A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration.

Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.

Modeling cerebrovascular responses to assess the impact of the collateral circulation following middle cerebral artery occlusion.

OBJECTIVE: An improved understanding of the role of the leptomeningeal collateral circulation in blood flow compensation following middle cerebral artery (MCA) occlusion can contribute to more effective treatment development for ischemic stroke. The present study introduces a model of the cerebral circulation to predict cerebral blood flow and tissue oxygenation following MCA occlusion. METHODS: The model incorporates flow regulation mechanisms based on changes in pressure, shear stress, and metabolic demand. Oxygen saturation in cerebral vessels and tissue is calculated using a Krogh cylinder model. The model is used to assess the effects of changes in oxygen demand and arterial pressure on cerebral blood flow and oxygenation after MCA occlusion. RESULTS: An increase from five to 11 leptomeningeal collateral vessels was shown to increase the oxygen saturation in the region distal to the occlusion by nearly 100%. Post-occlusion, the model also predicted a loss of autoregulation and a decrease in flow to the ischemic territory as oxygen demand was increased; these results were consistent with data from experiments that induced cerebral ischemia. CONCLUSIONS: This study highlights the importance of leptomeningeal collaterals following MCA occlusion and reinforces the idea that lower oxygen demand and higher arterial pressure improve conditions of flow and oxygenation.

Major aortopulmonary collateral arteries: clinical, echocardiographic, and radiologic characteristics.

Purpose: Major aortopulmonary collateral arteries (MAPCAs) are rare congenital anomalies with significant clinical implications, often associated with congenital heart diseases like tetralogy of Fallot (TOF) and pulmonary atresia (PA). This study aimed to investigate the clinical, echocardiographic, and radiologic characteristics of MAPCAs in patients with congenital heart diseases admitted to our clinic between 2016 and 2023. Material and methods: A retrospective analysis of 46 cases was conducted using chest computed tomography exams performed on a dual-source 128-slice CT scanner. Clinical data and radiologic characteristics were collected and analysed. Results: The study revealed a strong correlation between congenital heart diseases and the presence of MAPCAs, with TOF, PA, and ventricular septal defect (VSD) being the most common, and it indicated that these collaterals may exist with non-diagnosed congenital heart disease. Tricuspid regurgitation and aortic insufficiency were the predominant echocardiographic findings. Radiologically, MAPCAs primarily originated from the descending aorta (type II) in 85% of cases, and their sizes ranged from ≤ 3 mm to > 10 mm, with an average of 5 mm. Conclusions: This study provides comprehensive insights into the clinical and radiologic aspects of MAPCAs in patients with congenital heart diseases. The findings emphasise the importance of early detection and intervention for better managing of these complex conditions and the need for further research.

Abernethy malformation with unusual cardiac malformation: Case report and literature review.

Abernethy malformation, also known as congenital extrahepatic shunt, is a rare anomaly, which is characterized by partial or complete diversion of the portal blood into the systemic venous circulation. The clinical manifestations of Abernethy malformation during childhood include neonatal cholestasis, failure to thrive, mental retardation, and other congenital defects. We report a case of Abernethy malformation Type II in a 9-year-old boy, whose left ventricle was slightly enlarged because of several major aortopulmonary collateral arteries (MAPCAs) but laboratory examinations were normal 5 years earlier. The characteristics of congenital heart disease in patients with Abernethy malformation are discussed. We propose that physicians should be aware of the possibility of Abernethy malformation in children with enlargement of the left ventricular due to systemic-pulmonary collateral circulation.

Follow the MAPCA: an unusual source of right pulmonary artery flow.

Major aortopulmonary collateral arteries in the setting of pulmonary atresia with intact ventricular septum are very rarely encountered, having been documented in only a handful of case reports. We present the right ventriculogram of a patient found to have this rare combination of findings along with right ventricular-dependent coronary artery circulation and unusual supply of the right pulmonary artery.

Computed tomography in tetralogy of Fallot: pre- and postoperative imaging evaluation.

