Genetic biomarkers of life-threatening pheochromocytoma-induced cardiomyopathy.

The release of excessive amounts of catecholamine by pheochromocytoma-paragangliomas (PPGL) can lead to life-threatening catecholamine-induced cardiomyopathy (CIC). Single-nucleotide polymorphisms of the beta1 and alpha-2c adrenergic receptors alter myocyte receptor function and enhanced norepinephrine release. We tested the hypothesis that such genetic variations may impact the risk of developing CIC in the context of PPGL. Thirty-one patients with PPGL, including nine with a history of CIC, were analyzed for alpha-2-adrenergic receptors: ADRA2C, beta-1 and beta-2 adrenergic receptors: ADRB1 and ADRB2 genotyping. CIC was defined either by a history of heart failure or cardiogenic shock associated with dilated or Takotsubo cardiomyopathy. Subjects were genotyped for ADRA2C (rs61767072 for del322_325), ADRB1 (rs1801252 for Ser49Gly and rs1801253 for Arg389Gly) and ADRB2 (rs1042713 for Arg16Gly and rs1042714 for Gln27Glu). Single-locus analysis revealed that variant in ADRA2C (alpha 2CDel322-325) was more common among patients with CIC than among controls (allele frequency, 0.44 vs 0.05; P< 0.001). The lack of alpha 2CDel322-325 polymorphism has a negative predictive value of 95% for the onset of CIC. In a replication cohort including 26 patients with PPGL whom eight have developed a CIC, the association between Alpha 2CDel322-325 and CIC was confirmed (allele frequency, 0.33 vs 0.; P= 0.0001). In conclusion, Alpha 2CDel322-325 through the identification of patients at low risk of developing CIC can help physicians to better determine the most appropriate therapeutic approach, notably in patients at high risk of surgical complications.

The effect of camelina oil on vascular function in essential hypertensive patients with metabolic syndrome: a randomized, placebo-controlled, double-blind study.

BACKGROUND: The effects of a dietary supplementation with the vegetable ω-3 α-linolenic acid (ALA) on cardiovascular homeostasis are unclear. In this context, it would be interesting to assess the effects of camelina oil. OBJECTIVE: This study aimed to assess the cardiovascular and metabolic effects of camelina oil in hypertensive patients with metabolic syndrome. METHODS: In a double-blind, placebo-controlled randomized study, treated essential hypertensive patients with metabolic syndrome received, during 6 mo, either cyclodextrin-complexed camelina oil containing ≈ 1.5 g ALA/d (n = 40) or an isocaloric placebo (n = 41), consisting of the same quantity of cyclodextrins and wheat starch. Anthropometric data, plasma lipids, glycemia, insulinemia, creatininemia, TBARs, high-sensitivity C-reactive protein, and n-3, n-6, and n-9 fatty acids in erythrocyte membranes were measured. Peripheral and central blood pressures, arterial stiffness, carotid intima-media thickness, and brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent dilatation were assessed. RESULTS: Compared with placebo, camelina oil increased ALA (mean ± SD: 0 ± 0.04 compared with 0.08 ± 0.06%, P <0.001), its elongation product EPA (0 ± 0.5 compared with 0.16 ± 0.65%, P <0.05), and the n-9 gondoic acid (GA; 0 ± 0.04 compared with 0.08 ± 0.04%, P <0.001). No between-group difference was observed for cardiovascular parameters. However, changes in FMD were associated with the magnitude of changes in EPA (r = 0.26, P = 0.03). Compared with placebo, camelina oil increased fasting glycemia (-0.2 ± 0.6 compared with 0.3 ± 0.5 mmol/L, P <0.001) and HOMA-IR index (-0.8 ± 2.5 compared with 0.5 ± 0.9, P <0.01), without affecting plasma lipids, or inflammatory and oxidative stress markers. Changes in HOMA-IR index were correlated with the magnitude of changes in GA (r = 0.32, P <0.01). Nutritional intake remained similar between groups. CONCLUSION: ALA supplementation with camelina oil did not improve vascular function but adversely affected glucose metabolism in hypertensive patients with metabolic syndrome. Whether this adverse effect on insulin sensitivity is related to GA enrichment, remains to be elucidated.

Intracellular detection of singlet oxygen using fluorescent nanosensors.

