Familial risk of myocardial infarction with non-obstructive and obstructive coronary arteries -A nation-wide cohort study.

Background And Aims: The familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings. We therefore sought to investigate familial risk of MI without and with obstructive coronary arteries.

PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis.

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages.

Lipid droplets, autophagy, and ageing: A cell-specific tale.

Lipid droplets are the essential organelle for storing lipids in a cell. Within the variety of the human body, different cells store, utilize and release lipids in different ways, depending on their intrinsic function. However, these differences are not well characterized and, especially in the context of ageing, represent a key factor for cardiometabolic diseases.

Inhibition of COX-2 signaling favors E. coli during urinary tract infection.

Background: To avoid the overuse of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), acting via cyclooxygenase (COX) inhibition, have been used to reduce pain and as an alternative treatment for uncomplicated urinary tract infections (UTIs). However, clinical studies evaluating NSAIDs versus antibiotics have reported an increased risk of acute pyelonephritis. Therefore, we hypothesized that COX inhibition could compromise the innate immune response and contribute to complications in patients with uncomplicated UTI.

The tyrosine kinase inhibitor nilotinib targets the discoidin domain receptor DDR2 in calcific aortic valve stenosis.

Background And Purpose: Tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukaemia (CML) have been associated with cardiovascular side effects, including reports of calcific aortic valve stenosis. The aim of this study was to establish the effects of first and second generation TKIs in aortic valve stenosis and to determine the associated molecular mechanisms.

Experimental Approach: Hyperlipidemic APOE*3Leiden.

Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis.

Background: Understanding the processes behind carotid plaque instability is necessary to develop methods for identification of patients and lesions with stroke risk. Here, we investigated molecular signatures in human plaques stratified by echogenicity as assessed by duplex ultrasound.

Methods: Lesion echogenicity was correlated to microarray gene expression profiles from carotid endarterectomies (n=96).

Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia.

Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression.

Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells.

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age.

Lack of genetic susceptibility in takotsubo cardiomyopathy: a case-control study.

Background: Takotsubo cardiomyopathy (TCM), also known as "broken heart syndrome", is a type of heart failure characterized by transient ventricular dysfunction in the absence of obstructive coronary lesions. Although associated with increased levels of catecholamines, pathophysiological mechanisms are unknown. Relapses and family heritability indicate a genetic predisposition.

Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions.

miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (ApoemiR-21) were assessed.

Deficiency in perilipin 5 reduces mitochondrial function and membrane depolarization in mouse hearts.

Myocardial triglycerides stored in lipid droplets are important in regulating the intracellular delivery of fatty acids for energy generation in mitochondria, for membrane biosynthesis, and as agonists for intracellular signaling. Previously, we showed that deficiency in the lipid droplet protein perilipin 5 (Plin5) markedly reduces triglyceride storage in cardiomyocytes and increases the flux of fatty acids into phospholipids. Here, we investigated whether Plin5 deficiency in cardiomyocytes alters mitochondrial function.

Genetic variants of increased waist circumference in psychosis.

Objective: We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference.

Patients And Methods: We analyzed the association in (i) a case-case model in which patients with schizophrenia spectrum disorder with increased waist circumference (≥80 cm for women and ≥94 cm for men) (n=534) were compared with patients with normal waist circumference (<80 cm for women; <94 cm for men) (n=124), and in (ii) a case-control model in which schizophrenia spectrum disorder patients with increased waist circumference or irrespective of waist circumference were compared with population-derived controls (n=494) adjusted for age, sex, fasting glucose, smoking, and family history of diabetes.

Results: Genetic variants in five genes (MIA3, MRAS, P2RX7, CAMKK2, and SMAD3) were associated with increased waist circumference in patients with schizophrenia spectrum disorder (P<0.

Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM.

Objective: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability.

Approach And Results: Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.

MicroRNA 486-3P as a stability marker in acute coronary syndrome.