Tetralogy of Fallot (TOF) is the most common cause of cyanotic congenital heart disease (CHD) and the most frequent complex CHD encountered in adulthood. Although children with TOF share four characteristic features (subaortic ventricular septal defect, overriding aorta, right ventricular hypertrophy, pulmonary stenosis), the clinical spectrum and course are in fact greatly heterogeneous. Echocardiography remains the mainstay for diagnosis, presurgical planning and postoperative follow-up. However, with continued technological advances, CT now plays an increasing role in TOF evaluation and management, helping to minimize routine invasive catheter angiography. Preoperatively, CT is uniquely suited to assess associated pulmonary arterial, aortic and coronary anomalies as well as extra-cardiovascular structures and is particularly helpful for delineating complex anatomy in the TOF subtypes of absent pulmonary valve and pulmonary atresia with major aortopulmonary collaterals. Postoperatively, CT is useful for identifying surgical complications and for long-term monitoring including volumetry quantification, especially in children for whom MRI is contraindicated or limited by implanted devices such as pacemakers and stents. In this article, we review key clinical features and considerations in the pre- and postoperative TOF patient and the burgeoning role of CT for facilitating accurate diagnosis and personalized intervention.

Unifocalization with pericardial roll technique in pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVE: This study aims to compare both the pericardial roll technique with the patch augmentation technique of the unifocalization, and single-stage complete repair with the unifocalization and shunt for the repair of the ventricular septal defect, pulmonary atresia, and major aortopulmonary collateral arteries. METHODS: This was a retrospective review of the 48 patients undergoing unifocalization of the ventricular septal defect, pulmonary atresia, and major aorticopulmonary collateral arteries from a single center. Our cohort had two surgical pathways, including single-stage midline unifocalization (n = 40), unifocalization after pulmonary artery rehabilitation by creating an aortopulmonary window or central shunt (n = 8). There were two surgical techniques in single-stage midline unifocalizaton, including widening of the pulmonary arteries with a patch (n = 30), and connecting pulmonary arteries with a pericardial roll (n = 10). RESULTS: A total of 14 (29.2%) of 48 patients underwent single-stage complete repair, 26 patients underwent shunt palliation with unifocalization. Combined early and late mortality was seen in seven patients in those who underwent shunt palliation with unifocalization, while it was seen in one patient in those who underwent a single-stage complete repair (mortality ratio 26.8% vs. 7.1%, p = .22). There was no statistically significant difference between the pericardial roll and patch augmentation techniques in terms of pulmonary artery reintervention (p = .65). Although all pulmonary artery reinterventions were for unilateral pulmonary artery in the roll technique group, 41.7% of reinterventions were for bilateral pulmonary arteries in the pericardial augmentation group. CONCLUSION: Single-stage complete repair of the ventricular septal defect, pulmonary atresia, and major aorticopulmonary collateral arteries has better results than unifocalization with a shunt. In terms of nonvaluable raw material, the use of the pericardial roll technique is a considerable alternative for unifocalization.

Overview of Cardiopulmonary Bypass Techniques and the Incidence of Postoperative Complications in Pediatric Patients Undergoing Complex Pulmonary Artery Reconstruction.

Cardiopulmonary bypass (CPB) is routinely used for performing congenital heart operations. While most congenital heart operations can be performed with bypass times under 2 hours, complex pulmonary artery reconstructions require longer periods of CPB to facilitate the surgical repair. This article is intended to summarize the surgical and perfusion techniques utilized in patients undergoing complex pulmonary artery reconstructions at our institution. The initial portion of this manuscript provides an in-depth description of the surgical techniques employed for pulmonary artery reconstructions. This information is important in order to understand why prolonged CPB is a necessary requirement. The manuscript then provides a detailed description of the perfusion techniques and the modifications to the CPB circuit. Finally, the manuscript provides a summary of data from a clinical study evaluating the application of these techniques in 100 consecutive children undergoing complex pulmonary artery reconstruction. The data from this study demonstrated that there was a poor correlation between duration of CPB and both the number of postoperative complications and hospital length of stay. Major adverse cardiac events occurred in 11 (11%) patients with one hospital mortality. These results suggest that prolonged CPB does not predispose to adverse outcomes in this select population of patients.

The Case of a 44-Year-Old Survivor of Unrepaired Tetralogy of Fallot, Right Aortic Arch and Abdominal Aortopulmonary Collateral Vessels.