Detection of singlet oxygen is of great importance for a range of therapeutic applications, particularly photodynamic therapy, plasma therapy and also during photo-endosomolytic activity. Here we present a novel method of intracellular detection of singlet oxygen using biocompatible polymeric nanosensors, encapsulating the organic fluorescent dye, Singlet Oxygen Sensor Green (SOSG) within its hydrophobic core. The singlet oxygen detection efficiency of the nanosensors was quantified experimentally by treating them with a plasma source and these results were further validated by using Monte Carlo simulations. The change in fluorescence intensity of the nanosensors serves as a metric to detect singlet oxygen in the local micro-environment inside mammalian cancer cells. We used these nanosensors for monitoring singlet oxygen inside endosomes and lysosomes of cancer cells, during cold plasma therapy, using a room-temperature Helium plasma jet.

Severe hypertensive flare-up after intravitreal injection of ranibizumab for retinal venous branch occlusion.

Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of angiogenesis. Systemic adverse effects of some anti-VEGF include hypertension, proteinuria and cardiovascular complications which could involve lower systemic VEGF levels. However, the question regarding intravitreal administration of anti-VEGF remains controversial given that the patients receiving these drugs are often elderly and present cardiac risk factors such as arterial hypertension or atrial fibrillation. We report a case of hypertensive flare-up following intravitreal injection of ranibizumab for retinal vein occlusion. The outcome was favourable after adapted antihypertensive treatment. This case report adds to the growing body of evidence suggesting that intravitreal administration of anti-VEGF, regardless of agents, may result in hypertensive episodes in some predisposed patients. Listing this adverse effect should help to minimize risks by heightening clinician and patient awareness and to improve blood pressure monitoring following the intravitreal administration of anti-VEGF agents.

Spécificités du traitement médicamenteux antihypertenseur chez la femme.

The impact of antihypertensive drugs on blood pressure does not differ according to the sex. There are women-specific conditions or medical conditions encountered more frequently among womens that guide the selection of therapy such as a desire to become pregnant, a pregnancy, a polycystic ovarian syndrome, breast cancer, osteoporosis or migraine.

Breast cancer and spironolactone: an observational postmarketing study.

INTRODUCTION: Recent studies have discussed the risk of breast cancer with antihypertensive drugs. For spironolactone, data are conflicting. The present paper investigates this potential signal in VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database. METHODS: In VigiBase®, we performed a case/non-case study using data registered from 1981 (spironolactone's marketing authorization) to December 31, 2017. Among women ≥ 50 years, we measured the risk of reporting "Breast malignant tumors" compared with all other adverse drug reactions (as a crude and adjusted (a) reporting odds ratio (ROR 95% CI)) for spironolactone compared with first, all other drugs and second, pseudo aldosterone antagonists (amiloride, triamterene). ROR were adjusted for age, year of report, continent of report, number of drug prescribed, and completeness score. Sensitivity analyses were performed after exclusion of drug competitors (i.e., drugs like estroprogestative therapy and progestogens that could mask a putative signal) and reports from health professionals. RESULTS: During the study period, 125 ICSRs reported spironolactone exposure and breast malignant cancer in women ≥ 50 years. We failed to find a positive association between spironolactone exposure and breast cancer in comparison with exposure to other drugs (aROR = 0.63 95% CI [0.52-0.75]) or pseudo aldosterone antagonists (amiloride, triamterene) (0.56 [0.44-0.72]). Similar trends were found after exclusion of drug competitors and/or reports from health professionals. CONCLUSION: This study did not find evidence for breast cancer associated with spironolactone.

Arterial stiffness evaluated by pulse wave velocity is not predictive of the improvement in hypertension after adrenal surgery for primary aldosteronism: A multicentre study from the French European Society of Hypertension Excellence Centres.

BACKGROUND: Predictive factors associated with normal blood pressure (BP) after unilateral adrenalectomy for primary aldosteronism (PA) are not clearly identified. AIMS: To evaluate the predictive value of arterial stiffness before surgery on BP after surgery. METHODS: During 2009-2013, 96 patients with PA due to unilateral adrenal adenoma who underwent surgery were enrolled in a multicentre open-label, prospective study. Aortic pulse wave velocity (PWV) was assessed before surgery. Patients underwent ambulatory blood pressure monitoring (ABPM) before surgery and 6 and 12months after surgery. Twenty-four h SBP/DBP values were compared in subjects with PWV

Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance.

Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.

Retroperitoneoscopic adrenalectomy: comparison of retrograde and antegrade approach among a series of 279 cases.

