Nejvíce citovaný článek - PubMed ID 28845751
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Cardiovascular disease remains the leading global cause of mortality, with inflammation now recognized as a central driver of atherosclerosis and other cardiometabolic conditions. Recent advances have repositioned perivascular adipose tissue from a passive structural element to an active endocrine and immunomodulatory organ, now a key focus in cardiovascular and metabolic research. Among the most promising tools for assessing perivascular adipose tissue inflammation is the fat attenuation index, a non-invasive imaging biomarker derived from coronary computed tomography angiography. This review explores the translational potential of the fat attenuation index for cardiovascular risk stratification and treatment monitoring in both coronary artery disease and systemic inflammatory or metabolic conditions (psoriasis, systemic lupus erythematosus, inflammatory bowel disease, obesity, type 2 diabetes, and non-obstructive coronary syndromes). We summarize evidence linking perivascular adipose tissue dysfunction to vascular inflammation and adverse cardiovascular outcomes. Clinical studies reviewing the fat attenuation index highlight its ability to detect subclinical inflammation and monitor treatment response. As research advances, standardization of measurement protocols and imaging thresholds will be essential for routine clinical implementation.
BACKGROUND: Heart failure (HF) is becoming an increasingly prevalent issue, particularly among the elderly population. Lipids are closely associated with cardiovascular disease (CVD) pathology. Lipidomics as a comprehensive profiling tool is showing to be promising in the prediction of events and mortality due to CVD as well as identifying novel biomarkers. MATERIALS AND METHODS: In this study, eicosanoids and lipid profiles were measured in order to predict survival in patients with de novo or acute decompensated HF. Our study included 50 patients (16 females, mean age 73 years and 34 males, mean age 71 years) with de novo or acute decompensated chronic HF with a median follow-up of 7 months. Lipids were semiquantified using targeted lipidomic liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Eicosanoid concentrations were determined using a commercially available sandwich ELISA assay. RESULTS: From 736 lipids and 3 eicosanoids, 39 significant lipids were selected (by using the Mann-Whitney U test after Benjamini-Hochberg correction) with the highest number of representatives belonging to the polyunsaturated (PUFA) phosphatidylcholines (PC). PC 42:10 (p = 1.44 × 10-4) was found to be the most statistically significantly elevated in the surviving group with receiver operating characteristics of AUC = 0.84 (p = 3.24 × 10-7). A multivariate supervised discriminant analysis based on the aforementioned lipid panel enabled the classification of the groups of surviving and non-surviving patients with 90 % accuracy. CONCLUSIONS: In the present study we describe a trend in PUFA esterified in PC that were systematically increased in surviving patients with HF. This trend in low-abundant and rarely identified PUFA PC (mainly very long chain PUFA containing PC such as PC 42:10 or PC 40:9 containing FA 22:6, FA 20:5 and FA 20:4) suggests candidate biomarkers.
- Klíčová slova
- Atherosclerosis, Eicosanoids, HF survival, Heart failure, Lipidomics, PC, PUFA, Phosphatidylcholine, Survival rate,
- Publikační typ
- časopisecké články MeSH
Autologous cell therapy (ACT) is primarily used in diabetic patients with chronic limb-threatening ischemia (CLTI) who are not candidates for standard revascularization. According to current research, this therapy has been shown in some studies to be effective in improving ischemia parameters, decreasing the major amputation rate, and in foot ulcer healing. This review critically evaluates the efficacy of ACT in patients with no-option CLTI, discusses the use of mononuclear and mesenchymal stem cells, and compares the route of delivery of ACT. In addition to ACT, we also describe the use of new revascularization strategies, e.g., nanodiscs, microbeads, and epigenetics, that could enhance the therapeutic effect. The main aim is to summarize new findings on subcellular and molecular levels with the clinical aspects of ACT.
