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Ify R Mordi,1,2 Athar A Badar,2 R John Irving,2 Jonathan R Weir-McCall,1 J Graeme Houston,1 Chim C Lang1,2 1Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK; 2Department of Cardiology, Ninewells Hospital and Medical School, Dundee, UK Abstract: The aim of this review was to discuss the current literature regarding the utility of noninvasive imaging in diagnosis and management of stable coronary artery disease (CAD) including recent data from large randomized trials assessing diagnosis and prognosis. Current guidelines recommend revascularization in patients with refractory angina and in those with potential prognostic benefit. Appropriate risk stratification through noninvasive assessment is important in ensuring patients are not exposed to unnecessary invasive coronary angiograms. The past 20years have seen an unprecedented expansion in noninvasive imaging modalities for the assessment of stable CAD, with cardiovascular magnetic resonance and computed tomography complementing established techniques such as myocardial perfusion imaging, echocardiography and exercise electrocardiogram. In this review, we examine the current state-of-the-art in noninvasive imaging to provide an up-to-date analysis of current investigation and management options. Keywords: angina, noninvasive imaging, SPECT, stress echo, cardiovascular magnetic resonance, CT coronary angiography

Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Jagdeep SS Singh, Chim C Lang Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK Abstract: Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction. Keywords: heart failure, angiotensin receptor-neprilysin inhibitor, heart failure with preserved ejection fraction, nesiritide, candoxatril, omapatrilat, hypertension, renal impairment, myocardial infarction

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. OBJECTIVES: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). METHODS: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. RESULTS: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. CONCLUSIONS: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

Aims: Asymmetric wall thickening has been described in patients with aortic stenosis. However, it remains poorly characterized and its prognostic implications are unclear. We hypothesized this pattern of adaptation is associated with advanced remodelling, left ventricular decompenzation, and a poor prognosis.Methods and results: In a prospective observational cohort study, 166 patients with aortic stenosis (age 69, 69% males, mean aortic valve area 1.0 ± 0.4 cm2) and 37 age and sex-matched healthy volunteers underwent phenotypic characterization with comprehensive clinical, imaging, and biomarker evaluation. Asymmetric wall thickening on both echocardiography and cardiovascular magnetic resonance was defined as regional wall thickening ≥ 13 mm and > 1.5-fold the thickness of the opposing myocardial segment. Although no control subject had asymmetric wall thickening, it was observed in 26% (n = 43) of patients with aortic stenosis using magnetic resonance and 17% (n = 29) using echocardiography. Despite similar demographics, co-morbidities, valve narrowing, myocardial hypertrophy, and fibrosis, patients with asymmetric wall thickening had increased cardiac troponin I and brain natriuretic peptide concentrations (both P Conclusion: Asymmetric wall thickening is common in aortic stenosis and is associated with increased myocardial injury, left ventricular decompenzation, and adverse events. Its presence may help identify patients likely to proceed quickly towards AVR.Clinical Trial Registration: https://clinicaltrials.gov/show/NCT01755936: NCT01755936.

We present new observations of the quiescent giant molecular cloud GCM0.253+0.016 in the Galactic center, using the upgraded Karl G. Jansky Very Large Array. Observations were made at wavelengths near 1 cm, at the K (24-26 GHz) and Ka (27 and 36 GHz) bands, with velocity resolutions of 1-3 km s-1 and spatial resolutions of ∼0.1 pc, at the assumed 8.4 kpc distance of this cloud. The continuum observations of this cloud are the most sensitive yet made, and reveal previously undetected emission which we attribute primarily to free-free emission from external ionization of the cloud. In addition to the sensitive continuum map, we produce maps of 12 molecular lines: 8 transitions of NH3-(1, 1), (2, 2), (3, 3), (4, 4), (5, 5), (6, 6), (7, 7), and (9, 9), as well as the HC3N (3-2) and (4-3) lines, and CH3OH 4-1-30, the latter of which is known to be a collisionally excited maser. We identify 148 CH3OH 4-1-30 (36.2 GHz) sources, of which 68 have brightness temperatures in excess of the highest temperature measured for this cloud (400 K) and can be confirmed to be masers. The majority of these masers are concentrated in the southernmost part of the cloud. We find that neither these masers nor the continuum emission in this cloud provide strong evidence for ongoing star formation in excess of that previously inferred by the presence of an H2O maser.

