Periodontal (formerly type VIII) Ehlers-Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype.

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat.

BACKGROUND: Empagliflozin (empa), a selective sodium-glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its' lean control. METHODS: Lean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis. RESULTS: Empa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats. CONCLUSION: Empa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.

Oral Intake of EPA:DHA 6:1 by Middle-Aged Rats for One Week Improves Age-Related Endothelial Dysfunction in Both the Femoral Artery and Vein: Role of Cyclooxygenases.

In humans, aging is associated with endothelial dysfunction and an increased risk of venous thromboembolism. Although intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a ratio of 6:1 by old rats improved the endothelial dysfunction in arteries, the impact on veins remains unclear. Eight-month-old male Wistar rats were either untreated or orally administered corn oil, EPA:DHA 1:1, or EPA:DHA 6:1 (500 mg/kg/d) for seven days. Vascular reactivity was studied by myography. In middle-aged femoral artery rings, acetylcholine caused a partial relaxation at low concentrations and a contractile response at high concentrations, whereas in the old femoral vein only a partial relaxation was observed. The EPA:DHA 6:1 treatment blunted the contractile response to acetylcholine in the middle-aged femoral artery and both EPA:DHA 6:1 and 1:1 increased the relaxation to acetylcholine in the old femoral vein. No such effects were observed with corn oil. Both the non-selective cyclooxygenase inhibitor indomethacin and the COX-1 inhibitor SC-560 increased the relaxation to acetylcholine in the middle-aged femoral artery whereas the COX-2 inhibitor NS-398 increased that in the middle-aged femoral vein. In conclusion, our results indicate that aging is associated with an endothelial dysfunction in the femoral artery and vein, which can be improved by EPA:DHA 6:1 treatment-most likely via a cyclooxygenase-dependent mechanism.

Intake of omega-3 formulation EPA:DHA 6:1 by old rats for 2 weeks improved endothelium-dependent relaxations and normalized the expression level of ACE/AT1R/NADPH oxidase and the formation of ROS in the mesenteric artery.

Omega-3 polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to protect the cardiovascular system, in part, by stimulating the endothelial formation of nitric oxide (NO). EPA:DHA 6:1 has been identified as a potent omega 3 PUFA formulation to induce endothelium-dependent vasorelaxation and activation of endothelial NO synthase (eNOS). This study examined whether intake of EPA:DHA 6:1 (500 mg/kg/day) for 2 weeks improves an established endothelial dysfunction in old rats (20 months old), and, if so, the underlying mechanism was subsequently determined. In the main mesenteric artery rings, an endothelial dysfunction characterized by a blunted NO component, an abolished endothelium-dependent hyperpolarization component, and increased endothelium-dependent contractile responses (EDCFs) are observed in old rats compared to young rats. Age-related endothelial dysfunction was associated with increased vascular formation of reactive oxygen species (ROS) and expression of eNOS, components of the local angiotensin system, senescence markers, and cyclooxygenase-2 (COX-2), and the downregulation of COX-1. The EPA:DHA 6:1 treatment improved the NO-mediated relaxation, reduced the EDCF-dependent contractile response and the vascular formation of ROS, and normalized the expression level of all target proteins in the old arterial wall. Thus, the present findings indicate that a 2-week intake of EPA:DHA 6:1 by old rats restored endothelium-dependent NO-mediated relaxations, most likely, by preventing the upregulation of the local angiotensin system and the subsequent formation of ROS.

Pulmonary Embolism and Coexisting Deep Vein Thrombosis: A Detrimental Association?

BACKGROUND: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with symptomatic venous thromboembolism (VTE) from the REMOTEV registry. METHODS AND RESULTS: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with direct oral anticoagulants (DOACs) or standard anticoagulation (vitamin K antagonists (VKA) or parenteral heparin/fondaparinux alone) for at least 3 months. From 1 November 2013 to 28 February 2018, among 1241 consecutive patients included, 1192 had a follow-up of at least 3 months and, among them, 1037 had PE with (727) or without DVT (310). The median age was 69 (55-80, 25th-75th percentiles). Patients with PE-associated DVT had more severe forms of PE (p < 0.0001) and, when DVT was present, proximal location was significantly correlated to PE severity (p < 0.01). However, no difference in all-cause mortality rate (hazard ratio (HR) 1.36 (CI 95% 0.69-2.92)), nor in the composite criterion of all-cause mortality and recurrence rate (HR 1.56 (CI 95% 0.83-3.10)) was noted at 3 months of follow-up. CONCLUSION: In REMOTEV, coexisting DVT was associated with a higher severity of PE, with no impact on short-term prognosis.

Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension.

Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a four-drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high-performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.

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.

Association between periodontitis and arterial hypertension: A systematic review and meta-analysis.

BACKGROUND: Several studies have shown that periodontal diseases are associated with hypertension (HT). However, heterogeneity among populations, diagnosis criteria, and shared risk factors represent some difficulties in terms of interpretation. Therefore, the aim of this study was to determine the magnitude of the association between periodontal diseases and HT. METHODS AND RESULTS: A systematic review and meta-analysis, including studies published up to June 2016, have been performed. Sixteen studies assessing the association between periodontal diseases and HT have been included. The meta-analysis considering all included studies (moderate to severe periodontitis) showed that the presence of HT was associated with the presence of periodontal diseases (OR, 1.50; 95% CI, 1.27-1.78). To reduce potential bias, a stratified analysis has been performed illustrating the impact of inclusion criteria and adjustments on the magnitude of the association. Interestingly, when only studies with secure diagnosis of severe periodontitis and HT were considered, an OR=1.64 (95% CI, 1.23-2.19) has been measured. CONCLUSIONS: Periodontal diseases are associated with a higher risk of HT especially for severe periodontitis. However, no conclusions could be made regarding the causative involvement of periodontal diseases mainly due to the reduced number of available prospective studies and remaining questions regarding underlying biological mechanisms.