Easily accessible biomarkers are needed to diagnose cardiovascular disease precisely-particularly, to distinguish between disease subtypes that are encountered in clinical practice. Per the hypothesis that plasma miRNA is valuable for this purpose, we performed complete transcriptional profiling of an miRNA discovery-set in 14 samples: three patients with ST-elevated acute myocardial infarction (STEMI) at baseline and after three months of follow-up, four with stable ischaemic heart disease (stable-IHD) and four healthy age-matched volunteers. Our aim was to determine whether we could distinguish patients with unstable plaques from stable patients following a STEMI event.

A Case-Control Study of Risk Markers and Mortality in Takotsubo Stress Cardiomyopathy.

Background: Takotsubo stress cardiomyopathy (TSC) is a syndrome characterized by transient myocardial dysfunction with unknown etiology. Although recent studies have suggested that the syndrome is associated with comorbidity and has a dismal prognosis, there is a lack of comprehensive data describing the epidemiology and prognosis of TSC.

Objectives: This study compared risk markers and mortality in patients with TSC with that of individuals with or without coronary artery disease (CAD).

Melatonin receptor 1B gene associated with hyperglycemia in bipolar disorder.

Bipolar patients are at a higher risk of developing metabolic disorders. Cardiovascular morbidity and mortality is twice the rate reported in the population. Antipsychotic medication increases the risk of metabolic abnormalities.

An ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to glucocorticoids in surgically induced inflammation.

Introduction: An assay to determine glucocorticoid (GC) responsiveness in humans could be used to monitor GC non-responsiveness in states of GC insufficiency and could provide a tool to adapt GC treatment to individual patients. We propose an ex vivo assay to test GC responsiveness in peripheral leukocytes. The assay was evaluated in a human experimental model of surgery-induced inflammation.

ATG16L1 Expression in Carotid Atherosclerotic Plaques Is Associated With Plaque Vulnerability.

Objective: Autophagy has emerged as a cell survival mechanism critical for cellular homeostasis, which may play a protective role in atherosclerosis. ATG16L1, a protein essential for early stages of autophagy, has been implicated in the pathogenesis of Crohn's disease. However, it is unknown whether ATG16L1 is involved in atherosclerosis.

Genetic variation in SULF2 is associated with postprandial clearance of triglyceride-rich remnant particles and triglyceride levels in healthy subjects.

Context: Nonfasting (postprandial) triglyceride concentrations have emerged as a clinically significant cardiovascular disease risk factor that results from accumulation of remnant triglyceride-rich lipoproteins (TRLs) in the circulation. The remnant TRLs are cleared from the circulation by hepatic uptake, but the specific mechanisms involved are unclear. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for the hepatic clearance of remnant TRLs in mice, but its relevance in humans is unclear.

Peroxisome proliferator-activated receptor delta and cardiovascular disease.

Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD).

The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans.

Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program.

MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor δ in human monocytes during the inflammatory response.

PPARδ is involved in the inflammatory response and its expression is induced by cytokines, however, limited knowledge has been produced regarding its regulation. Since recent findings have shown that microRNAs, which are small non-coding RNAs that regulate gene expression, are involved in the immune response, we set out to investigate whether PPARδ can be regulated by microRNAs expressed in monocytes. Bioinformatic analysis identified a putative miR-9 target site within the 3'-UTR of PPARδ that was subsequently verified to be functional using reporter constructs.

Isoform-specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans.

Serum alanine aminotransferase (ALT) is used as a clinical marker to detect hepatic damage and hepatoxicity. Two isoforms of ALT have been identified, ALT1 and ALT2, which have identical enzymatic capacities and are detected simultaneously in human serum/plasma using classical clinical chemical assays. Differences exist in the expression patterns of the ALT1 and ALT2 proteins in different organs which suggest that changes in the proportion of ALT1 and ALT2 in plasma may arise and reflect damage to different human organs.