Induction of heart failure: haemodynamic comparison of three different canine models.

We compared three methods: arteriovenous anastomosis, doxorubicin administration, and combination of anastomosis and doxorubicin, with the intention of designing a simple, stable model of chronic heart failure. Twelve dogs were divided into three groups of four. One group received carotid-jugular anastomosis (Ana series), another group received anastomosis and doxorubicin injection (A/D series), and the last group received only doxorubicin (Dox series). Animals were followed for eight weeks. Fifteen different haemodynamic parameters were tracked and compared to baseline values. After eight weeks, diastolic pressure in the right atrium increased from 3.8+/-2.0 mmHg at baseline to 5.3+/-5.9 mmHg in the Ana series, to 6.3+/-3.3 mmHg in the Dox series and to 8.0+/-2.0 mmHg in the A/D series (P<0.05 A/D vs. baseline). Systolic pulmonary wedge pressure increased from 11.6+/-2.0 mmHg at baseline to 15.5+/-3.4 mmHg in the Ana series, 14.0+/-3.7 mmHg in the Dox series and 17.3+/-4.2 mmHg in the A/D series (P = NS vs. baseline). Left ventricular ejection fraction decreased from 53.9+/-10% at baseline to 36.1+/-5.6% in the Ana series (P<0.05 vs. baseline), 31.5+/-5.4% in the Dox series (P<0.05 vs. baseline) and 25.8+/-5.8% in the A/D series (P<0.001 vs. baseline, P<0.05 vs. Ana series and Dox series). In conclusion, eight weeks are not enough to produce stable heart failure using arteriovenous anastomosis alone. Doxorubicin administration alone produces a left ventricular failure. However, a combination of both of these interventions provides a more stable model of right-and left-sided heart failure.

Deferoxamine enhances neovascularization and recovery of ischemic skeletal muscle in an experimental sheep model.

BACKGROUND: Iron chelators have been reported to interfere with inflammatory cells and possibly enhance vascular growth factor expression. The objective of this study was to investigate the efficacy of the iron chelator deferoxamine mesylate in preventing skeletal muscle ischemia. METHODS: The latissimus dorsi muscle (LDM) was mobilized in 20 adult sheep. Two separate pockets were created in each sheep. Autologous fibrin sealant with or without 100 mg/mL of deferoxamine mesylate (10 pockets) was added to the pockets. Deferoxamine mesylate alone was also applied to another 10 pockets, whereas the 10 other pockets served as controls. RESULTS: Conventional, indirect immunofluorescent enface staining showed that in nonmobilized, nonischemic LDM the capillary density was 196 +/- 14 capillaries/mm2 in the distal and 207 +/- 19 capillaries/mm2 in the middle part. After severe ischemic shock (subtotal mobilization), the muscle did not recover completely even after 2 months (149 +/- 15 capillaries/mm2 in the distal part and 177 +/- 16 capillaries/mm2 in the middle part of the LDM). Fibrin application only increased muscle neovascularization. The number of capillaries per mm2 of muscle increased to 250 +/- 25 in the distal part and to 271 +/- 24 in the middle part of the LDM. However, when fibrin was applied with added deferoxamine mesylate, the capillary density increased to 361 +/- 25 capillaries/mm2 in the distal part (p < 0.05 vs fibrin only; controls) and to 401 +/- 20 capillaries/mm2 in the middle part of the LDM (p < 0.05 vs fibrin only and p < 0.001 vs controls). The data are concordant with the blood flow estimation before and after mobilization (severe ischemic shock) in the different parts of the LDM. CONCLUSIONS: Local application of deferoxamine mesylate enhances neovascularization and recovery of surgically induced skeletal muscle ischemia in a sheep model.

Deferoxamine-fibrin accelerates angiogenesis in a rabbit model of peripheral ischemia.

The intramuscular (i.m.) injection of a modified fibrin meshwork plus deferoxamine was tested in a rabbit model of acute hind-limb ischemia. After excision of the left external iliac and femoral arteries, 12 rabbits at the Milwaukee Heart Institute were divided into two groups: control and fibrin meshwork plus deferoxamine (FDEF) i.m. The rabbits underwent angiography before surgery, immediately after, and 1 month postoperatively. These data were compiled through counting by means of a grid overlay. Another 12 rabbits at the Vakhidov Center of Surgery, which did not undergo angiography, underwent lower limb-calf blood pressure (L-CBP) measurements made immediately after surgery and at postoperative days 10, 20 and 30. Biopsies from thigh skeletal muscles of rabbits that had L-CBP measurements underwent alkaline phosphatase staining on day 30 to determine the percentage of biopsied area that was occupied by capillaries. The number of arteries and arterioles crossing 71 grid intersections immediately post-surgery decreased from 30.2 +/- 2.3 to 18.0 +/- 2.0 (p < 0.05). One month postsurgery this number increased to 29.2 +/- 2.4 in controls (p < 0.05 vs immediately post-surgery) and to 59.6 +/- 3.2 in the FDEF group (p < 0.001 vs immediately post-surgery). By day 30 the L-CBP ratio improved in the FDEF group (0.8 +/- 0.02) vs controls (0.3 +/- 0.04). By day 30 the capillary density increased from that of normal muscle tissue (198.6 +/- 12.9/mm2) to 292 +/- 12.4/mm2 in the FDEF group (p < 0.05), but decreased in the control group to 98.7 +/- 7.7/mm2. I.m. injection of FDEF considerably accelerated angiogenesis in severely ischemic hind-limb tissue in this model, making it a viable treatment method for clinical use in patients who have critical limb ischemia.

