Structural Remodeling of the Extracellular Matrix in Arteriogenesis: A Review

Lower extremity arterial occlusive disease (AOD) results in significant morbidity and mortality for the population, with up to 10% of patients ultimately requiring amputation. An alternative method for non-surgical revascularization which is yet to be fully understood is the optimization of the body's own natural collateral arterial network in a process known as arteriogenesis. Under conditions of conductance vessel stenosis or occlusion resulting in increased flow, shear forces, and pressure gradients within collaterals, positive remodeling occurs to increase the diameter and capacity of these vessels. The creation of a distal arteriovenous fistula (AVF) will drive increased arteriogenesis as compared to collateral formation with the occlusion of a conductance vessel alone by further increasing flow through these arterioles, demonstrating the capacity for arteriogenesis to form larger, more efficient collaterals beyond what is spontaneously achieved after arterial occlusion. Arteries rely on an extracellular matrix (ECM) composed of elastic fibers and collagens that provide stability under hemodynamic stress, and ECM remodeling is necessary to allow for increased diameter and flow conductance in mature arterial structures. When positive remodeling occurs, digestion of lamella and the internal elastic lamina (IEL) by matrix metalloproteinases (MMPs) and other elastases results in the rearrangement and thinning of elastic structures and may be replaced with disordered elastin synthesis without recovery of elastic function. This results in transmission of wall strain to collagen and potential for aneurysmal degeneration along collateral networks, as is seen in the pancreaticoduodenal artery (PDA) after celiac occlusion and inferior mesenteric artery (IMA) with concurrent celiac and superior mesenteric artery (SMA) occlusions. Further understanding into the development of collaterals is required to both better understand aneurysmal degeneration and optimize collateral formation in AOD.

Collateral Predictors of Neovascularization After Indirect Revascularization in Adult Patients with Moyamoya Disease: A Single-Center Retrospective Study

Objective. The underlying factors of neovascularization after indirect bypass in the adult patients with moyamoya disease (MMD) remained unknow. The aim of this study was to explore potential predictors based on collateral characteristics for neovascularization after indirect bypass in adult MMD patients. Methods. The adult MMD patients treated by indirect bypass in a single-institution from August 2012 and January 2018 were retrospectively selected into our research. The collaterals based on cerebral angiography were classified into the following subtypes: intracerebral anastomosis, duro-cortical anastomosis, and leptomeningeal anastomosis. Neovascularization evaluation was based on Matsushima classification, with “good” collateral formation in level 2 and 3, and poor formation in level 0 and 1. Univariate and multivariate analyses were performed to identify neovascularization predictors after indirect bypass. Results. A total of 86 patients (97 hemispheres) (mean ± SD age 35.06 ± 15.09 years, range 18–61 years) were retrospectively included. Preoperative collateral circulation included intracerebral anastomosis in 49 (50.5%) cases, duro-cortical anastomosis in 19 (19.6%) cases, and leptomeningeal anastomosis in 29 (29.9%) cases, respectively. Postoperative good neovascularization was observed in 56 (57.7%) hemispheres. Multivariate analysis showed that intracerebral anastomosis (P<0.001, OR [95% CI] 2.984 [2.031-5.437]) was associated with favorable neovascularization, whereas older age (P<0.001, OR [95% CI] 0.827 [0.793-0.916]) and hemorrhagic onset (P<0.001, OR [95% CI] 0.138 [0.054–0.353]) were significantly associated with poor neovascularization. Hemispheres in the good neovascularization had lower modified Rankin scale score, and better long-term improvement than those in the poor neovascularization. Conclusions. Hemorrhagic onset and old age predict poor neovascularization after indirect bypass, while duro-cortical anastomosis and intracerebral anastomosis predict good neovascularization. Good neovascularization was associated with better long-term outcomes. The current study provides a basis for the selection of surgical procedure for MMD candidates.