OBJECTIVE: To compare the results of retroperitoneal laparoscopic adrenalectomy using the antegrade and retrograde approach. MATERIALS AND METHODS: We performed an analysis of a single-center series of 279 retroperitoneal laparoscopic adrenalectomies from 1996 to 2010. We compared 172 cases performed with an antegrade approach and 107 with a retrograde approach without dissection of the renal hilum and initial control of the adrenal vein in comparable populations. RESULTS: The operative time was shorter in the group treated with the retrograde technique, 101±51 vs 140±40 minutes, respectively (Student's t test, P<.001). Blood loss was similar in both groups, 85±224 vs 80±126 mL, respectively (P=NS). Hemodynamic instability was defined as the maximal systolic blood pressure minus the minimal systolic blood pressure divided the maximal systolic blood pressure. It was lower in the group who underwent the retrograde technique (32.7 vs 37.6 mL; Student's t test, P=.005) with a lower perioperative consumption of ephedrine (2.2 vs 5.1 mg, P=.004) and atropine (0.09 vs 0.22 mg, P=.026). No difference was found between the 2 groups in the frequency of perioperative complications or postoperative mortality (1 death in each group of causes unrelated to the surgery). CONCLUSION: Retroperitoneal laparoscopic adrenalectomy using a retrograde approach is a safe and reproducible technique. It makes it possible to perform adrenalectomy without dissection of the renal hilum, with a reduction in the operative time. The good hemodynamic stability observed with this technique makes it very attractive for the treatment of pheochromocytoma.

Metabolic syndrome, insulin resistance, and periodontitis: a cross-sectional study in a middle-aged French population.

AIM: Metabolic syndrome consists of a cluster of clinical and biological abnormalities, influenced by insulin resistance and promoting cardiovascular diseases. We examined the relationships between metabolic syndrome, its various components, insulin resistance, and periodontitis. MATERIALS AND METHODS: The study included 276 subjects (35-74 years) recruited within a cross-sectional survey on cardiovascular risk factors. Twenty-one were excluded because of infectious risk or total tooth loss. Clinical attachment loss (CAL), probing pocket depth (PD), gingival and plaque indexes were recorded. Periodontitis was classified into moderate and severe forms. RESULTS: The mean age was 58, 41% of the subjects had moderate and 39% had severe periodontitis. In univariate comparisons, periodontitis was associated with metabolic syndrome (p=0.050), most of its components, and HOMA index (homoeostasis model assessment of insulin resistance). After adjustment for confounders, only HOMA index remained associated with severe periodontitis (odds ratio [OR]=3.97 [95% confidence interval: 1.22-12.9], OR=3.78 [1.14-12.5] for third and fourth versus the first quartile of the HOMA index, respectively). The HOMA index was also associated with the number of periodontal sites with CAL>or=4 mm, CAL>or=5 mm, or PD>or=4 mm (greater number for higher HOMA-index values). This relationship disappeared in never-smokers. CONCLUSIONS: Our data support the relationships between metabolic disturbances and periodontitis, with a central role of insulin resistance.

Cardiovascular risk factors, atherosclerosis and pulse pressure.

Blood pressure is a complex phenomenon that can be divided into two components: a steady and a pulsatile component. The pulsatile component is estimated by the pulse pressure which is mainly influenced by the large artery stiffness. The purpose of this review was to describe the relation between pulse pressure, cardiovascular risk factors and atherosclerosis. Epidemiological studies have shown positive correlations between pulse pressure and smoking or glucose metabolism impairment. More controversial data have been reported on the relation between blood lipids and large artery stiffness or pulse pressure. In cross-sectional studies, carotid, aortic and coronary plaques were associated with aortic stiffness, particularly echogenic or ulcerative plaques, and in a longitudinal study, the progression of atherosclerosis is accompanied by an increase in pulse pressure. From a pathophysiological point of view, the deleterious influence of most risk factors on endothelial function and the development of atheroma are likely to contribute to these relations. Furthermore, with respect to the connections observed between C-reactive protein, most cardiovascular risk factors, atherosclerotic diseases and pulse pressure, subclinical inflammation might also underlie these relations.

[Retroperitoneal laparoscopic surgery for phaeochromocytoma: analysis of morbidity and haemodynamic instability]. / Chirurgie du phéochromocytome par laparoscopie rétropéritonéale: analyse de la morbidité et de l'instabilité hémodynamique.

