Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction

New Findings What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non‐diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal‐averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT‐PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara–Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal‐averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2 , KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after‐depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+–Ca2+ exchange current. These data suggest that diabetes leads to pro‐arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Molecular Genetics of the Renin-Angiotensin System: Implications for Angiotensin II Receptor Blockade

Angiotensin II (Ang II) is the main effector hormone of the renin-angiotensin system (RAS). The pathogenesis of many cardiovascular diseases, including heart failure and hypertension, appear to be related to Ang II production. The generation of Ang II involves angiotensin-converting enzyme (ACE) in circulating and tissue RAS’s, as well as non–ACE pathways. ACE and other components of the RAS show natural mutations. In this review, we discuss the molecular genetics of the human RAS in relation to cardiovascular disease, including the clinical effects of known ACE molecular variants and possible pharmacological treatment strategies. pharmacol. ther. 75(1):43–50, 1997

Angiotensin converting enzyme (ACE) gene expression in the human left ventricle: effect of ACE gene insertion/deletion polymorphism and left ventricular function

Aims: We investigated the effect of the angiotensin converting enzyme (ACE) I/D polymorphism and left ventricular (LV) function on ACE gene expression in tru‐cut LV myocardial biopsies from 50 consecutive patients (II: 18, ID: 18, DD: 14; 40 males) with ischaemic heart disease undergoing coronary artery bypass grafting (CABG). Methods: The polymerase chain reaction was used for ACE genotyping. LV function [normal (n = 22) or impaired] was determined by left ventriculography at cardiac catheterisation prior to bypass surgery. ACE expression was determined (n = 46) by a competitive quantitative reverse transcription PCR assay using 5×105, 12.5×105 and 20×105 copies of a mutant DNA internal standard (IS). PCR products were analysed by negative film photography and laser densitometry to determine the number of ACE transcripts present. Results: Mean age was similar (II: 59.1±10.4, ID: 57.0±10.6, DD: 61.4±6.2; P = NS) with no differences between groups in sex (P = 0.25); hypertension, P = 0.31; previous myocardial infarction, P = 0.44; LV function, P = 0.23; and ACE inhibitor therapy, P = 0.06. ACE expression per 100 ng of total RNA varied with genotype [12.5×105 (II: 4, ID: 2, DD: 8), Kendall's tau‐b coefficient (τb) = 0.43, P = 0.003]. Impaired LV function also correlated with higher levels of ACE expression, Kendall's τb = 0.40, P = 0.001. Conclusion: ACE gene expression in the left ventricle varied with ACE genotype and LV function in IHD patients undergoing CABG

Improvement of early detection of breast cancer through collaborative multi-country efforts: Medical physics component

Purpose: The International Atomic Energy Agency (IAEA) through a Coordinated Research Project on “Enhancing Capacity for Early Detection and Diagnosis of Breast Cancer through Imaging”, brought together a group of mammography radiologists, medical physicists and radiographers; to investigate current practices and improve procedures for the early detection of breast cancer by strengthening both the clinical and medical physics components. This paper addresses the medical physics component. Methods: The countries that participated in the CRP were Bosnia and Herzegovina, Costa Rica, Egypt, India, Kenya, the Frmr. Yug. Rep. of Macedonia, Mexico, Nigeria, Pakistan, Philippines, Slovenia, Turkey, Uganda, United Kingdom and Zambia. Ten institutions participated using IAEA quality control protocols in 9 digital and 3 analogue mammography equipment. A spreadsheet for data collection was generated and distributed. Evaluation of image quality was done using TOR MAX and DMAM2 Gold phantoms. Results: QC results for analogue equipment showed satisfactory results. QC tests performed on digital systems showed that improvements needed to be implemented, especially in thickness accuracy, signal difference to noise ratio (SDNR) values for achievable levels, uniformity and modulation transfer function (MTF). Mean glandular dose (MGD) was below international recommended levels for patient radiation protection. Evaluation of image quality by phantoms also indicated the need for improvement. Conclusions: Common activities facilitated improvement in mammography practice, including training of medical physicists in QC programs and infrastructure was improved and strengthened; networking among medical physicists and radiologists took place and was maintained over time. IAEA QC protocols provided a uniformed approach to QC measurements.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias Atómicas Nucleares y Moleculares (CICANUM

Quality control in cone-beam computed tomography (CBCT) EFOMP-ESTRO-IAEA protocol (summary report).

The aim of the guideline presented in this article is to unify the test parameters for image quality evaluation and radiation output in all types of cone-beam computed tomography (CBCT) systems. The applications of CBCT spread over dental and interventional radiology, guided surgery and radiotherapy. The chosen tests provide the means to objectively evaluate the performance and monitor the constancy of the imaging chain. Experience from all involved associations has been collected to achieve a consensus that is rigorous and helpful for the practice. The guideline recommends to assess image quality in terms of uniformity, geometrical precision, voxel density values (or Hounsfield units where available), noise, low contrast resolution and spatial resolution measurements. These tests usually require the use of a phantom and evaluation software. Radiation output can be determined with a kerma-area product meter attached to the tube case. Alternatively, a solid state dosimeter attached to the flat panel and a simple geometric relationship can be used to calculate the dose to the isocentre. Summary tables including action levels and recommended frequencies for each test, as well as relevant references, are provided. If the radiation output or image quality deviates from expected values, or exceeds documented action levels for a given system, a more in depth system analysis (using conventional tests) and corrective maintenance work may be required