The most common congenital cyanotic heart disease is described in the literature as the Tetralogy of Fallot. This abnormality is characterized by the presence of ventricular septal defect (VSD), obstruction of the right ventricular (RV) outflow tract, right ventricular hypertrophy, and overriding aorta. In patients with pulmonary atresia with ventricular septal defect (PA/VSD), major aortopulmonary collateral arteries (MAPCA) are common; however, although some of them do not have PA/VSD, they do have other particular anatomical variants. The case we are presenting in this article is a rare mild symptomatic adult noncorrected TOF, with preserved RV function, right aortic arch, and MAPCAs ("classic" thoracic MAPCAs but also abdominal MAPCAs). The anatomy of a complex congenital defect is well illustrated by cardiac magnetic resonance (CMR) and computer tomography angiography (CTA), and these imaging techniques are mostly used to understand the relative clinical "silence" TOF. Imaging scans thus play a key role in the evaluation of these patients, being very important to know the indications and limitations of each method, but also to learn to combine them with each other depending on the clinical picture of the patient's presentation. Additionally, the close collaboration between clinicians and imagers is essential for a correct, complete and detailed preoperative evaluation, being subsequently essential for cardiovascular surgeons, the whole team thus deciding the best therapeutic management.

Outcomes in Patients with Alagille Syndrome and Complex Pulmonary Artery Disease.

OBJECTIVE: To assess outcomes in a large cohort of patients with Alagille syndrome (ALGS) who underwent pulmonary artery reconstruction surgery for complex pulmonary artery disease. STUDY DESIGN: Patients with ALGS who underwent pulmonary artery reconstruction surgery at Lucile Packard Children's Hospital Stanford were reviewed. Patients were examined as an overall cohort and based on the primary cardiovascular diagnosis: severe isolated branch pulmonary artery stenosis, tetralogy of Fallot (TOF) without major aortopulmonary collateral arteries (MAPCAs), or TOF with MAPCAs. RESULTS: Fifty-one patients with ALGS underwent pulmonary artery surgery at our center, including 22 with severe branch pulmonary artery stenosis, 9 with TOF without MAPCAs, and 20 with TOF and MAPCAs. Forty-one patients (80%) achieved a complete repair. Five of the patients with TOF with MAPCAs (25%) underwent complete repair at the first surgery, compared with 8 (89%) with TOF without MAPCAs and 19 (86%) with isolated branch pulmonary artery stenosis. At a median follow-up of 1.7 years after the first surgery, 39 patients (76%) were alive, 36 with a complete repair and a median pulmonary artery:aortic systolic pressure of 0.38. Nine patients (18%), including 8 with isolated branch pulmonary artery stenosis, underwent liver transplantation. CONCLUSIONS: Most patients with ALGS and complex pulmonary artery disease can undergo complete repair with low postoperative right ventricular pressure. Patients with TOF/MAPCAs had the worst outcomes, with higher mortality and more frequent pulmonary artery interventions compared with patients with TOF without MAPCAs or isolated branch pulmonary artery stenosis. Complex pulmonary artery disease is not a contraindication to liver transplantation in patients with ALGS.

Outcome after surgery for pulmonary atresia with ventricular septal defect, a long-term follow-up study.

AIM: To study the long-term outcome after surgery for pulmonary atresia and ventricular septal defect (PA-VSD), and to determine association between the contribution of major aorto-pulmonary collateral arteries (MAPCAs) to the pulmonary blood flow, comorbidity and cause of death. METHODS: Patients who had undergone surgery for PA-VSD from January 1st 1994 to December 31st 2017 were studied retrospectively. Survival was cross-checked against the Swedish National Population Register. RESULTS: Seventy patients were identified, giving an incidence of 5.3 newborns per 100 000 live births. In 41 patients (59%) the pulmonary blood flow originated from a patent ductus arteriosus (PDA), while 29 patients (41%) had contribution of the pulmonary blood flow from MAPCAs. Extracardiac disease was found in 34 patients (49%), 16 of whom had 22q11-microdeletion syndrome (23%). Survival at follow-up was similar in patients with and without MAPCAs (72.4% vs. 75.6%, n.s.), with a median follow-up time of 14.3 years (3.2-41.8 years). No difference was found in mortality in patients with or without any syndrome or extracardiac disease. CONCLUSION: Long-term survival did not differ between those with and without MAPCAs and no difference in mortality was seen in patients with and without concomitant extracardiac disease or any kind of syndrome.

