Assessing the role of extracellular signal-regulated kinases 1 and 2 in volume overload-induced cardiac remodelling.

AIMS: Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen-activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown. METHODS AND RESULTS: Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif (-28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. CONCLUSIONS: VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte-specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.

Use of end-to-side arterial and venous anastomosis techniques for renal transplantation in two dogs.

CASE DESCRIPTION: A sexually intact male Old English Sheepdog and a sexually intact female Bull Terrier were evaluated for renal dysplasia and chronic renal failure, respectively. CLINICAL FINDINGS: Both dogs were anemic and had high serum concentrations of urea nitrogen and creatinine. Electrolyte abnormalities (calcium and phosphorus) were also evident. The decision was made to pursue renal transplantation, and donor dogs were identified. TREATMENT AND OUTCOME: End-to-side anastomosis of the renal artery and vein of each donor's left kidney to the recipient's ipsilateral external iliac artery and vein, respectively, was performed. The left caudal abdominal musculature was scarified by making an incision, and nephropexy to that musculature was performed with a simple interrupted pattern of polypropylene sutures. No intraoperative or postoperative complications associated with the vascular anastomoses were encountered. Azotemia, anemia, and electrolyte imbalances resolved after transplantation. CLINICAL RELEVANCE: The end-to-side anastomosis technique described here, which is a preferred method in human medicine, was successful, providing an alternative to other renal transplantation techniques in dogs. Additional studies are needed to determine whether any vascular anastomosis technique is preferable for use in dogs requiring renal transplantation.

Use of a jugular vein graft in a modified Blalock-Taussig procedure in dogs.

OBJECTIVE: To determine whether autologous jugular veins provide functional grafts with high 30-day patency rates in an experimental model of systemic-to-pulmonary shunting performed with a modified Blalock-Taussig procedure. ANIMALS: 15 healthy Beagles. PROCEDURE: A segment of the left jugular vein was implanted between the left subclavian and pulmonary arteries. Echocardiograms were obtained prior to surgery, at day 4 to 7, and at day 30 after surgery. Selective angiograms were performed immediately after surgery and on day 30. Oximetric shunt calculations were made via terminal angiography prior to euthanasia. Gross and histologic evaluations of the grafts were conducted. RESULTS: Grafts were patent in 12 of 15 dogs 30 days after surgery as assessed via auscultation, color Doppler ultrasonography, angiography, and histologic examination. Echocardiographic analysis revealed compensatory eccentric left ventricular hypertrophy. Mean pulmonary-to-systemic flow ratio was 1.5:1. Histologic evidence of endothelialization of the anastomotic sites and vein graft arterialization was detectable at 30 days. CONCLUSIONS AND CLINICAL RELEVANCE: Autologous jugular vein grafts were effectively used to create a systemic-to-pulmonary shunt by use of a modified Blalock-Taussig procedure. High patency, ready accessibility, low cost, and theoretical adaptative remodeling during patient growth make autologous jugular vein grafts a valuable alternative to synthetic materials.

Evaluation of three peripheral arteriovenous fistulas for hemodialysis access in dogs.

OBJECTIVE: To design and create 3 types of arteriovenous fistulas (AVF) in normal dogs, to monitor the dogs for secondary cardiovascular complications, and to verify adequacy of these fistulas for hemodialysis vascular access. STUDY DESIGN: Experimental study. ANIMALS: Four normal adult dogs. METHODS: Cadaveric dissections were performed, and surgical protocols were generated for carotid-jugular (CJ), brachial-cephalic (BC), and distal caudal femoral-lateral saphenous anastomosis (DCFLS) AVF. Each surgical procedure was then performed in 2 live dogs. Echocardiography was performed at days 0, 1, 3, 7, 14, 28, and 56 to evaluate the dogs for evidence of volume overload secondary to AVF formation. Estimation of luminal diameter and confirmation of fistula patency were performed using percutaneous color Doppler ultrasound. At day 56, hemodialysis was performed using each fistula as a vascular access. RESULTS: No significant changes occurred in the echocardiographic variables over time. All fistulas were patent at day 56 with mean luminal diameters of 4.5 mm (CJ), 4 mm (BC), and 1.5 mm (DCFLS). The BC fistula was superior for ease of needle placement and stabilization and provided adequate blood flow for clinical hemodialysis. CONCLUSIONS: Based on this short-term study, arteriovenous fistulas appear to be a safe and effective means for hemodialysis access in dogs. CLINICAL RELEVANCE: The arteriovenous fistulas described provide an alternative to the central venous catheters currently used for chronic hemodialysis access in dogs.

A modified technique for the production of an arterio-venous shunt in sheep, allowing a comparison of biocompatibility of synthetic materials.