MicroRNA-495 Regulates Collateral Formation And Predicts Myocardial Perfusion In Coronary Chronic Total Occlusion Disease

How miRNAs play a role in collateral formation of chronic total occlusion (CTO) patients and in predicting myocardial perfusion has not been investigated. In this study, we screened circulating miRNAs in CTO and stable coronary artery disease patients using high-throughput sequencing and found 42 differential expressed miRNAs, including miR-329, miR-494 and miR-495, which belong to 14q32 miRNAs gene cluster. The down regulation of miR-329, miR-494 and miR-495 was confirmed in an independently larger cohort. Then in vitro and in vivo study, we demonstrated that miR-495 inhibited angiogenesis and collateral formation through Notch1 pathway. Finally we came back to a clinical view and found that miR-329, miR-494 and miR-495 were able to predict whether myocardial perfusion can be improved in CTO patients after revascularization. These data indicate that miRNAs are involved into the collateral formation of CTO patients and could be potentially biomarkers to help individualise therapeutic decisions.

N-terminal pro-brain natriuretic peptide and coronary collateral formation in patients undergoing primary percutaneous coronary intervention

There is insufficient information on the relationship between the N-terminal pro-brain natriuretic peptide (NT-proBNP) level and collateral circulation (CC) formation after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction. We analyzed 857 patients who underwent primary PCI. The serum NT-proBNP levels were measured on the day of admission, and the CC was scored according to Rentrop’s classification. Log-transformed NT-proBNP levels were significantly higher in patients with good CC compared to those with poor CC (6.13 ± 2.01 pg/mL versus 5.48 ± 1.97 pg/mL, p < 0.001). The optimum cutoff value of log NT-proBNP for predicting CC was 6.04 pg/mL. Log NT-proBNP ≥ 6.04 pg/mL (odds ratio 2.23; 95% confidence interval 1.51–3.30; p < 0.001) was an independent predictor of good CC. CC development was higher in patients with a pre-TIMI flow of 0 or 1 than those with a pre-TIMI flow of 2 or 3 (22.6% versus 8.8%, p = 0.001). The incidence of left ventricular (LV) dysfunction (< 50%) was greater in patients with a pre-TIMI flow of 0 or 1 (49.8% versus 35.5%, p < 0.001). The release of NT-proBNP was greater in patients with LV dysfunction (34.3% versus 15.6%, p < 0.001). The incidence of good CC was greater in patients with log NT-proBNP levels ≥ 6.04 pg/ml (16.8% versus 26.2%, p = 0.003). The association between NT-proBNP and collateral formation was not influenced by pre-TIMI flow and LV function. NT-proBNP appears to reflect the degree of collateral formation in the early phase of STEMI and might have a new role as a useful surrogate biomarker for collateral formation in patients undergoing primary PCI.

974 Paget-Schroetter Syndrome in A Young Fitness Enthusiast with A Negative D-Dimer. Highlighting the Balance Between Clinical Suspicion and Diagnostic Modalities

This case illustrates an athletic 22-year-old, who presented to the hospital with a 3-week history of spontaneous right arm ache, discolouration and swelling. His blood tests were normal, with a negative D-dimer (&lt;150ng/ml). He underwent a CT venogram for suspicion of venous obstruction which was unremarkable. However due to a high clinical suspicion, an ultrasound doppler was performed. This identified the presence of axillary-subclavian thrombosis which in conjunction with other clinical and radiological parameters confirmed the diagnosis of Paget-Schroetter Syndrome (PSS). Our patient was commenced on anticoagulation as the venous obstruction was suspected to be sub-acute with clinical suggestion of collateral formation. Unfortunately, his symptoms failed to resolve over a 6-month period, and he underwent an elective right rib resection with right subclavian bypass using the great saphenous vein with good outcome post-operatively. PSS is a rare manifestation of venous thoracic outlet syndrome (TOS) commonly seen in young, healthy, athletic individuals. Despite the high effectiveness of D-Dimers in ruling out acute thrombotic process and the accuracy of dedicated CT angiography in excluding vascular thrombotic events, both tests proved inconclusive in this particular case. This latter observation highlights the importance of the clinical context, and risk profiling in guiding results interpretation.

