Apolipoprotein E and Paraoxonase 1 polymorphisms are associated with lower serum thyroid hormones in postmenopausal women

Objective  Autoimmune thyroiditis and overt or subclinical hypothyroidism have been associated with increased prevalence of cardiovascular disease (CVD).
Design  Cross-sectional investigation of the association between gene polymorphisms related to CVD with thyroid function and autoimmunity.
Patients  In total 84 healthy postmenopausal women aged 49–69 years.
Measurements  FT3, FT4, anti-TPO and anti-TG were assessed in the sera of participants. The following polymorphisms were assessed from peripheral lymphocyte DNA: Apolipoprotein E E2/E3/E4, paraoxonase 1 A/B, Glycoprotein IIIa leu33pro, MTHFR ala222val, ApoBarg3500gln, plasminogen activator inhibitor 1 4G/5G, cholesterol 7-α hydroxylase A204C and cholesterol ester transfer protein B1/B2.
Results  A statistically significant correlation was found between Apolipoprotein E and paraoxonase1 polymorphisms and serum thyroid hormones: carriers of the E2 or E4 allele of the ApoE gene had lower levels of FT4 ( P  = 0·0005) than women with the E3/E3 genotype. Carriers of the B allele of paraoxonase 1 gene had lower levels of FT3 compared to women with the wild-type genotype ( P =  0·047). A statistically significant positive association ( P =  0·049) was also observed between anti-TG antibodies and the presence of the E2 allele of the Apolipoprotein E gene.
Conclusions  Polymorphisms of apolipoprotein E and paraoxonase 1 are associated with different levels of thyroid hormone and anti-Tg antibody levels in the study population in this pilot study. The mechanism underlying this association remains to be elucidated.     

Radiofrequency Catheter Ablation of Posteroseptal Accessory Pathways–Results of a Step-by-Step Ablation Approach

Introduction: Transcatheter radiofrequency ablation of posteroseptal accessory pathways (AP) is challenging. A number of different interventional approaches have been suggested by different groups. The selection of the initial approach is crucial in order to reduce radiation exposure and the number of unsuccessful lesions applied. We present our ablation technique as guided by a simplified electrocardiographic analysis of the delta wave polarity and the electrophysiologic mapping results. Methods and Results: Out of 35 manifest APs encountered in the right (n=17) or the left posteroseptum (n=18) in 35 patients, 34 were successfully ablated. Despite their left sided location, 7 of the 18 left sided APs were ablated after switching from an initial arterial to a venous approach looking for an appropriate target site in the right posteroseptal space or within the coronary sinus network. The other 11 left sided APs were ablated in the mitral ring, on 2 occasions, on their atrial aspect through a retrograde transmitral approach. On the contrary, 16 of the 17 right sided APs were successfully ablated exclusively through a venous approach. Fourteen of these were ablated in the right posteroseptum, in 2 cases, only after reaching their ventricular aspect. Two right sided APs were interrupted in the coronary sinus os and the middle cardiac vein respectively. Conclusion: It appears that even though the electrocardiographic and electrophysiologic location of the AP in the posteroseptal space helps select the appropriate initial approach, it does not always guarantee a successful ablation procedure in the expected site of the corresponding atrioventricular ring. Not uncommonly, it will be necessary to look after intermediate target sites within the coronary sinus to improve the overall ablation success rate.     

The interplay between metabolic alterations,diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study

Background

Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity.

Methods

Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent ¹H-cardiovascular magnetic resonance spectroscopy (¹H-CMRS) to measure MTG (lipid/water, %), ³¹P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate.

Results

When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45?±?0.25% vs. 0.64?±?0.16%, p?=?0.009) and reduced PCr/ATP (1.60?±?0.09 vs. 2.00?±?0.10, p?=?0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO₂ max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO₂ max.

Conclusions

Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.

     

EUS-guided FNA of the left adrenal gland in patients with thoracic or GI malignancies

BACKGROUND: The diagnostic yield and safety of trans-gastric EUS-guided FNA of the left adrenal gland are not well defined. METHODS: All patients with an enlarged left adrenal gland on abdominal imaging and known or suspected malignancy referred to two EUS centers over a 3-year period were included in this study. EUS-guided FNA was performed on an outpatient basis by one of 4 experienced endosonographers. RESULTS: Thirty-one consecutive patients (21 men, 10 women; mean age 64.8 years) were evaluated. Tissue adequate for interpretation was obtained in all patients; no attempt to obtain tissue was unsuccessful. The median number of needle passes was 4.5 (range 1-8). No immediate complications were encountered. EUS-guided FNA confirmed malignant left adrenal involvement in 42% (13/31) of the patients. Patients with malignant left adrenal masses were more likely to have known cancer at another site (OR 12.0: 95% CI[1.6, 87.9]). Patients with benign masses were more likely to have preservation of the normal sonographic appearance of the adrenal gland ("seagull" configuration) compared with those with malignant masses (OR 9.8: 95% CI[1.9, 51.0]). The accuracy of EUS imaging based on size (> or =3 cm) alone was 81%: 95% CI[63, 93]). Of the patients with malignant adrenal masses, 85% (11/13) died or their clinical condition deteriorated during follow-up, while 15% (2/13) were being treated and were stable clinically. CONCLUSIONS: EUS-guided FNA of the left adrenal gland is a minimally invasive, safe, and highly accurate method that confirms or excludes malignant adrenal involvement in patients with thoracic or GI malignancies.     

Ida-FLAG plus imatinib mesylate-induced molecular remission in a patient with chemoresistant Ph1+ acute myeloid leukemia

Imatinib mesylate is a potent, selective inhibitor of the tyrosine kinase activity of bcr-abl,which is now established as the state-of-the-art treatment for chronic, accelerated or even blastic phase of Philadelphia-positive [Ph(1)(+)] chronic myelogenous leukemia. It is also active in Ph(1)(+) acute lymphoblastic leukemia, but its role in Ph(1)(+) acute myeloid leukemia (AML) is less well investigated. We report here a patient with chemoresistant Ph(1)(+) AML, who responded promptly to one cycle of Ida-FLAG second-line chemotherapy by achieving complete morphologic, immunophenotypic, and cytogenetic remission but not a molecular one. The addition of imatinib mesylate led to a molecular remission, which is sustained for 10 months so far.     

Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity. T-cell proliferation and differentiation to effector cells require increased glucose consumption, aerobic glycolysis and glutaminolysis. The effect of IDO on the above metabolic pathways was evaluated in alloreactive T-cells. Mixed lymphocyte reaction (MLR) in the presence or not of the IDO inhibitor, 1-methyl-dl-tryptophan (1-MT), was used. In MLRs, 1-MT decreased tryptophan consumption, increased cell proliferation, glucose influx and lactate production, whereas it decreased tricarboxylic acid cycle activity. In T-cells, from the two pathways that could sense tryptophan depletion, i.e. general control nonrepressed 2 (GCN2) kinase and mammalian target of rapamycin complex 1, 1-MT reduced only the activity of the GCN2 kinase. Additionally 1-MT treatment of MLRs altered the expression and/or the phosphorylation state of glucose transporter-1 and of key enzymes involved in glucose metabolism and glutaminolysis in alloreactive T-cells in a way that favors glucose influx, aerobic glycolysis and glutaminolysis. Thus in alloreactive T-cells, IDO through activation of the GCN2 kinase, decreases glucose influx and alters key enzymes involved in metabolism, decreasing aerobic glycolysis and glutaminolysis. Acting in such a way, IDO could be considered as a constraining factor for alloreactive T-cell proliferation and differentiation to effector T-cell subtypes.