OBJECTIVE: To study the morbidity and haemodynamic parameters on a consecutive series of adrenalectomies performed Jbr phaeochromocytoma by retroperitoneal laparoscopy. MATERIAL AND METHODS: The study population comprised 23 phaeochromocytomas in 20 patients treated by controlled retroperitoneal laparoscopic surgery. The following parameters were studied: intraoperatively: operating time, blood loss, blood pressure, heart rate, and postoperatively: infectious, haemorrhagic and thromboembolic complications. RESULTS: The mean operating time was 156 minutes (range: 105-224). Mean blood loss was 58 ml (range: 0-300). Intraoperatively, 1500 of patients presented a peak SBP >220 mmHg and 70% presented a peak SBP >200 mmHg. In contrast, 200 of patients presented a nadir SBP <60 mmHg, but no patient presented a nadir SBP less than 40 mmHg. One case of intraoperative haemorrhage was observed (4.3%). Three postoperative complications (1 case of respiratory distress, 1 case of haemorrhagic shock, and 1 abscess) were observed (13%). CONCLUSION: Laparoscopic surgery for phaeochromocytoma is associated with a risk of haemodynamic instability. Phaeochromocytoma surgery should therejbre continue to be performed in specialized centres (surgical, anaesthetic and endocrinological).

Interleukin 6 is associated with subclinical atherosclerosis: a link with soluble intercellular adhesion molecule 1.

BACKGROUND: Among the markers of inflammation, a cytokine, interleukin (IL)-6, promotes the expression of intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (CRP) synthesis, and leads to a series of procoagulant actions with potential major implications on the progression of atherosclerosis. AIM OF THE STUDY: To analyse in a population-based study, the relationship between IL-6 and atherosclerotic lesions and the role of serum ICAM-1 and CRP on this relationship. POPULATION: Among 1015 individuals randomly recruited between 1995 and 1997 in Haute-Garonne, a French region with a low cardiovascular risk, 953 subjects with complete data for all measurements were analysed. Common carotid intima-media thickness (IMT) and the presence of plaques in the carotid and femoral arteries were assessed by ultrasonography. RESULTS: Quartiles of IL-6, serum ICAM-1 and CRP were positively associated with plaques and IMT. After adjustment for traditional risk factors, IL-6 (P < 0.001) and serum ICAM-1 (P < 0.002) remained positively associated with plaques but not CRP (P = 0.20). Neither IL-6, nor serum ICAM-1, nor CRP were independently associated with IMT. When serum ICAM-1 was entered into the model in addition to traditional risk factors and IL-6, the percentage of variance in the number of plaques explained by the model did not increase significantly. CONCLUSION: IL-6 levels are associated with subclinical atherosclerotic lesions independently of traditional risk factors; the influence of IL-6 on ICAM-1 secretion may play a role in this association. These results argue the interest of IL-6 in the stratification of cardiovascular risk.

CD14 C(-260)T gene polymorphism, circulating soluble CD14 levels and arteriosclerosis.

BACKGROUND: CD14 pathway is at the crossroads between infection and inflammation. In human pathology, divergent results have been reported on the relationship between a polymorphism in the promoter of receptor CD14 (C260T), expression of soluble CD14 (sCD14) receptor and atherosclerosis. The aim of the study was to investigate in a cross-sectional population-based sample the relationships between C260T polymorphism in CD14 gene, sCD14 blood levels and arterial wall. METHODS: Among 1015 subjects, randomly recruited by the Toulouse MONICA center between 1995 and 1997, 899 subjects with complete data for all the measurements, were analyzed. sCD14 was measured using an immuno-enzymatic method. Common carotid intima-media thickness (IMT) and the presence of plaques in the carotid and femoral arteries were assessed by ultrasonography. A genotypic examination for the CD14 C260T polymorphism was performed. RESULTS: An increase in sCD14 expression was observed in subjects carrying t allele (P < 0.01). No significant difference in intima-media thickness, number of plaques and pulse wave velocity was noticed according to C260T polymorphism. An interaction (P < 0.05) was observed between C260T polymorphism and current smoking in sCD14 expression: among smokers, no significant change in sCD14 was observed in individuals carrying t allele. CONCLUSION: Although (C260T) polymorphism in CD14 gene in this study is associated with expression of sCD14, no significant association was found between this polymorphism and early markers of atherosclerosis. This polymorphism affects plasma levels of sCD14 in relation to current smoking status. Further studies are needed to determine whether this interaction influences the deleterious effect of smoking on vascular events.