Cardiomyoplasty: first clinical case with new cardiomyostimulator.

Dynamic cardiomyoplasty was performed in a patient using a new cardio-myostimulator (LD-PACE II) designed to enable a novel stimulation regimen that utilizes a new range of stimulation options, including cessation during sleep. After treatment, left ventricular ejection fraction improved in 24 months from 15% to 25% and New York Heart Association classification improved from class IV to II.

Pathologic and histologic results of electrical impulses in a rabbit model of atherosclerosis: 24-hour versus 8-hour regimen.

OBJECTIVE: Low frequency electrical impulses (EIs) reduce new atherosclerotic plaque formation in previously diseased arteries and may reverse the extent of previous pathologic damage in these structures. METHODS: A pacemaker was implanted on the left side of rabbit abdominal aortas, and an electrode was placed close to the other side of the aorta in the psoas major muscle. For the induction of atherosclerosis, the rabbits were placed on a high cholesterol diet (HCD) for 11 weeks. No EIs were applied to the control series I. In the experimental series, the rabbits were fed an HCD for 3 weeks, after which EIs were applied simultaneously with an HCD for 8 additional weeks (3V, 30 contractions per minute). Experimental series II had 24-hour/day EIs, and series III had 8-hour/day EIs. RESULTS: The closer to the area where the EIs were applied, the more local severity increased (atherosclerosis level and surface area). In the control series, the severity of atherosclerosis in the lower aorta assessed with an arbitrary grading system was 1.75 +/- 0.5 (versus 1.5 +/- 0.57 with 8-hour/day EIs and 0.5 +/- 0.3 with 24-hour/day EIs). The involved surface area was 32.5% +/- 9.5% (versus 1.0% +/- 0.8% with 8-hour/day EIs and 0.75% +/- 0.95% with 24-hour/day EIs). CONCLUSION: Both 24-hour/day and 8-hour/day EIs applied close to the abdominal aorta decreased the severity of atherosclerosis in rabbits placed on a HCD, but 24-hour/day EIs decreased the severity more extensively.

Direct fibrin injection to promote new collateral growth in hind limb ischemia in a rabbit model.

UNLABELLED: Local stimulation of angiogenesis is a new approach for the treatment of critical limb ischemia. Our investigation tested intramuscular (i.m.) injection of a modified fibrin meshwork in a rabbit model. METHODS: The left external iliac and femoral arteries were excised in 24 rabbits that were divided into four groups: control; i.m. saline injection; fibrin meshwork plus low dose (2.5 mg) fibrinogen i.m.; fibrin meshwork plus high-dose (5.0 mg) fibrinogen i.m. Angiography was performed before surgery, immediately after surgery, and one month postoperatively. Lower limb-calf blood pressure was measured immediately after surgery and at postoperative days 10, 20, and 30. On day 30, conventional indirect immunostaining was performed to determine the percentage of the area occupied by capillaries. RESULTS: Immediately after surgery, in all four groups, the number of contract-opacified arteries (COA) crossing a specific segment of a grid decreased from 5.3 +/- 1.3 to 3.2 +/- 1.0 (p < 0.05); the number of grid intersections decreased from 30.2 +/- 6.5 to 19.3 +/- 4.8 (p < 0.05); and the total number of grids with COA decreased from 18.3 +/- 3.8 to 12.2 +/- 2.5 (p < 0.05). One month after surgery, in the control group, these parameters were 6.2 +/- 1.1, 33.2 +/- 5.7 and 20.3 +/- 1.5, respectively; in the saline-treated group, these parameters were 6.1 +/- 0.8, 28.3 +/- 6.9 and 19.8 +/- 1.1, respectively (p > 0.05 versus control and versus baseline data). When fibrin containing 5.0 mg fibrinogen was used, these parameters increased to 8.5 +/- 0.9, 48.3 +/- 5.1, and 27.1 +/- 0.9, respectively (p < 0.001 versus immediately after surgery and p < 0.05 versus control). In all four series, no Doppler flow signal was detected from the posterior tibial artery by day 10. By day 30, the lower limb-calf blood pressure ratio had improved in all four series, but was significantly improved in only the two groups treated with fibrin sealant (0.3 +/- 0.05 control; 0.3 +/- 0.08 saline; 0.6 +/- 0.06 fibrinogen 2.5; 0.7 +/- 0.05 fibrinogen 5.0). CONCLUSION: Intramuscular injection of a fibrin meshwork considerably increased angiogenesis in the severely ischemic hind limb and may be strongly recommended for clinical use in patients with limb-threatening ischemia.