Development Of Collateral Circulation Research Articles

Local Extravascular Growth Factor Delivery in Myocardial Ischemia.

A number of angiogenic growth factors have been demonstrated in vivo to promote angiogenesis in ischemic myocardium, including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). We used the porcine ameroid constrictor model to simulate chronic ischemia in an effort to study the role of exogenous growth factor delivery in the development of coronary collateral circulation. Heparin alginate microspheres were used to deliver bFGF, while an implantable osmotic pump was used for VEGF delivery. Anti-von Willebrand antibody staining was used to visualize microvessels in the porcine heart sections obtained from both ischemic and non-ischemic myocardium. A significant increase in the number of microvessels in growth factor-treated pigs compared to control animals was noted. Myocardial blood flow was used to determine the physiologic impact of these findings. In bFGF and VEGF treated animals resting collateral flow values significantly exceeded those of the control group. In addition, both bFGF and VEGF administration resulted in improvements in myocardial perfusion sufficient to prevent stress-induced deterioration of myocardial performance. Results of the studies demonstrate that local perivascular drug delivery can be effectively used to induce angiogenesis in chronically ischemic myocardium.

Angiotensin-II-induced angiogenesis in sponge implants in mice.

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating would healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (AII) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with AII (1 microgram), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with AII (2 micrograms) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 +/- 15 vs. 424 +/- 27 mg), total protein (18 +/- 1 vs. 25 +/- 1 micrograms/ww) and GAG (98 +/- 10 vs. 160 +/- 13 ng/ww). The local blood flow has been determined by measuring the washout rate of 133Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.

The anterior choroidal artery syndrome

We reviewed 12 cases of infarcts in the territory of the anterior choroidal artery (AChA) on CT and/or MRI. In each case vascular occlusion in the region was verified angiographically. Although the extent of the lesion on CT/MR images was variable, all were located on the axial images within an arcuate zone between the striatum anterolaterally and the thalamus posteromedially. The distribution of the lesions on mutiplanar MRI conformed well to the territory of the AChA demonstrated microangiographically. The variability of the extent of the infarcts may be explained by variations in the degree of occlusive changes in the AChA or the development of collateral circulation through anastomoses between the AChA and the posterior communicating and posterior cerebral arteries. The extent of the lesion appeared to be closely related to the degree of neurological deficit.

Effect of coronary collateral circulation on myocardial ischemia and ventricular dysfunction.

Although a functional role of coronary collaterals has been continuously debated, we observed the following facts in our studies during intracoronary thrombolytic therapy: (a) Myocardial ischemia is important for the development of collateral circulation, (b) collaterals can perfuse the infarcted myocardium, and (c) the presence of collaterals prevents the left ventricular aneurysm formation in acute myocardial infarction, even when the amount of the salvaged tissue is small. Thus, coronary collaterals are not merely markers of severe ischemia but help to preserve the functional integrity of the myocardium in the presence of coronary obstruction. We then attempted to promote collateralization to treat patients with angina pectoris. Patients with chronic stable effort angina were treated with heparin followed by treadmill exercise twice a day for 10 days. Treadmill capacity was found to improve in association with an increase in coronary collateral circulation. Heparin treatment of ischemic patients was found to be a noninvasive alternative to percutaneous transluminal coronary angioplasty and coronary bypass surgery for patients who are not candidates for invasive procedures.

