTFE) vascular grafts. These were then exposed to varying shear stresses of up to 13.8 +/- 0.6 dyn/cm2 using a pulsatile flow model. Dynamic scintigraphy images were acquired using a gamma camera linked to an on-line computer during 6 h of perfusion and data presented as mean +/- standard error of mean. RESULTS Mean seeding efficiencies were significantly different at 4,316 +/- 505 and 825 +/- 504 CPM/cm2 on the CPU and PTFE grafts, respectively (p = 0.018). The flow experiment showed a higher percentage of cells retained on the CPU graft after exposure to shear stress caused by pulsatile flow compared to PTFE with respect to time. After 6 h pulsatile perfusion there was a significantly higher proportion of initial cells attached to CPU graft compared to PTFE graft (73 +/- 8% vs 42 +/- 8%, p = 0.018). The areas under the time activity curves over the 6-hour period were 280 +/- 26.4 for CPU and 176.0 +/- 30.0 for PTFE, confirming a significant greater total cell loss from PTFE compared with CPU grafts (51 +/- 7.0% vs 23 +/- 8.3%, p = 0.018, Wilcoxon matched-pairs signed-ranks test). CONCLUSIONS This flow model provides an effective method of assessing cell retention on graft materials under physiological conditions over a 6-hour period; CPU combines both excellent compliance and endothelial cell attachment rates after 6 h exposure to shear stress.

N-Acetylcysteine ameliorates the late phase of liver ischaemia/reperfusion injury in the rabbit with hepatic steatosis

Steatotic livers are highly susceptible to I/R (ischaemia/reperfusion) injury and, therefore, the aim of the present study was to evaluate the in vivo effect of NAC (N-acetylcysteine) on hepatic function in the early and initial late phase of warm liver I/R injury in steatotic rabbits. Twelve New Zealand White rabbits were fed a high-cholesterol (2%) diet. The control group (n=6) underwent lobar liver ischaemia for 1 h, followed by 6 h of reperfusion. In the treated group receiving NAC (n=6), an intravenous infusion of NAC was administered prior to and during the 6 h reperfusion period. Systemic and hepatic haemodynamics were monitored continuously. ALT (alanine aminotransferase) activity and bile production were measured. NMR spectroscopy was used to analyse bile composition. Oxidation of DHR (dihydrorhodamine) to RH (rhodamine) was used as a marker of production of reactive oxygen and nitrogen species. Moderate centrilobular hepatic steatosis was demonstrated by histology. The results showed that NAC administration significantly improved portal flow, hepatic microcirculation, bile composition and bile flow after 5 h of reperfusion. NAC administration was also associated with less hepatocellular injury, as indicated by ALT serum activity, and decreased the oxidation of DHR to RH. In conclusion, NAC administration decreased the extent of I/R injury in the steatotic liver, particularly during the late phase of reperfusion.

Effect of remote ischemic preconditioning on hepatic microcirculation and function in a rat model of hepatic ischemia reperfusion injury

BACKGROUND Liver transplantation involves a period of ischemia and reperfusion to the graft which leads to primary non-function and dysfunction of the liver in 5-10% of cases. Remote ischemic preconditioning (RIPC) has been shown to reduce ischemia reperfusion injury (IRI) injury to the liver and increase hepatic blood flow. We hypothesized that RIPC may directly modulate hepatic microcirculation and have investigated this using intravital microscopy. METHODS A rat model of liver IRI was used with 45 min of partial hepatic ischemia (70%) followed by 3 h of reperfusion. Four groups of animals (Sham, IRI, RIPC+IRI, RIPC+Sham) were studied (n= 6, each group). Intravital microscopy was used to measure red blood cell (RBC) velocity, sinusoidal perfusion, sinusoidal flow and sinusoidal diameter. Neutrophil adhesion was assessed by rhodamine labeling of neutrophils and cell death using propidium iodide. RESULTS RIPC reduced the effects of IRI by significantly increasing red blood cell velocity, sinusoidal flow and sinusoidal perfusion along with decreased neutrophil adhesion and cell death. CONCLUSIONS Using intravital microscopy, this study demonstrates that RIPC modulates hepatic microcirculation to reduce the effects of IRI. HO-1 may have a key role in the modulation of hepatic microcirculation and endothelial function.

Effect of graded hypoxia on hepatic tissue oxygenation measured by near infrared spectroscopy.

BACKGROUND/AIMS In liver transplantation ischaemia-reperfusion injury of the graft reduces hepatic tissue oxygenation which has prognostic value for patient survival. Near infrared spectroscopy (NIRS) can measure extracellular (haemoglobin oxygenation) and intracellular tissue oxygenation (cytochrome oxidase oxidation). However, it has not been validated for measuring hepatic tissue oxygenation in an experimental model with graded hypoxia. METHODS New Zealand White rabbits (2.9+/-0.3 kg, n=9) underwent laparotomy for liver exposure. Heart rate, blood pressure, temperature, arterial blood pH and blood gas partial pressures were monitored during the experiments. Near infrared spectroscopy probes were placed on the liver surface to record continuously hepatic oxyhaemoglobin, deoxyhaemoglobin and cytochrome oxidase oxidation. Graded hypoxia was achieved by stepwise reduction of the inspired oxygen from 15 to 4%. During recovery from hypoxia 30% oxygen was administered. RESULTS There was an immediate reduction of hepatic oxyhaemoglobin with hypoxia and a simultaneous increase of hepatic deoxyhaemoglobin. Hepatic oxyhaemoglobin showed a positive correlation with arterial oxygen pressure (r=0.77, p<0.001). Hepatic deoxyhaemoglobin showed a negative correlation with arterial oxygen pressure (r=-0.75, p<0.001). Hepatic cytochrome oxidase decreased significantly with an inspired oxygen of 10% or less and showed a positive correlation with arterial oxygen pressure (r= 0.90, p<0.001). CONCLUSIONS Near infrared spectroscopy is an effective method for monitoring hepatic extracellular and intracellular tissue oxygenation.