New Research Is Shining Light on How Collateral Arteries Form in the Heart: a Future Therapeutic Direction?

PURPOSE OF REVIEW: Collateral arteries create artery-artery anastomoses that could serve as natural bypasses that in the heart could relieve the various complications of ischemia heart disease. Recent work using animal models have begun to reveal details of how coronary collateral arteries form. RECENT FINDINGS: Mouse genetics has been used to study the cellular and molecular mechanisms of collateral artery development. Collateral arteries are not pre-existing in the mouse heart, and only form in response to injury. Myocardial infarction creates tissue hypoxia that triggers the expression of growth factors and chemokines that guide collaterogenesis. Collateral development is more robust in neonatal hearts when compared with adults, and contributes to neonatal heart regeneration. The identification of signaling pathways and cellular responses underlying coronary collateral artery development suggests potential translational strategies. Continued investigation into this subject could lead to the identification of targetable pathways that induce collateral arteries for cardiac revascularization.

Unique foetal diagnosis of aorto-pulmonary collaterals in right atrial isomerism.

Right atrial isomerism is associated with complex cardiac malformations, particularly single-ventricle lesions; right atrial isomerism is rarely associated with aorto-pulmonary collateral arteries. We report a foetal diagnosis of right atrial isomerism, with an unbalanced atrioventricular septal defect, pulmonary stenosis, total anomalous venous drainage, and significant aorto-pulmonary collaterals diagnosed at 22 weeks' gestation.

Successful surgical management of cyanotic congenital heart disease complicated by pulmonary aspergillosis.

Pulmonary aspergillosis associated with cyanotic congenital heart disease is a rare condition, which is known to have a poor prognosis. We report a case of a 21-year-old woman with truncus arteriosus and major aortopulmonary collateral arteries who underwent primary Rastelli procedure after thoracoscopic lobectomy for the management of progressive pulmonary aspergillosis.

Rare cause of dynamic aortic obstruction in pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries: a case report.

A 2-month-old infant with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries developed an aneurysmatic elongation of the tricuspid valve tissue that partially closed and dynamically protruded through the ventricular septal defect, beneath the aortic valve. This rare finding caused dynamic left ventricle outflow tract obstruction and recurrent cardiac arrests and ultimately required surgical intervention.

Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis.

Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.

Assessing the hemodynamic contribution of capillaries, arterioles, and collateral arteries to vascular adaptations in arterial insufficiency.

OBJECTIVE: There is currently a lack of clarity regarding which vascular segments contribute most significantly to flow compensation following a major arterial occlusion. This study uses hemodynamic principles and computational modeling to demonstrate the relative contributions of capillaries, arterioles, and collateral arteries at rest or exercise following an abrupt, total, and sustained femoral arterial occlusion. METHODS: The vascular network of the simulated rat hindlimb is based on robust measurements of blood flow and pressure in healthy rats from exercise and training studies. The sensitivity of calf blood flow to acute or chronic vascular adaptations in distinct vessel segments is assessed. RESULTS: The model demonstrates that decreasing the distal microcirculation resistance has almost no effect on flow compensation, while decreasing collateral arterial resistance is necessary to restore resting calf flow following occlusion. Full restoration of non-occluded flow is predicted under resting conditions given all chronic adaptations, but only 75% of non-occluded flow is restored under exercise conditions. CONCLUSION: This computational method establishes the hemodynamic significance of acute and chronic adaptations in the microvasculature and collateral arteries under rest and exercise conditions. Regardless of the metabolic level being simulated, this study consistently shows the dominating significance of collateral vessels following an occlusion.

Systemic-to-pulmonary shunt vs right ventricle to pulmonary artery connection in the treatment of pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries.