Long-term changes in cerebral blood flow according to different types of ischemic stroke

Recurrence of ischemic stroke may be related to chronic hemodynamic failure of the brain. Long-term changes in cerebral blood flow (CBF) remain undetermined for each ischemic stroke subtype. We performed the present study to clarify this issue. The study group consisted of 77 unilateral, hemispheric, ischemic stroke patients who had a single stroke episode; atherothrombotic stroke in 34, cardioembolic in 26 and lacunar in 17. We measured baseline CBF in the affected and unaffected hemispheres 1.0–3.4 months after stroke onset, then repeated the measurements 10 months to 10 years later (mean 43.7 months), with the xenon-133 inhalation method. We analyzed changes in CBF in relation to other clinical characteristics. CBF in the affected hemisphere changed differently among the stroke subtypes ( P < 0.01); increased in the atherothrombotic group, particularly within 40 months of stroke; remained unchanged in the cardioembolic group; and decreased in the lacunar group, especially later than 40 months of stroke. In the atherothrombotic group, CBF increased in hypertensive patients but decreased in normotensives (7.9 ± 2.4% and −3.6 ± 3.9%, respectively; P < 0.05). Present results suggest that long-term changes in CBF depend on ischemic stroke subtype. Development of collateral circulation may occur after several years in atherothrombotic stroke patients. The findings raise doubts about the significance of chronic hemodynamic failure as a cause of stroke recurrence.

Bronchial arteries in experimental pulmonary infarction: angiographic and morphometric study

The aim was to investigate (1) whether collateral bronchopulmonary circulation developing due to chronic pulmonary embolism could prevent the evolution of pulmonary infarction after induction of pulmonary venous outflow impairment; and (2) how collateral bronchopulmonary circulation developed after acute embolisation of the lung with impaired pulmonary venous outflow. Fifty two mongrel dogs were studied. Thirty six dogs were experimental animals and 16 were in a control group. Unilateral impairment of pulmonary venous outflow was induced by constriction of the left pulmonary veins in two groups of experimental dogs: (1) three months after and (2) one hour before bilateral embolisation of the pulmonary artery. All animals were killed 12 days after constriction. The size of the bronchial arteries was evaluated from angiograms. The diameter and the wall thickness of the arteries were measured during histology. In all experimental dogs, haemorrhagic infarctions developed distally to emboli in the left lung regardless of whether the bronchial arteries were dilated before induction of pulmonary venous constriction or whether collateral circulation started to develop after pulmonary venous constriction. Constriction of the pulmonary veins was an essential factor for pulmonary infarction to develop as no infarction developed in the embolised regions of the right lungs with intact pulmonary venous outflow. Pulmonary venous constriction alone did not cause dilatation or hypertrophy of the bronchial arteries. After pulmonary artery embolisation, the same enlargement and hypertrophy of the bronchial arteries occurred both in the left lung with previously impaired venous outflow and in the right lung with intact pulmonary veins. Expanded bronchopulmonary circulation did not prevent the development of infarction in the embolised region of the lung with impaired pulmonary venous outflow. Development of collateral bronchopulmonary circulation was not influenced by previously impaired pulmonary venous outflow.

Management of gallstones in cirrhotic patients

34 cirrhotic patients who underwent either cholecystectomy alone or in conjunction with common duct exploration were retrospectively reviewed. In Child A and B patients morbidity was low and there were no postoperative deaths. However, all patients who underwent additional cholecystectomy during the non-shunting operation for esophageal varices required blood transfusion. Cholecystectomy in Child C patients is frequently associated with considerable intraoperative bleeding and subsequent postoperative complications. In the 23 patients who were not operated upon for gallstones, no patients developed symptomatic biliary disease. Ultrasonographically, most of these gallstones were strongly suspected to be black stones. Elective surgical intervention for symptomatic Child A and B patients would normally be warranted, but hemorrhage and resulting complications due to additional cholecystectomy for asymptomatic gallstones during the non-shunting operation should be minimized. An additional cholecystectomy should be considered, provided such a cholecystectomy is thought to be easily performed judging from the degree of development of collateral circulation around the hepatoduodenal ligament and unless black stones are suspected ultrasonographically. For symptomatic gallstones in Child C patients every type of medical treatment should be attempted. After considering the bleeding tendency or ascites, percutaneous transhepatic gallbladder drainage is considered to be one of the safest treatments.