Polytetrafluorethylene (PTFE) prostheses were implanted in 12 sheep as a shunt between the carotid artery and the jugular vein using an end-to-side anastomosis technique. This technique allows repeated tests of the pharmacological and toxicological safety of artificial kidney units after both single and multiple administration. Furthermore, it enables the investigation of detoxification of compounds via dialysis, thus contributing to drug safety. Implantation of the prosthesis was uncomplicated. Connection to the extracorporeal circulation was achieved via catheters and maintained using a pump with an output of up to 300 ml/min. This enabled maintenance of extracorporeal circulation for several hours without clinical impairment to the animals. The AV-shunts remained functional for between 8 and 253 days (mean 112.3 days).

Long-term blood access by catheters implanted into arteriovenous fistulas of sheep.

Reliable long-term blood access in sheep was provided by implanting one or two catheters into the high velocity blood flow in the vein draining an arteriovenous fistula created in the neck. Thrombosis of the catheterized vein occurred in only one of 31 cases in which a catheter with rounded intravascular tip was used, as compared with seven in 10 cases using a sharp-tipped catheter. The mean duration of placement for all rounded-tip catheters was 228.6 days. Extrusion from the vessel occurred with 3 of 8 short catheters (2 cm intravascular length), but only after a period of more than seven months of implantation. Using a program of trice-weekly disinfection of the skin exit site, exterior portion of the catheter, and catheter lumen resulted in failure of only two catheters due to infection. Rounded-tip catheters with 5 cm intravascular length had 75% life table functional rate at 15 months. Implantation of two catheters permitted extracorporeal circulation at flows of up to 300 ml/min using a blood pump to withdraw blood from one catheter while simultaneously returning it through the second.

Renal arteriovenous fistula: a model for renovascular hypertension in rat.

Renal arteriovenous fistula (RAVF) was created in the rat. For this purpose the left renal artery and vein were connected by a latero lateral anastomosis. This operation was performed in 40 rats and 12 animals were sham operated. All these animals were subsequently reoperated after 4 weeks to check the fistula and the kidney. Eleven among the 40 operated rats died during or after the surgery. In 16 others animals hypertension developed. Their blood pressure was 161 +/- 4.3 mm. Hg at 4 weeks vs. 105 +/- 1.65 mm. Hg before surgery. All these animals had after 4 weeks a permeable fistula and an atrophic but nonnecrotized left kidney (kidney weight was 0.56 +/- 0.33 gm. vs. 1.32 +/- 0.22 gm. for the sham operated group). They underwent a left nephrectomy without closure of the fistula and subsequently their blood pressure fell back to normal values 120 +/- 2.9 mm. Hg 2 weeks after nephrectomy). In the removed kidney, renal renin content per mg. of protein was found to be higher than in the kidney of the sham operated animals (28.5 +/- 7.9 vs. 0.66 +/- 0.2 micrograms. AI/mg. protein/hour). In 13 other animals the blood pressure remained normal after the initial surgery. These animals had a permeable fistula but a necrotic left kidney. It is concluded that RAVF can induce hypertension in the rat. This hypertension only develops when the ipsilateral kidney remains vascularized and disappears when this kidney is removed without closure of the fistula. Since the renin content in the kidney distal to the shunt was higher than in the kidney of the sham operated rats and since there was a positive correlation between renal renin content and blood pressure in hypertensive animals, it is suggested that an activation of the renin angiotensin system in the ipsilateral ischemic kidney is responsible for hypertension. RAVF therefore appears to be an experimental model for renovascular hypertension in rats.

Use of an extracorporeal arterio-venous shunt and capillary tubes for frequent micro-blood sampling in rats.

Because of the importance of frequent sampling during kinetic analysis, we have developed a method that permits frequent, reliable, and rapid access to the blood stream in rats. The method comprises the establishment of an extracorporeal arterio-venous shunt between femoral blood vessels. Quantitative samples of whole blood and plasma are obtained with capillary micro hematocrit tubes. The small sample volume permits repetitive analysis without major changes in hematocrit. There is good agreement between these measures and ordinary pipetting techniques. Kinetic analysis showed good resolution with close correspondence between actual measurements and the final curve of best fit. This method could be employed advantageously in small conscious animals, when frequent small samples are required by experimental design.

A modification of the canine carotid-jugular shunt.

A shunt modification was used for implantation in the carotid-jugular vessels of the dog. The shunt was made of plastic tubing and was tied to each vessel with three silk ligatures. The tubing was exteriorized and anchored to the skin. The exposed tubing was cut and attached to the input and output lines of a tubing kit for leukapheresis with a continuous flow centrifuge. Surgical implantation of the shunt was accomplished with ease and minimum trauma to the animal. Useful life of the shunt extended over a 3-week period with minimal requirements for anticoagulants.

Acquired peripheral arteriovenous fistula in a dog.

A pulsating mass with a continuous bruit was discovered in a dog's flank during routine examination. Based on a history of trauma and clinical signs, an acquired arteriovenous (AV) fistula and a false aneurysm were included in the differential diagnosis. Arteriography confirmed the presence of an AV fistula and outlined the lesion for successful surgical extirpation. Hsitopathologic characteristics of the AV fistula were similar to those in man.