OBJECTIVE: The systemic-to-pulmonary shunt (SPS) and right ventricle to pulmonary artery (RV-PA) connection were evaluated to pursue the goal of rehabilitating dysplastic native PAs via establishment of antegrade blood flow. However, the application of these two palliative operations was still confusing. We compared the two operations to determine their different effects on patients who have pulmonary atresia, ventricular septal defects, and major aortopulmonary collateral arteries (MAPCAs). METHODS: From January 2011 to January 2016, 44 patients received the SPS procedure, and 54 patients received the RV-PA connection procedure; these procedures were compared based on perioperative data and follow-up data. There was no significant difference between the two groups for follow-up time (15.5 ± 11.8 vs 11.4 ± 10 months; P = .073). RESULTS: The SPS patients had a smaller preoperative pulmonary artery index (68.57 ± 38.25 vs 112.62 ± 61.63 mm2 /m2 ; P < .01), more MAPCAs (2.4 ± 1.1 vs 1.8 ± 1.5; P = .045) and had a shorter intubation time (26.73 ± 27.20 vs 40.88 ± 36.93 hours; P = .045), intensive care unit stay (3.6 ± 3.9 vs 5.7 ± 5.5 days; P = .033), and hospital stay (9.9 ± 3.9 vs 14.7 ± 11.9 days; P = .014) than the RV-PA connection patients. The cumulative complete repair rate and cumulative survival rate did not differ significantly between the two groups. CONCLUSIONS: Both the SPS and the RV-PA connection could rehabilitate the PA and produce complete repair, while the SPS could achieve better early postoperative outcomes and be suitable for patients with severe dysplastic PAs and large MAPCAs.

Placental growth factor levels in quadriceps muscle are reduced by a Western diet in association with advanced glycation end products.

In peripheral artery disease (PAD), atherosclerotic occlusion chronically impairs limb blood flow. Arteriogenesis (collateral artery remodeling) is a vital adaptive response to PAD that protects tissue from ischemia. People with type II diabetes have a high risk of developing PAD and would benefit from arteriogenesis. However, arteriogenesis is suppressed in people with diabetes by a multifaceted mechanism which remains incompletely defined. Upregulation of placental growth factor (PLGF) is a key early step in arteriogenesis. Therefore, we hypothesized that metabolic dysfunction would impair PLGF expression in skeletal muscle. We tested this hypothesis in C57BL/6J and ApoE-/- mice of both sexes fed a Western diet (WD) for 24 wk. We first assessed baseline levels of PLGF, vascular endothelial growth factor (VEGF-A), and VEGF receptor 1 (VEGFR1) protein in hindlimb skeletal muscle. Only PLGF was consistently decreased by the WD. We next investigated the effect of 24 wk of the WD on the response of PLGF, VEGF-A, VEGFR1, and monocyte chemoattractant protein-1 (MCP-1) to the physiological stimulus of vascular occlusion. Hindlimb ischemia was induced in mice by gradual femoral artery occlusion using an ameroid constrictor. Growth factor levels were measured 3-28 days postsurgery. In C57BL/6J mice, the WD decreased and delayed upregulation of PLGF and abolished upregulation of VEGF-A and VEGFR1 but had no effect on MCP-1. In ApoE-/- mice fed either diet, all factors tested failed to respond to occlusion. Metabolic phenotyping of mice and in vitro studies suggest that an advanced glycation end product/TNFα-mediated mechanism could contribute to the effects observed in vivo.NEW & NOTEWORTHY In this study, we tested the effect of a Western diet on expression of the arteriogenic growth factor placental growth factor (PLGF) in mouse skeletal muscle. We provide the first demonstration that a Western diet interferes with both baseline expression and hindlimb ischemia-induced upregulation of PLGF. We further identify a potential role for advanced glycation end product/TNFα signaling as a negative regulator of PLGF. These studies provide insight into one possible mechanism by which type II diabetes may limit collateral growth.

Insulin Treatment Forces Arteriogenesis in Diabetes Mellitus by Upregulation of the Early Growth Response-1 (Egr-1) Pathway in Mice.

The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of Egr-1 in promoting collateral outward remodeling. However, the role of Egr-1 in the presence of DM in outward vessel remodeling was not studied. We hypothesized that Egr-1 expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor Egr-1 for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of Egr-1 endothelial downstream genes Intercellular Adhesion Molecule-1 (ICAM-1) and urokinase Plasminogen Activator (uPA), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of Egr-1 and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.