- Klíčová slova
- chronic limb-threatening ischemia, peripheral artery disease, stem cell therapy,
- MeSH
- autologní transplantace * MeSH
- buněčná a tkáňová terapie metody MeSH
- chronická kritická ischemie končetin terapie MeSH
- diabetes mellitus terapie MeSH
- ischemie terapie MeSH
- lidé MeSH
- transplantace mezenchymálních kmenových buněk metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.
INTRODUCTION: In pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH. METHODS: We used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs). RESULTS: Single-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism. CONCLUSION: This study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH.
- Klíčová slova
- HDAC inhibitors, T-cells, Tregs, pulmonary fibroblasts, pulmonary hypertension, γδ T-cells,
- MeSH
- interleukin-10 MeSH
- interleukin-4 MeSH
- kultivační média speciální metabolismus MeSH
- lidé MeSH
- plicní hypertenze * metabolismus MeSH
- skot MeSH
- T-lymfocyty - podskupiny metabolismus MeSH
- transformující růstový faktor beta MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- interleukin-10 MeSH
- interleukin-4 MeSH
- kultivační média speciální MeSH
- transformující růstový faktor beta MeSH
BACKGROUND: Left ventricular ejection fraction (EF) is an independent predictor of adverse outcomes after myocardial infarction (MI). However, current data on trajectories and determinants of EF are scarce. The present study aimed to describe the epidemiology of EF after MI. METHODS: Data from a single-center prospectively-designed registry of consecutive patients hospitalized at a large tertiary cardiology center were utilized. RESULTS: Out of 1,593 patients in the registry, 1,065 were hospitalized for MI type I (65.4% STEMI) and had no previous history of heart failure or MI. At discharge, EF < 40% was present in 238 (22.3%), EF 40-50% in 326 (30.6%) and EF > 50% in 501 (47.0%). Patients with EF < 40% were often those who suffered subacute and anterior STEMI, had higher heart rate at admission and higher maximal troponin level, and had more often HF signs requiring intravenous diuretics. Among subjects with EF < 40%, the follow-up EF was available in 166 (80% of eligible). Systolic function recovered to EF > 50% in 39 (23.1%), slightly improved to EF 40-50% in 44 (26.0%) and remained below 40% in 86 (50.9%). Systolic function improvement to EF > 40% was predicted by lower severity of coronary atherosclerosis, lower leukocyte count, and the absence of atrial fibrillation. CONCLUSIONS: Despite recent improvements in in-hospital MI care, one in five patients has systolic dysfunction at hospital discharge. Out of these, EF improves in 51%, and full recovery is observed in 23%. The severity of coronary atherosclerosis, inflammatory response to MI, and atrial fibrillation may affect EF recovery.
- Klíčová slova
- atrial fibrillation, ejection fraction (EF%), epidemiology, inflammation, myocardial infarction, systolic dysfunction,
- Publikační typ
- časopisecké články MeSH
The high mortality of coronary heart disease (CHD) among Czech men-one of the highest worldwide-began to decline in 1991 soon after the abolition of government subsidies to all foodstuffs rich in animal fat. As participants in the WHO MONICA Project, we were able to analyze the CHD risk factors just before and after this major economic change. We had previously documented that the originally subsidized prices decreased animal fat consumption and consequently non-HDL cholesterol concentrations in the population. By the early 1990s, no progress had been made in the treatment of acute myocardial infarction, statins were unavailable as was not the currently more effective antihypertensive therapy. Our recent research proved a close relationship between cholesterolemia and proinflammatory macrophages in adipose tissue and accelerated macrophage polarization with increased palmitate and palmitoleate contents in cell membrane phospholipids. By contrast, the proportion of proinflammatory macrophages decreases with increasing presence of n-3 fatty acids in the cell membrane. The combination of non-HDL cholesterol drop and a decreased proportion of proinflammatory macrophages due to replacement of alimentary fat decreased CHD mortality immediately.