Myocardial respiratory chain enzyme activities in anomalous origin of the left main coronary artery from the pulmonary trunk (Bland-White-Garland syndrome) and comparison with atherosclerotic coronary artery disease

Both anomalous origin of the left main coronary artery from the pulmonary trunk and atherosclerotic coronary artery disease are conditions associated with myocardial ischemia. In contrast to atherosclerotic coronary artery disease, ischemia in the anomalous origin of the left main coronary artery from the pulmonary trunk is gradual in onset owing to the high pulmonary artery pressure that limits blood flow through the anomalous left coronary artery in the postnatal period. Survival to adulthood depends on the development of collateral circulation from the right coronary or may eventually be related to a marked right coronary artery dominance. 1 In contrast to atherosclerotic coronary artery disease, left ventricular ejection fraction is only moderately depressed or normal in most patients with anomalous origin of the left main coronary artery from the pulmonary trunk. 2 The energy required to build up myocardial highenergy phosphates is mainly generated by the mitochondrial respiratory chain. The present study suggests that different respiratory chain capacities in the myocardium of patients with these 2 forms of ischemic heart disease may account for the differences in left ventricular performance.

Do dietary fatty acids affect endothelial cell production of growth factors? How might these factors relate to thrombogenesis?

Endothelial cells (ECs) can secrete potent growth factors and chemoattractants for neighboring connective-tissue cells ( 1). This EC function may be critically important in such processes as vessel neogenesis, both during embryogenesis and during the development of collateral circulation in adult animals, and in wound repair, in which ECs may orchestrate temporal. wellregulated secretion ofpolypeptide mitogens for local fibroblasts. Uncontrolled secretion ofparacrine growth factors may represent a triggering mechanism for proliferative lesions developing in tissue. Atherosclerotic plaque development involves hyperplasia of intimal smooth muscle cells (SMCs) in response to an undetermined stimulus. We proposed that inappropriate expression

Surgical Treatment of Moyamoya Disease in Pediatric Patients–Comparison between the Results of Indirect and Direct Revascularization Procedures

Either encephaloduroarteriosynangiosis (EDAS) or superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis combined with encephalomyosynangiosis (EMS) has been performed on most of the children with moyamoya disease in our department. EDAS alone was done in the parietal region of 13 sides in 10 patients, and STA-MCA anastomosis with EMS in the parietal region was done on 7 sides in 6 patients. The surgical results of these two different procedures were then compared. Postoperative collateral formation was observed on external carotid angiograms, and the improvement of clinical symptoms was monitored for 1 year after the bypass procedure. STA-MCA anastomosis with EMS was found to be superior to EDAS in both the development of collateral circulation (P less than 0.05) and postoperative clinical improvement (P less than 0.01). EDAS can be done easily and safely on small children with moyamoya disease, but STA-MCA anastomosis with EMS is considered to be more appropriate, whenever possible.

Long-term effects of percutaneous laser balloon ablation from the canine coronary sinus.

Radiofrequency catheter ablation of left-sided accessory pathways is becoming the first line of therapy for patients with symptomatic Wolff-Parkinson-White syndrome. Nevertheless, alternative ablation techniques merit development, at least as supplementary modalities for cases in which conventional ablation approaches may prove unsuccessful. We recently reported the short-term results with transcatheter laser balloon ablation from the coronary sinus in a canine model, proving that the procedure is feasible for the potential ablation of left-sided accessory pathways. We now report the effects of percutaneous transcatheter laser balloon ablation in a chronic canine model. Twenty adult mongrel dogs were studied. After baseline coronary arteriography, left ventriculography, and coronary sinus angiography were obtained, 15 dogs received two or three consecutive laser doses from the coronary sinus of 30-40 W for 15-30 seconds, for a total cumulative energy of 1,200-2,400 J. The five remaining animals underwent a procedure consisting of balloon sham inflation without laser exposure and served as controls. After a mean follow-up of 6 weeks, the angiographic procedures were repeated, and the animals were killed. The mean extent of the fibrotic lesion was 15 mm long, 6 mm wide, and 4.5 mm deep and involved the coronary sinus wall, atrium, and, frequently, the summit of the posterior left ventricular wall. Six animals (four in the study group and two in the control group) showed asymptomatic narrowing of the coronary sinus lumen but always with total angiographic reconstitution due to extensive collateral circulation. The circumflex artery and mitral valve were intact angiographically and histologically in all animals. Percutaneous transcatheter laser balloon ablation via the coronary sinus produces a lesion that may be anatomically well suited for left-sided accessory pathway ablation. Although coronary sinus narrowing may occur, adverse physiological effects are unlikely due to the development of extensive collateral circulation. Systematic clinical studies of this new approach to catheter ablation appear warranted.