Statins and prevention of venous thromboembolism: Myth or reality?

The pleiotropic effects of statins, beyond their cholesterol-lowering properties, are much debated. In primary prevention, several observational cohort and case-control studies appear to show that statins reduce the incidence of venous thromboembolism by about 30%. In a single randomized placebo-controlled clinical trial (JUPITER), which included 17,000 patients, rosuvastatin 20mg/day reduced the risk of venous thromboembolism by 43%. However, these patients were at low risk of venous thromboembolism, and the frequency of the event was, in principle, low. In secondary prevention, several observational studies and post-hoc analyses of randomized clinical trials have suggested that statins may prevent recurrence of venous thromboembolism. However, none of these studies had enough scientific weight to form the basis of a recommendation to use statins for secondary prevention. The putative preventive effect of statins appears to be independent of plasma cholesterol concentration and could be a pharmacological property of the statin class, although a dose-effect relationship has not been demonstrated. The mechanism through which statins might prevent venous thrombosis is thought to involve their anti-inflammatory and antioxidant effects or perhaps a more specific action, by blocking the degradation of antithrombotic proteins. A mechanism involving the action of statins on interactions between risk factors for atherosclerosis and venous thromboembolism is supported by some studies, but not all. In the absence of firm evidence, statins cannot currently be recommended for primary or secondary prevention of venous thromboembolism.

Endovascular Surgery, Open Surgery, and Primary Amputation in Nonagenarians Presenting with Critical Limb Ischemia.

BACKGROUND: The aim was to report the midterm outcome for nonagenarians with critical limb ischemia (CLI) and to identify factors affecting survival or limb salvage rates. METHODS: Nonagenarians who underwent endovascular surgery (ES), open surgery (OS), or primary amputation (PA) for CLI between 2005 and 2014 were included. Cox regression model identified factors affecting survival and limb salvage. RESULTS: ES was performed in 116 patients (119 limbs), OS in 73 patients (73 limbs), and PA in 54 patients (57 limbs). Mean follow-up was 10.38 months. There was no difference in survival between ES, OS, and PA groups: survival rate was 51.2% at 1 year and 38.9% at 2 years after ES, 48.3% at 1 year and 39.6% at 2 years after OS, and 50.6% at 1 years and 40.8% at 2 years after PA (P = 0.58). There was no difference in limb salvage between ES and OS groups: limb salvage rate was 88.2% and 77.8% at 1 and 2 years after ES and 87.3% and 77.6% at 1 and 2 years after OS. Coronary artery disease (hazard ratio [HR] 1.54; confidence interval [CI] 1.04-1.08; P = 0.01) was risk factor for death. Fully dependent state was risk factor for death (HR 4.2; CI 3.55-4.87; P < 0.001) and major amputation (HR 5.3; CI 1.32-1.67; P < 0.001). In fully dependent patients, 1-year and 2-year survival rate was 28.9% and 20.6%, respectively, and 1-year and 2-year limb salvage rate was 61.2% and 44.5%, respectively. CONCLUSIONS: With acceptable early and late mortality, limb salvage and maintenance of functional status and level of independent living, revascularization in nonagenarians is effective as long as the patient is not fully dependent.

Promising Results of the Forearm Basilic Fistula Reveal a Worthwhile Option between Radial Cephalic and Brachial Fistula.

BACKGROUND: Use of the forearm basilic vein for the creation of an arteriovenous fistula has been codified as second-choice vascular access for hemodialysis in the last clinical guidelines of the Society for Vascular Surgery in 2008. Poor literature data on this technical option and on its evaluation and outcomes led us to initiate a retrospective single-center study. METHODS: We analyzed the outcomes of every arteriovenous fistula using the forearm basilic vein created in our department. It is a retrospective study in which we collected data prospectively by contacting dialysis centers, nephrologists, and patients. Primary end point was primary patency rate at 1 year. Secondary end points were secondary patency rate at 1 year, time of maturation, and Doppler flow measurement before the first puncture. RESULTS: From February 2004 to June 2014, 49 forearm basilic arteriovenous fistulas were created: 33 ulnar-basilic and 16 radial basilic arteriovenous fistulas. Initial technical success rate was 98%. Functional success rate was 60%. Primary and secondary patency rates at 1 year were respectively 21% and 48%. Median time of maturation was 81 days, and mean Doppler flow measurement was 678 mL/min. Ulnar-basilic fistulas had a statistically significant shorter time of maturation than radial basilic fistulas (P ≤ 0.05). CONCLUSIONS: Despite poor primary patency rate and a long time of maturation, forearm basilic arteriovenous fistula has satisfactory secondary patency rate and keeps all the advantages of a distal-located vascular access concerning complications. It is worth its second-choice place in the current algorithm of creation of vascular access for hemodialysis.