Primary Non-Aortic Lesions Are Not Rare in Marfan Syndrome and Are Associated with Aortic Dissection Independently of Age.

PURPOSE: The study sought to estimate the prevalence of primary non-aortic lesions (PNAL) unrelated to extension of aortic dissection (AD) in a cohort of patients with Marfan syndrome (MFS). METHODS: Adult patients presenting with pathogenic FBN1 mutations and an available pan-aortic contrast-enhanced CTA in eight French MFS clinics from April to October 2018 were included. Clinical and radiological data, particularly the presence of aortic lesions and PNAL (including aneurysm and ectasia), were retrospectively analyzed. RESULTS: Out of 138 patients, 28 (20.3%) had PNAL. In total, 27 aneurysms in 13 patients and 41 ectasias in 19 patients were reported mainly in the subclavian, iliac, and vertebral segments. Four patients (31%) with aneurysms and none with ectasia required prophylactic intervention during follow-up (median: 46 months). In multivariate analysis, factors associated with PNAL were history of AD (OR = 3.9, 95%CI: 1.3-12.1, p = 0.018), history of previous descending aortic surgery (OR = 10.3, 95%CI: 2.2-48.3, p = 0.003) and age (per 10 years OR = 1.6, 95%CI: 1.1-2.4, p = 0.008). CONCLUSION: PNAL is not rare in MFS patients with evolutive aortic disease. Natural history may differ between aneurysms and ectasia, emphasizing the need for standardized definitions and systematic screening for PNAL.

The Conundrum of Occult Cancer Screening in Venous Thromboembolism: Lessons from the REMOTEV Registry.

(1) Background and Objectives: Venous thromboembolism (VTE) is strongly associated with cancer, and may be the first event revealing occult neoplasia. Nonetheless, the reasonable extent of the etiological assessment after an unprovoked VTE event remains debated. The main objective of this study was to evaluate the incidence of occult neoplasia one year after an episode of VTE, in consecutively hospitalized patients for VTE from the REMOTEV registry. The secondary objectives were to assess the performance of the various tests used for occult cancer screening in a real-life setting and analyze the risk factors associated with the discovery of cancer and the 1-year prognosis. (2) Methods: REMOTEV is a prospective, non-interventional cohort study of patients with acute VTE. Patients included in the registry from 23 October 2013 to 28 July 2018 were analyzed after a follow-up of 12 months. Cancer detection was performed according to local practices and consisted of a limited strategy to which an abdominal ultrasound was added. In the presence of suggestive clinical manifestations, further examinations were performed on an individual basis. (3) Results: A total of 993 patients were included in the study. At 1 year, the incidence of newly diagnosed cancer was low (5.3%). Half of the detected cancers were metastatic at discovery (51%) and had a poor global prognosis (32% of mortality at 1 year). Admission pulmonary CT scans as well as (thoracic)-abdomino-pelvic CT scans (when performed) were responsible for the majority of detected cancers. Age over 65 years and the concomitant presence of an unusual site and lower-limb deep vein thrombosis were the only factors associated with occult neoplasia in this cohort. After 1-year FU, mortality was higher in cancer patients (HR 6.0 (CI 95% 3.5−10.3, p < 0.0001)), and cancer evolution was the leading cause of death in the cancer group. (4) Conclusions: In REMOTEV, VTE-revealed occult cancer prevalence was low, but similar to recent reports and associated with higher age, multiple thrombotic sites and worse prognosis.

Systematic duplex ultrasound screening in conventional units for COVID-19 patients with follow-up of 5 days.