INTRACEREBRAL THROMBOSIS

A 29-yr-old writer presented with seizures and left hemiparesis 8 days post-partum. Studies revealed right parietal hemorrhagic infarction secondary to superior sagittal sinus thrombosis. An anticoagulant was given for clot extension associated with increasing cerebral edema and coma. Inpatient rehabilitation was undertaken for residual left hemiparesis, most severe in the leg. Left arm strength rapidly returned to normal. Significant improvement in left leg strength occurred but was delayed for many months. Intracerebral thrombosis is an uncommon but significant cause of stroke in young adults. It frequently occurs in the puerperium and may be associated with unilateral or bilateral neurologic deficits. Treatment with anticoagulants is controversial because of the risk of hemorrhagic cerebral infarction, but may be beneficial in some cases. Recovery may be delayed for several months pending recanalization of the sinus or the development of collateral circulation. The overall prognosis for neurologic and functional recovery in survivors of intracerebral thrombosis is good.

血管新生阻害剤ＴＮＰ‐４７０マイクロスフィアーの化学塞栓によるＶＸ‐２担癌家兎における制癌効果

Chemoembolization is a useful cancer treatment which combines chemotherapy and tumor devascularization using an anticancer drug and transcatheter embolization of the arteries running to the tumor. TNP-470 is a new type of anticancer durg which prevents tumor neovascularization thereby blocking nutrient supply. We expected that the chemoembolization using microspheres containing this angiogenesis inhibitor would produce strong anticancer activity attributed to sitespecific inhibition of the tumor neovascularization, especially the development of collateral circulation. We examined the anticancer effects of chemoembolization using TNP-470 microspheres prepared with poly(DL-lactic/glycolic acid) in rabbits bearing VX-2 carcinoma. It is assumed that microspheres of 53-125 μm in diameter persistently embolized the arterial capillaries surrounding the tumor for 2∼3weeks and released the drug over 5 days. When TNP-470 was injected s. c. 5 times at a dose of 5 mg at 2-or 3-day intervals, tumor growth was found to be significantly inhibited after the 3rd injection(P<0.05). A single i. a. injection of 1 mg of TNP-470 aqueous solution or 50 mg of placebo microspheres provided slight suppression of tumor growth, but microspheres containing the same dose of TNP-470 caused striking regression of the tumor for 9 days, and this effect was dose-dependent. Chemoembolization should offer promising and reliable therapy using angiogenesis inhibitors with less systemic side effects.