© 2015. The American Astronomical Society. All rights reserved. We present new observations of the quiescent giant molecular cloud GCM0.253+0.016 in the Galactic center, using the upgraded Karl G. Jansky Very Large Array. Observations were made at wavelengths near 1 cm, at the K (24-26 GHz) and Ka (27 and 36 GHz) bands, with velocity resolutions of 1-3 km s-1and spatial resolutions of ∼0.1 pc, at the assumed 8.4 kpc distance of this cloud. The continuum observations of this cloud are the most sensitive yet made, and reveal previously undetected emission which we attribute primarily to free-free emission from external ionization of the cloud. In addition to the sensitive continuum map, we produce maps of 12 molecular lines: 8 transitions of NH3-(1, 1), (2, 2), (3, 3), (4, 4), (5, 5), (6, 6), (7, 7), and (9, 9), as well as the HC3N (3-2) and (4-3) lines, and CH3OH 4-1-30, the latter of which is known to be a collisionally excited maser. We identify 148 CH3OH 4-1-30(36.2 GHz) sources, of which 68 have brightness temperatures in excess of the highest temperature measured for this cloud (400 K) and can be confirmed to be masers. The majority of these masers are concentrated in the southernmost part of the cloud. We find that neither these masers nor the continuum emission in this cloud provide strong evidence for ongoing star formation in excess of that previously inferred by the presence of an H2O maser.

At a distance of 8 kpc, the center of our Galaxy is the nearest galactic nucleus, and has been the subject of numerous key projects undertaken by great observatories such as Chandra, Spitzer, and Herschel. However, there are still no surveys of molecular gas properties in the Galactic center with less than 30" (1 pc) resolution. There is also no sensitive polarization survey of this region, despite numerous nonthermal magnetic features apparently unique to the central 300 parsecs. In this paper, we outline the potential the VLASS has to fill this gap. We assess multiple considerations in observing the Galactic center, and recommend a C-band survey with 10 micro-Jy continuum RMS and sensitive to molecular gas with densities greater than 10^4 cm^{-3}, covering 17 square degrees in both DnC and CnB configurations ( resolution ~5"), totaling 750 hours of observing time. Ultimately, we wish to note that the upgraded VLA is not just optimized for fast continuum surveys, but has a powerful correlator capable of simultaneously observing continuum emission and dozens of molecular and recombination lines. This is an enormous strength that should be fully exploited and highlighted by the VLASS, and which is ideally suited for surveying the center of our Galaxy.

BACKGROUND Circumferential pulmonary vein ablation (CPVA) is an effective treatment for atrial fibrillation (AF). Accurate left atrial (LA) mapping is essential for creating lesions at the LA‐ pulmonary vein (PV) junction, avoiding PV stenosis. OBJECTIVES The purpose of this study was to establish whether endocardial impedance varies within the LA and PVs and whether it is a useful tool for mapping and ablation. METHODS Pilot Phase: Three-dimensional LA maps were created using CARTO. Impedance (Z) was measured using a radiofrequency generator at multiple points in the LA, PV ostia (PVO), and deep PVs in 79 patients undergoing their first AF ablation (group 1) and 29 patients undergoing repeat CPVA (group 2). Prospective Phase: In an additional 20 patients, using pilot phase data, one operator defined catheter tip location as either LA or PVO based on CARTO and fluoroscopy. A second operator blinded to CARTO simultaneously did the same based on impedance at 15 4 points per patient. RESULTS Group 1: ZLA was 99.4 9.0 .Z PVO was higher (109.2 8.5 ), rising further as the catheter advanced into deep PV (137 18). ZPVO differed from ZLA by 9 4 . Group 2 had a lower ZLA and ZPVO compared with group 1 (P .05). Impedance monitoring differentiated between LA and PVO, with 91% specificity and sensitivity, 96% positive predictive value, and 81% negative predictive value. At 3-month follow-up, no patients had evidence of PV stenosis on magnetic resonance imaging. CONCLUSION Impedance mapping reliably identifies the LA‐PV transitional zone, facilitating AF ablation, and its use is associated with a low incidence of PV stenosis.

Background— Radiofrequency ablation for atrial fibrillation is becoming widely practiced. Methods and Results— Two patients undergoing circumferential pulmonary vein ablation for atrial fibrillation in different centers developed symptoms compatible with endocarditis 3 to 5 days after the procedure. Their clinical condition deteriorated rapidly, and both suffered multiple gaseous and/or septic embolic events causing cerebral and myocardial damage. One patient survived after emergency cardiac and esophageal surgery; the other died of extensive systemic embolization. An atrio-esophageal fistula was identified in both patients. Conclusions— Atrio-esophageal fistulas can occur after catheter ablation in the posterior wall of the left atrium. This diagnosis should be excluded in any patient with symptoms or signs of endocarditis after left atrial ablation, and expeditious cardiac surgery is critical if the diagnosis is confirmed. Lower power and temperature settings for applications of radiofrequency energy along the posterior left atrial wall may prevent further cases of fistula formation.