OBJECTIVE: COVID-19 patients may develop coagulopathy, which is associated with poor prognosis and high risk of thrombosis. The main objective of this work was to evaluate the prevalence of deep venous thrombosis of lower limbs (DVT) through ultrasonography in patients infected with COVID-19 admitted to conventional units at our hospital with 5 days of monitoring. The secondary objective was to determine if D-dimer levels, body mass index, and C-reactive protein were associated with DVT. METHODS: A total of 72 patients, with a mean age of 65 ± 12.3 years, infected with COVID-19 were admitted to three conventional units at our institution; 28 patients were women. A COVID-19 diagnosis was made by a transcriptase polymerase chain reaction by means of nasopharyngeal swab or by chest computer tomography without iodine contrast media. Demographics, comorbidities, and laboratory parameters were collected. A preventive anticoagulation treatment was established on admission with low-molecular-weight heparin. A complete venous duplex ultrasound (DU) test of lower limbs was performed on day (D) 0 and D5. A pulmonary computer tomography angiogram with iodine contrast media was required when pulmonary embolism was suspected. RESULTS: On D0, the DU showed acute DVT in seven patients (9.75%). A pulmonary computer tomography angiogram was performed in 12 patients (16.65%), 3 (25%) of whom had an acute pulmonary embolism. On D0, acute DVT was not significantly associated with C-reactive protein (mean 101 ± 98.6 in the group without DVT vs 67.6 ± 58.4 mg/L, P = .43) or body mass index (27.7 ± 5.04 vs 28.1 ± 2.65 kg/m2, P = .54). However, we found a significant association between acute DVT and D-dimer levels (1536 ± 2347 vs 9652 ± 10,205 ng/mL, P < .01). Among the patients included on D0, only 32 had a DU on D5. Forty of them (55.55%) were not examined for the following reasons: 7 (9.7%) were previously diagnosed with venous thromboembolism on D0 and therefore were excluded on D5, 8 (11%) were transferred to the intensive care unit, 10 (14%) were discharged from the hospital, 5 (7%) died, and 10 (13.9%) were excluded because of technical issues. On D5, five (15.6%) patients had acute DVT in addition to those found on D0; three were distal and two proximal despite preventive anticoagulation with low-molecular-weight heparin. CONCLUSIONS: Hospitalized non-intensive care unit patients with COVID-19 pneumonia have a high frequency of venous thrombotic events justifying screening with DU.

Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia　- Results of a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.Methods and Results:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52-0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29-0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO2, and ankle-brachial index value) were not statistically different between groups. CONCLUSIONS: Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.

Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): Analysis of 6-month outcomes.

BACKGROUND: This study aimed to provide safety and efficacy data of rivaroxaban in routine patient care in a non-selected symptomatic venous thromboembolism (VTE) population. METHODS AND RESULTS: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with oral rivaroxaban, VKA or parenteral heparin/fondaparinux alone for at least 3months and who are followed up for 6months. From Nov. 2013 to July 2015, 499 consecutive patients were retained for baseline analysis and 445 for safety analysis. The mean age was 65.1years, 7.6% had previously known active cancer, 18.6% had creatinine clearance 30≤CrCl<60mL/min, and 87.8% had pulmonary embolism with or without deep venous thrombosis. The major and clinically relevant bleeding rate was 5.4% (15/280) in the rivaroxaban group, 9.4%/(9/96) in the VKA group and 7.2% (5/69) in the heparin/fondaparinux group. The recurrent VTE rate was 1.4% (4/280) in the rivaroxaban group, 3.1% (3/96) in the VKA group and 11.6% (8/69) in the heparin/fondaparinux group. In the propensity score-adjusted samples, major and clinically relevant non-major bleeding (HR 0.37 [95% CI, 0.15 to 0.93], p<0.05), all-cause death (HR 0.21 [95% CI, 0.06 to 0.66], p<0.01) and the composite of recurrent VTE, major and clinically relevant non-major bleeding and all-cause mortality (HR 0.35 [95% CI, 0.17 to 0.71], p<0.01), were significantly lower in the rivaroxaban group compared to the VKA group. CONCLUSION: In REMOTEV 6-month outcomes are consistent with the findings of the phase 3 randomized trials and post-marketing data, with low rates of major bleeding and symptomatic recurrent VTE.

Place of non-vitamin K antagonist oral anticoagulants in anticoagulant-antiplatelet combinations in peripheral artery disease.

Non-vitamin K antagonist oral anticoagulants are becoming increasingly important in the prophylaxis and treatment of thrombosis in atrial fibrillation and venous thromboembolism. Antiplatelets are widely prescribed in the primary and secondary prevention of cardiac and vascular diseases. There are potentially numerous situations where anticoagulants and antiplatelets may be combined; these combinations have been explored in coronary artery disease, and some have been included in updated recommendations. Is it legitimate to transpose these recommendations to the management of peripheral artery disease? The specific characteristics of the treated vessels, the stents used, the respective frequencies of stent thrombosis and its effect on the target organ are probably different, and explain why opinions differ. However, because of a lack of evidence, empirical behaviours are being established without scientific validation. This review of the literature details the situations in which combinations of an anticoagulant and an antiplatelet have been explored in peripheral artery disease. We discuss the issue of antithrombotic combinations in stable peripheral artery disease and for vascular or endovascular surgery.

