Epigenetic Network in Immunometabolic Disease.

Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated. Epigenetic changes, including DNA methylation, histone modification, and noncoding RNA, determine gene activity by altering the accessibility of chromatin to transcription factors. Various factors influence these alterations, including genetics, lifestyle, and environmental cues. Moreover, acquired epigenetic signals can be transmitted across generations, thus contributing to early disease traits in the offspring. A closer investigation is critical in this aspect as it can help to understand the underlying molecular mechanisms further and gain insights into potential therapeutic targets for preventing and treating diseases arising from immuno-metabolic dysregulation. In this review, the role of chromatin alterations in the transcriptional modulation of genes involved in insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and nonalcoholic fatty liver disease (NAFLD), is discussed. An overview of emerging chromatin-modifying drugs and the importance of the individual epigenetic profile for personalized therapeutic approaches in patients with immuno-metabolic disorders is also presented.

Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature.

Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress.

Intractable Neck Pain in an Oncologic Palliative Care Setting: Is Cancer Always the Answer?

Refractory pain is a common manifestation in an oncologic palliative care setting and represents a major challenge for health care professionals involved in care provision. The underlying neoplasm and its dissemination are the foremost pathophysiologic mechanism for the development of pain in patients with advanced cancer. Nonetheless, other etiologies such as trauma and infections need to be considered by clinicians in this particular care setting. The authors present the case of a patient with a recent diagnosis of hepatocellular carcinoma, suffering from intractable neck pain, progressive worsening of her general conditions, and the onset of a generalized seizure. The clinical suspicion of a bacteremia with central nervous system involvement was confirmed by the performed work-up, and a Listeria monocytogenes meningoencephalitis was diagnosed. The purpose of this case report is to raise clinicians' awareness on infectious complications, which may increase the symptom burden in patients treated in an oncologic palliative care setting. Moreover, the manifestation of such complications may be misinterpreted as the consequence of the underlying neoplasm, further delaying the diagnostic and therapeutic management in this particular population.

Early rule-out and rule-in of myocardial infarction using sensitive cardiac Troponin I.

BACKGROUND: It is currently unknown, whether and to what extent sensitive cardiac troponin (s-cTn) allows shortening of the time required for safe rule-out and rule-in of acute myocardial infarction (AMI). METHODS: We aimed to develop and validate early rule-out and rule-in algorithms for AMI using a thoroughly-examined and commonly used s-cTnI assay in a prospective multicenter study including 2173 patients presenting to the emergency department with suspected AMI. S-cTnI was measured in a blinded fashion at 0 h, 1 h, and 2 h. The final diagnosis was centrally adjudicated by two independent cardiologists. In the derivation cohort (n = 1496), we developed 1h- and 2h-algorithms assigning patients to "rule-out", "rule-in", or "observe". The algorithms were then prospectively validated in the validation cohort (n = 677). RESULTS: AMI was the adjudicated diagnosis in 17% of patients. After applying the s-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 65% of patients were classified as "rule-out", 12% as "rule-in", and 23% to "observe". The negative predictive value for AMI in the "rule-out" group was 98.6% (95% CI, 96.9-99.5), the positive predictive value for AMI in the "rule-in" group 76.3% (95% CI, 65.4-85.1). Overall, 30-day mortality was 0.2% in the "rule-out" group, 1.0% in the "observe" group, and 3.0% in the "rule-in" group. Similar results were obtained for the 2h-algorithm. CONCLUSION: When used in conjunction with other clinical information including the ECG, a simple algorithm incorporating s-cTnI values at presentation and after 1h (or 2h) will allow safe rule-out and accurate rule-in of AMI in the majority of patients.

Aortic root dimensions among patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

OBJECTIVES: The aim of this study was to characterize aortic root dimensions of patients with aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) and to evaluate sex differences. BACKGROUND: The advent of TAVR makes a precise delineation of the aortic root anatomy mandatory and requires a profound anatomic understanding. METHODS: Patients planned to undergo TAVR underwent screening imaging with use of a 64-slice or dual-source electrocardiogram-gated contrast-enhanced computed tomography. Anatomic dimensions were assessed at the level of the left ventricular outflow tract (LVOT), annulus, sinus of Valsalva, and ascending aorta. RESULTS: The study population comprised 80 men and 97 women (age: 82 ± 6 years) with symptomatic severe aortic valve stenosis. Multislice computed tomography aortic root assessment revealed larger annular and LVOT dimensions in men than women (area annulus: 483.1 ± 75.6 mm(2) vs. 386.9 ± 58.5 mm(2), p = 0.0002; area LVOT: 478.2 ± 131.0 mm(2) vs. 374.0 ± 94.2 mm(2), p = 0.0024), whereas dimensions of the ascending aorta were comparable. Both LVOT and annulus were predominantly oval without sex differences, with a higher mean ellipticity index for the LVOT compared with the annulus (1.49 ± 0.2 vs. 1.29 ± 0.1); the ascending aorta was primarily circular (1.07 ± 0.1). Although similar in mean surface area, an area mismatch of annulus and LVOT of more than 10%, 20%, and 40% was detected in 42, 9, and 2 patients, respectively. The mean distance from annulus to the left coronary ostium was smaller than the mean distance of the right coronary ostium (14.4 ± 3.6 mm vs. 16.7 ± 3.6 mm), and distances were lower among women than men. CONCLUSIONS: The aortic root has specific anatomic characteristics, which affect device design, selection, and clinical outcome in patients undergoing TAVR. Female sex is associated with smaller annular and LVOT but not aortic dimensions. The degree of ellipticity as well as a significant mismatch between annular and LVOT dimensions in selected patients deserve careful evaluation.