Molecular Biology of the Coronary Vascular and Myocardial Responses to Ischemia

To understand the complex mechanism(s) involved in molecular responses to ischemia, we developed two experimental models in pigs. In a "stunning" model of repetitive ischemia and reperfusion, we studied the mRNA expression of immediate early genes like c-fos, c-myc and heat shock protein-70 (HSP-70). Myocardial stunning was achieved by two cycles of 10-min left anterior descending coronary artery (LAD) occlusion and 30 min reperfusion. We observed several-fold enhanced expression of c-fos and HSP-70 mRNA in the stunned myocardium as compared with the control, whereas c-myc mRNA levels remained almost unchanged. In the second model, we examined the expression of the peptide mitogens heparin-binding growth factor 1 (HBGF-1) and transforming growth factor beta 1 (TGF-beta 1) after a chronic coronary artery occlusion leading to myocardial collateralization. Progredient stenosis of the circumflex coronary artery was induced by implanting a hygroscopic ameroid constrictor ring around it and occlusion was verified by in vivo angiography. Using polymerase chain reaction (PCR) and Northern hybridization techniques, we observed significantly enhanced expression of HBGF-1 and TGF-beta 1 in collateralized myocardium as compared with normal. In situ techniques revealed the localization of HBGF-1 transcripts in the blood vessel wall, and TGF-beta 1 in cardiac myocytes and Purkinje cells. Our results clearly indicate that myocardial stunning stimulates the expression of transcription factors which might be involved in regulation of certain growth factors like HBGF-1 and TGF-beta 1 which may play a significant role in the development of a collateral circulation.

巨大内頸動脈瘤に対するcarotid ligationの有用性

The authors describe the efficacy and safety of carotid ligation designed especially for surgical treatment of a giant aneurysm of the internal carotid artery (ICA) in clinical and experimental studies. To determine the safety of ICA ligation, the balloon Matas test was administered for the ipsilateral ICA in nine patients with ICA aneurysms, seven of whom had giant aneurysms. Neither ischemic symptoms nor EEG changes developed during testing of the giant ICA aneurysms. Further, angiograms demonstrated that the contrast material filled poorly into the intracranial arteries distal to the aneurysm. In four of the seven giant aneurysms. ICA ligation effected good results with no complications.Using five models of an experimental giant aneurysm made of a canine descending aortic segment, the intra-arterial pressures of the common carotid artery was measured at the proximal and distal portions of the aneurysm with the transcatheter technique. Significant reductions of the arterial blood pressure and pulse pressure at the distal portion of the giant aneurysm model were noted.The data suggest that reductions of the mean pressure and pulse pressure in the distal ICA of the giant ICA aneurysm promote the development of collateral circulation. Thus, in many cases of giant aneurysm, ICA ligation would tend to preclude hemodynamic ischemia. When the neck of a giant aneurysm is difficult to clip, carotid ligation may be a safe alternative surgical treatment that yields good results.

Development of collateral circulation in a replanted rat hindlimb model

The development of collateral circulation was studied in a replanted rat hindlimb model by use of the hemodynamic techniques of hydrogen washout and laser Doppler capillary perfusion monitoring. Collateral development occurred and provided blood flow whose magnitude increased linearly over time. Twenty-seven percent of preligation blood flow was present at 2 weeks after replantation, 39% at 4 to 5 weeks, and 77% at 8 to 9 weeks by laser Doppler assessment. Laser Doppler correlated more closely with limb survival than did the hydrogen washout technique. Uniform necrosis (eight of eight) occurred after pedicle interruption in the 2-week group. Partial limb survival was noted in five of eight replants at 4 to 5 weeks on transection of the vascular pedicle, while complete survival of all replants (nine of nine) was seen at 8 to 9 weeks.