A new algorithm for deriving pulsatile blood flow waveforms tested using simulated dynamic angiographic data

SummaryIn vascular pathology the assessment of disease severity and monitoring of treatment requires quantitative and reproducible measurements of arterial blood flow. We have developed a new technique for processing sequences of dynamic digital X-ray angiographic images. We have tested it using computer simulated angiographic data which includes the effect of pulsatile blood flow and X-ray quantum noise. A parametric image was formed in which the image grey-level represents dye concentration as a function of time and distance along a vessel segment. Adjacent concentration — distance profiles in the parametric image were re-registered along the vessel axis until a match occurred. A match was defined as the point where the sum of squares of the differences in the two profiles was a minimum. The distance translated per frame interval is equal to the bolus velocity. We have tested several contrast medium injection methods including constant flow and a range of discrete pulses per second. The technique proved to be robust and independent of injection technique. Average blood flow was measured for simulated pulsatile waveforms with mean flows of up to 650 ml/min (peak velocities up to 186 cm/s) in a range of diameters from 2 mm to 6 mm. The standard deviation of the error in the mean flow estimates over the whole range of velocities and vessel sizes was ±1.4 cm/s.

Superior mesenteric artery blood flow in man measured with intra-arterial Doppler catheters: Effect of octreotide

Changes in splanchnic blood flow are important in the pathogenesis of portal hypertension, but research in this area is hampered by the difficulty in measuring splanchnic arterial blood flow in man. We therefore investigated the use of intra-arterial Doppler catheters in measuring superior mesenteric artery blood flow in man and assessed the effect of intravenous octreotide on superior mesenteric artery blood flow in a placebo-controlled double-blind study. Nine experiments were performed in a flow model using vessels with internal diameters of 6.5, 4.5 and 3.0 mm, with flow rates ranging from 50 to 700 ml/min. In this model the catheters gave instantaneous, reproducible measurements of blood flow in vessels of 6.5 mm internal diameter with a mean error ranging from +5.3% to +36.4%, compared to electromagnetic flowmetry, but were less accurate in smaller vessels. When used in patients, the catheters provided stable, reproducible measurements of superior mesenteric blood flow, in 16 out of 20 patients studied. In a double-blind placebo-controlled study, including 12 subjects, superior mesenteric artery blood flow was significantly reduced in patients receiving octreotide. We suggest that measurement of splanchnic arterial blood flow using intra-arterial Doppler catheters may be a useful additional investigation in the assessment of splanchnic vascular pathophysiology and pharmacology in man.

VALIDATION OF VOLUME BLOOD FLOW MEASUREMENTS USING THREE-DIMENSIONAL DISTANCE-CONCENTRATION FUNCTIONS DERIVED FROM DIGITAL X-RAY ANGIOGRAMS

RATIONALE AND OBJECTIVES.The authors present phantom validation of a method for computing pulsatile flow waveforms in arterial vessels from high–frame-rate biplane x-ray angiograms. METHODS.The three-dimensional course of a blood vessel is constructed from biplane digital x-ray angiograms. A parametric image of contrast mass versus time and true three-dimensional path length is generated. Adjacent contrast mass-distance profiles are matched to compute instantaneous velocity, which is multiplied by cross-sectional area to yield volume flow. An electromagnetic flowmeter was used to validate flow estimates in a phantom consisting of 150-mm tubes 3, 4, and 6 mm in diameter, orientated 15°, 30°, and 35° to the imaging plane, with flow rates and waveforms expected in vivo. RESULTS.Mean and peak flows were accurate to within 9% and 10%, respectively, for velocities of less than 1 meter/second at a frame rate of 25 frames per second. CONCLUSIONS.A practical method for computing highly pulsatile flow waveforms in vivo in tortuous vessels is presented.

Validation of a quantitative radiographic technique to estimate pulsatile blood flow waveforms using digital subtraction angiographic data

We have validated a new radiographic technique for determining pulsatile volume flow in arteries following an intraarterial injection of contrast material. Instantaneous blood velocities were estimated by generating a parametric image from dynamic angiographic images in which the image grey level represents contrast material concentration as a function of time and distance along a vessel segment. Adjacent concentration--distance profiles in the parametric image were shifted with respect to distance until a match occurred. A match was defined as the point where the sum of squares of the differences in the two profiles was a minimum. The distance translated per frame interval gives the instantaneous contrast material bolus velocity. We have validated the technique using an experimental phantom of blood circulation, consisting of a pump, flexible plastic tubing, the tubular probe of an electromagnetic flowmeter (EMF) and a solenoid, to simulate a pulsatile flow waveform, which includes reverse flow. Small boluses of contrast material can be injected at various positions in the circuit. Measurements of pulsatile velocity flow were taken at 40 ms intervals, using a tube of 6.6 mm internal diameter and an imaged tube length of 200 mm. The shape of the flow velocity waveform was faithfully reproduced but there was an overestimation of peak velocity of 40% at low velocities (peak velocity of 540 mm s-1), reducing to 19% at peak velocities of 964 mm s-1 with an underestimation of 16% at the peak velocities of 1899 mm s-1. The validation was repeated for distances ranging from 130 to 230 mm between injection and measurement sites and for imaged tube lengths varying from 200 to 20 mm.(ABSTRACT TRUNCATED AT 250 WORDS)