Platelet antiaggregation therapy and subinguinal endovascular revascularization.

BACKGROUND: Platelet antiaggregation therapy (PAT) is widely acknowledged to be a positive prognostic factor after revascularization, either at the coronary or the peripheral level. This study evaluated the results of infrainguinal endovascular procedures performed for critical ischemia, in accordance with patient compliance to clopidogrel treatment. MATERIALS AND METHODS: This retrospective study included patients who underwent infrainguinal endovascular therapy for critical ischemia between January 2003 and December 2009. For 1 month, patients received the same postoperative PAT protocol: aspirin associated with clopidogrel, and then clopidogrel in the long term. Patient follow-up was set at 3 months, 6 months, 1 year, and then yearly thereafter. Survival rates, primary patency (PP), and limb salvage (LS) were studied in accordance with therapy compliance. Patients were classified into 2 groups: group 1 for compliant patients and group 2 for noncompliant patients in the long term. From January 2003 to December 2009, 153 infrainguinal endovascular procedures were performed on 150 patients experiencing critical ischemia who had benefited from the authors' postoperative PAT protocol. RESULTS: Both groups were comparable in terms of comorbidity. Of the procedures performed in groups 1 (N = 105) and 2 (N = 45), 62.8% (n = 66) and 44.4% (n = 20), respectively, were femoral, 14.3% (n = 15) and 22.2% (n = 10), respectively, were infrapopliteal, and 22.9% (n = 24) and 33.4% (n = 15), respectively, were mixed. Mean follow-up time was 30.3 ± 20.2 months (range, 1-70 months). The survival rate was comparable between the groups (P = 0.46). PP and LS rates were significantly higher in group 1 than in group 2 (PP: 84% vs. 80%, respectively, at 1 year, 79% vs. 50%, respectively, at 2 years, 65% vs. 30%, respectively, at 3 years, and 60% vs. 18%, respectively, at 4 years; P = 0.02; LS: 92% vs. 78%, respectively, at 1 year, 86% vs. 62%, respectively, at 2 years, 80% vs. 55%, respectively, at 3 years, and 77% vs. 36%, respectively, at 4 years; P = 0.04). CONCLUSIONS: This study shows that in common practice, 31% of patients stop their clopidogrel therapy, with a negative impact on PP and LS. These results indicate that medical follow-up after endovascular surgery must be reinforced.

In-hospital complications after invasive strategy for the management of Non STEMI: women fare as well as men.

BACKGROUND: To analyze the in-hospital complication rate in women suffering from non-ST elevation myocardial infarction treated with percutaneous coronary intervention (PCI) compared to men. METHODS: The files of 479 consecutive patients (133 women and 346 men) suffering from a Non STEMI (Non ST-segment elevation myocardial infarction) between the January 1st 2006 and March 21st 2009 were retrospectively analyzed with special attention to every single complication occurring during hospital stay. Data were analyzed using nonparametric tests and are reported as median unless otherwise specified. A p value < .05 was considered significant. RESULTS: As compared to men, women were significantly older (75.8 vs. 65.2 years; p < .005). All cardiovascular risk factors but tobacco and hypertension were similar between the groups: men were noticeably more often smoker (p < .0001) and women more hypertensive (p < .005). No difference was noticed for pre-hospital cardiovascular drug treatment. However women were slightly more severe at entry (more Killip class IV; p = .0023; higher GRACE score for in-hospital death - p = .008 and CRUSADE score for bleeding - p < .0001). All the patients underwent PCI of the infarct-related artery after 24 or 48 hrs post admission without sex-related difference either for timing of PCI or primary success rate. During hospitalization, 130 complications were recorded. Though the event rate was slightly higher in women (30% vs. 26% - p = NS), no single event was significantly gender related. The logistic regression identified age and CRP concentration as the only predictive variables in the whole group. After splitting for genders, these parameters were still predictive of events in men. In women however, CRP was the only one with a borderline p value. CONCLUSIONS: Our study does not support any gender difference for in-hospital adverse events in patients treated invasively for an acute coronary syndrome without ST-segment elevation and elevated troponin.

Antiangiogenic properties of lupulone, a bitter acid of hop cones.