The elusive cause of instability in unstable angina

The causes of unstable angina are still largely unknown. However, some facts deriving from angiographic, postmortem, and pathophysiologic studies are well established. Angiographic findings: coronary thrombi and complicated stenoses are more frequent in unstable than in stable angina. Conversely, the severity of coronary atherosclerosis and the development of collateral circulation is similar in both coronary syndromes. Postmortem findings: the following features are more frequent in unstable than in stable angina: (1) mural thrombi, which often represent outgrowth from the inside of a fissured plaque; (2) inflammatory cells at the site of plaques and in perivascular nerves; and (3) contraction bands in smooth muscle cells of the media surrounding plaques. However, fissured plaques can be found in 10% of individuals dying of noncardiac causes, and fissured plaque may occasionally be missing under the coronary thrombus in unstable angina. Pathophysiologic findings: patients with unstable angina compared with those with stable angina exhibit: (1) higher levels of serotonin in the coronary sinus; (2) higher systemic levels of fibrinopeptide A; (3) higher urinary levels of thromboxane A 2 metabolites; and (4) a greater coronary reactivity to constrictor stimuli. A critical analysis of these established facts is required to set the stage for a better comprehension of the causes which can cause a coronary segment to progress in a stuttering way toward acute persistent coronary occlusion and myocardial infarction. Plaque fissure is likely to be an important background thrombogenic stimulus in many cases. However, it does not explain the stuttering evolution of coronary thrombosis, which, instead, might be due to: (1) additional, yet unidentified local thrombogenic stimuli; (2) transient modifications of the systemic hemostatic equilibrium toward thrombosis; and (3) transient episodes of local or distal vasoconstriction resulting in stagnation, a strong thrombogenic stimulus. The simultaneous presence, in some patients, of two or more of these mechanisms might determine the evolution toward irreversible occlusion. Until more precise information becomes available, it will not be possible to formulate a single pathogenetic hypothesis, since the causes of instability might be different in different patients. For the time being, medical treatment of unstable angina remains less than optimal because, to prevent occasional, local thrombosis and vasoconstriction, a persistent, systemic modification of the hemostatic equilibrium and vasomotor tone must be achieved.

Left ventricular function in dogs 1 year after coarctectomy

Juxtaductal aortic coarctation was surgically created in beagle puppies at the age of 2 months and resected at the age of 10 months, after the development of good collateral circulation. Control dogs undergoing sham operations on each occasion were studied in the same environment. Cardiac catheterization was performed 1 year after the coarctectomy to evaluate the recovery of the heart. Cardiac output, heart rate, end-diastolic pressure, and Vmax were similar in both groups of seven dogs, but the systolic pressure gradient (SPG) over the operated area during isoproterenol infusion was significantly higher in the coarctectomized group, with a mean of 8.9 +/- 6.3 (SD) vs. 0.1 +/- 0.3 mmHg (p less than 0.05). The preejection period [PEP, 58 +/- 8 vs. 47 +/- 5 ms (p less than 0.01)], electromechanical delay [EMD, 18 +/- 3 vs. 13 +/- 3 ms (p less than 0.05)], and isometric contraction time [ICT, 39 +/- 7 vs. 32 +/- 4 ms (p less than 0.05)], were all significantly longer in the coarctation group after isoproterenol infusion. The results demonstrate that, even though cardiac output increased adequately during loading and mechanical pumping efficiency was preserved, excitation-contraction coupling was still prolonged. Thus, an anatomical successful coarctectomy, even at the age of 10 months, does not fully restore left ventricular function in dogs after chronic experimental coarctation.

Collateral circulation as a marker of the presence of viable myocardium in patients with recent myocardial infarction

The relationship between the presence of viable myocardium and the extent of coronary collateral circulation to the infarct area was evaluated in 20 patients with a recent anterior myocardial infarction who had complete obstruction of the left anterior descending coronary artery. The viability of myocardial tissue was assessed by exercise thallium-201 myocardial scintigraphy, and the collateral circulation was angiographically evaluated by means of a collateral index ranging from 0 to 3. Patients were divided into two groups according to the presence (group 1, n = 10) or absence (group 2, n = 10) of viable myocardium in the perfusion territory of the infarct-related artery. The collateral index in group 1 was 2.5 ± 0.5 (SD), which was significantly higher than the 0.7 ± 0.8 in group 2. These findings indicate that the presence of ischemic but viable myocardium is intimately related to the development of collateral circulation in patients with myocardial infarction, and the existence of well-developed collateral channels predicts the presence of viable myocardium in the infarct area.

Development of collateral circulation in heterotopic auxiliary liver transplantation

Development of collateral circulation in heterotopic auxiliary liver transplantation