Collateral Formation from Left Lateral Thoracic Artery to the Adamkiewicz Artery

A 68-year-old man who had undergone descending thoracic aortic replacement was referred to our hospital with a thoracoabdominal aortic aneurysm. During the original surgery, the Adamkiewicz artery was directly reconstructed. However, multidetector row computed tomography showed occlusion of the reconstructed artery at its orifice, with supply by a collateral vessel from the left lateral thoracic artery. With careful incision to avoid damage to the collateral vessel, no postoperative neurological deficit was observed.

Pathological Circulating Factors in Moyamoya Disease

Moyamoya disease (MMD) is a cerebrovascular disease that presents with vascular stenosis and a hazy network of collateral formations in angiography. However, the detailed pathogenic pathway remains unknown. Studies have indicated that in addition to variations in the of genetic factor RNF213, unusual circulating angiogenetic factors observed in patients with MMD may play a critical role in producing “Moyamoya vessels”. Circulating angiogenetic factors, such as growth factors, vascular progenitor cells, cytokines, inflammatory factors, and other circulating proteins, could promote intimal hyperplasia in vessels and excessive collateral formation with defect structures through endothelial hyperplasia, smooth muscle migration, and atypical neovascularization. This study summarizes the hypothesized pathophysiology of how these circulating factors affect MMD and the interactive modulation between them.

Testicular vein thrombosis mimicking epididymo-orchitis after suspected Covid-19 infection

A 70-year-old man presented to our vein clinic with intermittent and recurrent left testicular and groin pain, clinically resembling epididymo-orchitis. He had never had any genitourinary problems until contracting a severe flu-like illness in January 2020, strongly suspected to have been Covid-19. He had failed to respond on four separate occasions to antibiotics prescribed by his GP and had only responded on these occasions to aspirin. Duplex ultrasonography at our clinic showed thrombosis of the left testicular vein with venous collateral formation. The testicle itself showed mild oedema, but a reduced arterial flow supporting the pain to be secondary to thrombosis. Covid-19 is known to be associated with venous thromboembolic disease, but usually in patients sick enough to be hospitalised and particularly in those requiring intensive care. This man appears to have had a left testicular vein thrombosis secondary to relatively mild Covid-19 infection, as he did not require hospitalisation.

Postoperative Neovascularization, Cerebral Hemodynamics and Clinical Prognosis Between Combined and Indirect bypass Revascularization Procedures in Hemorrhagic Moyamoya Disease.

BACKGROUND: Present primary focus was rebleeding and prognosis of hemorrhagic moyamoya disease (MMD), while limited researches emphasized the postoperative collateral formation and cerebral hemodynamics. OBJECTIVE: To compare the diverse effects of combined (CB) and indirect (IB) bypass revascularization procedures on the postoperative collateral formation and hemodynamics in hemorrhagic MMD patients.METHODS: Hemorrhagic MMD patients treated surgically were retrospectively collected and dichotomized into CB and IB group. Postoperative complications and clinical prognosis, as well as pre- and post-operative Modified Rankin Scale (mRS), collateral circulation status and cerebral hemodynamics were observed and compared between the CB and IB groups. RESULTS: A total of 37 patients with hemorrhagic MMD were identified. Of 68 cerebral hemispheres, 47(69.1%) were combined revascularization and the rest indirect. During an average follow-up of 16.5±8.7 months, the recurrent stroke events were significantly lower, as well as postoperative mRS scores≤2, satisfactory postoperative collateral formation, improved dilation or extension of anterior choroidal /posterior communication artery (AchA/PcoA) were significantly higher in the CB group than in the IB group (all P< .05). Compared with preoperative cerebral hemodynamics, relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), mean transit time (MTT) and relative time to peak (rTTP) in the CB group; but in the IB group, rCBF, rCBV and MTT were significantly improved (all P< .001). The CB group’s postoperative rCBF was significantly improved as compared with the IB group (P< .001).CONCLUSION: CB can obtain better postoperative collateral formation, cerebral hemodynamics, and clinical prognosis as compared with IB.