BACKGROUND: Angiogenesis is the result of intricate steps regulated by the balance between agonistic and antagonistic effectors. Disturbance of this balance leads to an 'angiogenic' switch critical for tumor development. MATERIALS AND METHODS: Using human umbilical vein endothelial cells (HUVEC) the effects of lupulone were analyzed on proliferation induced by angiogenic growth factors, transmembrane cell migration toward fibronectin and formation of a network of tubular-like structures on Matrigel. RESULTS: Lupulone (2.5-50 microg/ml) induced a concentration-dependent inhibition of HUVEC proliferation and chemotaxis. Lupulone caused a significant reduction of closed capillary-like structures in Matrigel indicating a strong inhibitory effect on neovascularisation. In mice receiving lupulone (20 mg/kg/day) in drinking water for 21 days, new vessel formation was reduced by 50% in matrigel plugs implanted under the skin when compared with controls. CONCLUSION: The present data demonstrate that lupulone is able to inhibit angiogenesis in vitro and in vivo. Lupulone emerges as a potential chemopreventive agent when considering its strong antiangiogenic properties.

Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia.

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats.

OBJECTIVE: Potassium-sparing diuretics have different effects on angiogenesis that may mediate some abilities to treat cardiovascular diseases. The aim of the current study was to compare the effects of spironolactone and an active metabolite, canrenone, or a derivative, eplerenone, and amiloride, a diuretic without affecting mineralocorticoid activity, on the proliferation of human umbilical vein endothelial cells (HUVEC) and on angiogenesis in fibrin gel chambers implanted in rats. MATERIALS AND METHODS: We measured the effects of spironolactone, canrenone, eplerenone, and amiloride on the proliferation of HUVEC in the presence or absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also examined the effects of these compounds on migration and capillary tube formation by HUVEC. Finally, the effects of the compounds on neovessel formation in vivo were investigated by implanting Wistar rats for 14 days with perforated Plexiglas chambers containing rat fibrin. RESULTS: Spironolactone and amiloride inhibited the proliferation of HUVEC, but canrenone and eplerenone had no effect. The inhibitory effect of spironolactone was not prevented by VEGF or bFGF. Aldosterone had no effect on spironolactone-induced inhibition of HUVEC proliferation. Spironolactone induced a dose-dependent reduction of both cell chemotaxis and capillary tube formation. In fibrin gel chambers, spironolactone and amiloride significantly reduced the numbers of both peripheral and central neovessels. Canrenone and eplerenone, in contrast, had no antiangiogenic effect. CONCLUSION: Spironolactone and amiloride significantly inhibited angiogenesis in vitro and in the fibrin gel chamber in vivo. Spironolactone antiangiogenic effects are unrelated to antimineralocorticoid activity.

Angiogenesis and arteriogenesis are increased in fibrin gel chambers implanted in prehypertensive spontaneously hypertensive rats.

OBJECTIVE: Microvascular rarefaction by an unbalanced angiogenesis could promote the onset of hypertension in spontaneously hypertensive rats and in hypertensive patients. We studied the angiogenic potency in the fibrin gel chamber model in prehypertensive spontaneously hypertensive rats and their controls, Wistar-Kyoto rats. METHODS: Four-week-old prehypertensive spontaneously hypertensive rats (n = 9) and Wistar-Kyoto rats (n = 9) were implanted with four fibrin gel chambers located in the dorsal subcutaneous space. After 14 days, vasculoconjunctive buds had invaded the fibrin gel through the 10 hole-perforated bottom slip of the chamber. The intact vascular buds were studied using optical microscopy, alpha-actin and von Willebrand factor stainings. Capillaries and arterialized vessels were counted in three peripheral and one central field in each bud. The immunodetection of vascular endothelial growth factor and fibroblast growth factor 2 was performed on the neovascular buds. RESULTS: In fibrin chambers implanted in spontaneously hypertensive rats, the number of peripheral vessels was significantly higher than in Wistar-Kyoto rats. There were significantly more arterialized vessels in spontaneously hypertensive rats compared with Wistar-Kyoto rats. The number of immunostained cells for fibroblast growth factor 2 was significantly greater in spontaneously hypertensive rats compared with Wistar-Kyoto rats. There was no significant difference in vascular endothelial growth factor staining between the two strains of rats. CONCLUSION: Angiogenesis and arteriogenesis are increased in fibrin chambers implanted in prehypertensive spontaneously hypertensive rats compared with Wistar-Kyoto rats. These results argue against microvascular rarefaction as a cause of hypertension using this model of angiogenesis.