Citations

ABSTRACTPurposeWe aimed to explore the hypothesis that early subclinical cardiac chamber dysfunction secondary to tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma could be signaled by abnormal cardiac mechanics demonstrated by velocity vector imaging.MethodsEchocardiographic images were acquired from the apical views in 23 metastatic renal cell carcinoma patients. All patients had baseline and at least a 3‐month follow‐up echocardiogram after receiving TKI therapy. Subendocardial borders of all the cardiac chambers were traced to obtain volumetric and deformation indices.ResultsMean age was 67 ± 9 years with 92% men. The right ventricle peak systolic global longitudinal strain (GLɛ) and strain rate were significantly lower after TKIs (−23.49 ± 5.1 versus −19.81 ± 5.5, p = 0.002 and −1.52 ± 0.52 versus −1.24 ± 0.35 p = 0.02, respectively). LV GLɛ was not statistically different. Volumetric and deformation indices showed a minimal decrease of the right atrium reservoir and conduit functions, and no significant changes of left atrial function.ConclusionsThe right heart exhibited greater strain changes than the left heart after TKI treatment. The implications of these findings and their potential significance warrant further work. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:221–230, 2016

SummaryBackgroundAzathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount.AimTo provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy inIBD.MethodsA literature search up to July 2015 was performed in PubMed using a combination of relevant MeSHterms.ResultsPre‐treatment thiopurine S‐methyltransferase typing plus measurement of 6‐tioguanine nucleotides and 6‐methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3‐7%, and to improve efficacy by 15–30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association betweenAOXactivity andAZAdose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate‐linked moiety X‐type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S‐transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice.ConclusionsMeasurement of thiopurine‐related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.

Objective The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Methods This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects. Results During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013). Conclusions In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial. Trial registration number NCT00391872; Results.

Objective Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Methods The ARISTOTLE trial randomised 18 201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14 954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Results The IL-6 median level was 2.3 ng/L (IQR 1.5–3.9), median CRP level was 2.2 mg/L (1.0–4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Conclusions In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding. Trial registration number ClinicalTrials.gov identifier: NCT00412984 post-results.

Objective Spontaneous coronary artery dissection (SCAD) is an under-recognised but important cause of myocardial infarction and sudden cardiac death. We sought to determine the role of medical and molecular genetic screening for connective tissue disorders in patients with SCAD. Methods We performed a single-centre retrospective descriptive analysis of patients with spontaneous coronary artery disease who had undergone medical genetics evaluation 1984–2014 (n=116). The presence or absence of traits suggestive of heritable connective tissue disease was extracted. Genetic testing for connective tissue disorders and/or aortopathies, if performed, is also reported. Results Of the 116 patients (mean age 44.2 years, 94.8% women and 41.4% with non-coronary fibromuscular dysplasia (FMD)), 59 patients underwent genetic testing, of whom 3 (5.1%) received a diagnosis of connective tissue disorder: a 50-year-old man with Marfan syndrome; a 43-year-old woman with vascular Ehlers–Danlos syndrome and FMD; and a 45-year-old woman with vascular Ehlers–Danlos syndrome. An additional 12 patients (20.3%) had variants of unknown significance, none of which was thought to be a definite disease-causing mutation based on in silico analyses. Conclusions Only a minority of patients with SCAD who undergo genetic evaluation have a likely pathogenic mutation identified on gene panel testing. Even fewer exhibit clinical features of connective tissue disorder. These findings underscore the need for further studies to elucidate the molecular mechanisms of SCAD.

Low-flow, low-gradient (LF/LG) severe aortic stenosis (AS) with preserved ejection fraction refers to the condition of AS with aortic valve area ≤1 cm2, stroke volume index <35 mL/m2, mean aortic valve gradient <40 mm Hg and left ventricular ejection fraction ≥50%. This mismatch of aortic valve area suggesting severe stenosis and ‘low’ gradient in some patients has led to confusion as to the severity of stenosis. Conditions previously labelled as LF/LG severe AS include a spectrum, with measurement error probably being the most common cause of marked inconsistency between gradient, valve area and patient presentation. The presence of LG severe AS may be overestimated in petite patients, who may have aortic valve area slightly less than 1 cm2 with only moderate AS. Concomitant cardiac conditions besides AS, including significant mitral and tricuspid regurgitation, intracardiac shunts and constrictive pericarditis, may contribute to reduced stroke volume, and evidence for these must be sought at the time of echocardiography. True LF/LG severe AS is associated with a unique and probably maladaptive remodelling pattern with smaller ventricles, increasing relative wall thickness, progressive worsening of diastolic function and higher afterload, as demonstrated by lower systemic arterial compliance, higher systemic vascular resistance and higher valvuloarterial impedance. Control of hypertension is essential to the appropriate management of patients with AS. Aortic valve replacement should be considered in patients with compelling evidence of severe AS who remain symptomatic despite optimal treatment of hypertension.

Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques. Bioinformatics analysis of the data found that genes of theDNA replication/DNA metabolism processgroup (with upregulation of theapex1, mcm2, mcm4, orc3,lig1, anddnmt1 genes) were altered in the DM state and these molecular changes continued into MM. Interestingly, DNA methylation changes could be found as far as 6–13 kb upstream of the transcription start site for these genes suggesting potential higher levels of epigenetic control. In conclusion, DNA methylation changes in members of theDNA replication/repair processgroup best explain the heritable nature of cell proliferation impairment found in the zebrafish DM/MM model. These results are consistent with human diabetic epigenetic studies and provide one explanation for the persistence of long term tissue complications as seen in diabetes.