- Klíčová slova
- cholesterol, coronary heart disease mortality, diet, economy, inflammation, macrophages, n-3 fatty acids,
- Publikační typ
- časopisecké články MeSH
Cardiovascular disease (CVD) is a global public health issue due to its high morbidity, mortality, and economic impact. The implementation of innovative therapeutic alternatives for CVD is urgently required. Specialized proresolving lipid mediators (SPMs) are bioactive compounds derived from ω-3 and ω-6 fatty acids, integrated into four families: Lipoxins, Resolvins, Protectins, and Maresins. SPMs have generated interest in recent years due to their ability to promote the resolution of inflammation associated with the pathogeneses of numerous illnesses, particularly CVD. Several preclinical studies in animal models have evidenced their ability to decrease the progression of atherosclerosis, intimal hyperplasia, and reperfusion injury via diverse mechanisms. Large-scale clinical trials are required to determine the effects of SPMs in humans. This review integrates the currently available knowledge of the therapeutic impact of SPMs in CVD from preclinical and clinical studies, along with the implicated molecular pathways. In vitro results have been promising, and as such, SPMs could soon represent a new therapeutic alternative for CVD.
- Klíčová slova
- atherosclerosis, inflammation, intimal hyperplasia, reperfusion injury, resolution, specialized proresolving mediators,
- MeSH
- ateroskleróza * metabolismus MeSH
- kardiovaskulární nemoci * farmakoterapie MeSH
- kyseliny dokosahexaenové metabolismus farmakologie terapeutické užití MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- omega-3 mastné kyseliny * metabolismus farmakologie terapeutické užití MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- kyseliny dokosahexaenové MeSH
- mediátory zánětu MeSH
- omega-3 mastné kyseliny * MeSH
Membrane cholesterol is essential for cell membrane properties, just as serum cholesterol is important for the transport of molecules between organs. This review focuses on cholesterol transport between lipoproteins and lipid rafts on the surface of macrophages. Recent studies exploring this mechanism and recognition of the central dogma-the key role of macrophages in cardiovascular disease-have led to the notion that this transport mechanism plays a major role in the pathogenesis of atherosclerosis. The exact molecular mechanism of this transport remains unclear. Future research will improve our understanding of the molecular and cellular bases of lipid raft-associated cholesterol transport.
- Klíčová slova
- cell membrane, cholesterol, macrophages,
- MeSH
- ateroskleróza * MeSH
- biologický transport MeSH
- buněčná membrána chemie metabolismus MeSH
- cholesterol chemie metabolismus MeSH
- homeostáza MeSH
- lidé MeSH
- lipoproteiny metabolismus MeSH
- makrofágy metabolismus MeSH
- membránové mikrodomény chemie metabolismus MeSH
- metabolismus lipidů MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- cholesterol MeSH
- lipoproteiny MeSH
Excessive LDL cholesterol concentration together with subclinical inflammation, in which macrophages play a central role, are linked pathologies. The process starts with the accumulation of macrophages in white adipose tissue and the switch of their polarization toward a pro-inflammatory phenotype. The proportion of pro-inflammatory macrophages in adipose tissue is related to the main risk predictors of cardiovascular disease. The cholesterol content of phospholipids of cell membranes seems to possess a crucial role in the regulation of membrane signal transduction and macrophage polarization. Also, different fatty acids of membrane phospholipids influence phenotypes of adipose tissue macrophages with saturated fatty acids stimulating pro-inflammatory whereas omega3 fatty acids anti-inflammatory changes. The inflammatory status of white adipose tissue, therefore, reflects not only adipose tissue volume but also adipose tissue macrophages feature. The beneficial dietary change leading to an atherogenic lipoprotein decrease may therefore synergically reduce adipose tissue driven inflammation.
- MeSH
- ateroskleróza * metabolismus MeSH
- lidé MeSH
- makrofágy metabolismus MeSH
- mastné kyseliny metabolismus MeSH
- tuková tkáň * metabolismus MeSH
- zánět metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- mastné kyseliny MeSH
