Endovascular treatment of atherosclerotic lesions in the superficial femoral artery and proximal popliteal artery using the sinus-SuperFlex-635 stent: twelve-month results from the HERO Registry.

BACKGROUND: The aim of this study was to evaluate the safety and performance of the sinus-SuperFlex-635 self-expandable nitinol stent (Optimed GmbH) for the treatment of steno-occlusive lesions in the superficial femoral artery (SFA) and proximal popliteal artery (PPA). METHODS: The prospective, multicenter, observational HERO study recruited 117 eligible patients (83 men; mean age 69.4±9.7y) from 7 centers in Belgium. RESULTS: A total of 129 stents were successfully deployed in 121 lesions in 117 patients (100%). The patients presented with symptomatic ≥50% stenosis or chronic total occlusion (CTO) (30.6%). Mean lesion length was 71.4±56.3 mm. Moderate to severe calcification was present in 82.6% of the lesions. Acute lesion success (<30% residual stenosis) was achieved in 96.0%. There were no in-hospital serious adverse events. Duplex ultrasound-driven primary patency at 12 months was recorded in 84 of 107 (78.5%) lesions. The overall target lesion revascularization (TLR) rate was 8.4% at 12 months; the target extremity revascularization (TER) rate was 4.7%. Clinical assessment at 12 months demonstrated improvement by at least 1 Rutherford class, without the need for TLR (i.e. primary sustained clinical improvement) in 83.9% of patients and with the need for TLR in 90.6% of patients (i.e. secondary sustained clinical improvement). CONCLUSIONS: Based on the high primary patency, low stent fracture rate and significant clinical improvement, combined with refined stent design and long stent availability, the sinus-SuperFlex-635 self-expandable nitinol stent proves its value in the treatment of complex femoropopliteal lesions.

Laparoscopic ventral hernia repair using a composite mesh with polypropylene and expanded polytetrafluoroethylene: a prospective, multicentre registry.

BACKGROUND: Abdominal wall hernias are a common problem. Composite meshes placed intraperitoneally for abdominal wall hernia repair are widely used. This registry evaluated the safety and efficacy of one specific composite mesh with polypropylene and expanded polytetrafluoroethylene (Intramesh® T1) in laparoscopic ventral hernia repair. METHODS: A prospective multicentre registry with data from seven centres was collected between January 2013 and September 2014. Primary endpoint was recurrence rate at 12 months determined by clinical examination. Secondary outcome measures included intraoperative complications, complications during hospitalisation and at 1-month and 12-months follow-up. RESULTS: The registry included 90 patients (30 female and 60 male). Fifty-five patients (61.1%) presented with primary ventral hernias and 35 patients (38.9%) with incisional ventral hernias. Median hernia size was 4 cm2. Intraoperative complications were reported in two patients (2.2%). Complications during hospitalisation were reported in four (4.4%) patients. At 1-month follow-up, 17 (18.9%) patients had postoperative complications, of which 5 complications were major and 19 were minor. Late complications at 12-months were observed in 10 patients (11.1%), of which 2 were major and 8 minor complications. CONCLUSION: Intramesh® T1 is a safe and effective composite mesh with favourable short and midterm outcome and morbidity. (NCT01816867).

Irradiation of existing atherosclerotic lesions increased inflammation by favoring pro-inflammatory macrophages.

BACKGROUND AND PURPOSE: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE(-/-) mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. MATERIAL AND METHODS: ApoE(-/-) mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. RESULTS: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. CONCLUSIONS: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque.

Local heart irradiation of ApoE(-/-) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis.

BACKGROUND AND PURPOSE: Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. MATERIAL AND METHODS: Hypercholesterolemic and atherosclerosis-prone ApoE(-/-) mice received local heart irradiation with a single dose of 0, 2, 8 or 16 Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40 weeks. RESULTS: Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40 weeks after 8 and 16 Gy. Microvascular density decreased at both follow-up time-points after 8 and 16 Gy. Remaining vessels had decreased alkaline phosphatase activity (2-16 Gy) and increased von Willebrand Factor expression (16 Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16 Gy, with foam cell accumulations at 20 weeks, and fibrosis and protein leakage at 40 weeks. Despite an accelerated coronary atherosclerotic lesion development at 20 weeks after 16 Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20 weeks. CONCLUSIONS: The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE(-/-) mice was maintained.

Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature.

BACKGROUND: Radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiotoxicity, but the underlying mechanisms are unclear. METHODS: Single doses of 2, 8, or 16 Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60 weeks, relative to age matched controls. Single photon emission computed tomography (SPECT/CT) and ultrasound were used to measure cardiac geometry and function, which was related to histo-morphology and microvascular damage. RESULTS: Gated SPECT/CT and ultrasound demonstrated decreases in end diastolic and systolic volumes, while the ejection fraction was increased at 20 and 40 weeks after 2, 8, and 16 Gy. Cardiac blood volume was decreased at 20 and 60 weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40 weeks after 8 and 16 Gy. Microvascular density in the left ventricle was decreased at 40 and 60 weeks after 8 and 16 Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16 Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16 Gy), and amyloidosis (16 Gy). 16 Gy lead to sudden death between 30 and 40 weeks in 38% of mice. CONCLUSIONS: Irradiation with 2 and 8 Gy induced modest changes in murine cardiac function within 20 weeks but this did not deteriorate further, despite progressive structural and microvascular damage. This indicates that heart function can compensate for significant structural damage, although higher doses, eventually lead to sudden death.

Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice.

BACKGROUND AND PURPOSE: We previously showed that irradiating the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis. MATERIAL AND METHODS: ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries were harvested at 4 or 28 weeks after irradiation. Atorvastatin (15 mg/kg/day) or clopidogrel (20 mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L(-/-)/ApoE(-/-) and ApoE(-/-) littermates were also given 0 or 14 Gy to the neck and the carotid arteries were harvested after 30 weeks. RESULTS: Clopidogrel decreased MCP-1 expression in the carotid artery at 4 weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis. CONCLUSIONS: The effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis.

Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels.

Previous studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.