miR-130a expression is related to aortic dilation in bicuspid aortic valve children.

BACKGROUND: Bicuspid aortic valve disease (BAV) is present in 0.5-2% of the population and can promote aortic dilation, eventually leading to fatal consequences. Although some biomarkers have been proposed in adults, no studies have tested these candidates in children. We aimed to evaluate four miRNAs previously described to be related to BAV disease and aortic dilation in adults in a paediatric cohort. METHODS: Eighty participants ≤17 years old (4-17; mean 12) were included. From the BAV group, 40% had a dilated aorta (z score >2). RT‒qPCR were performed in plasma samples to quantify miR-122, miR-130a, miR-486, and miR-718 using the delta-delta Ct method. Functional and enrichment analyses of miR-130a were also performed. RESULTS: miR-130a expression in plasma was found to be significantly lower in BAV patients with a dilated aorta versus nondilated patients (p = 0.008) and healthy TAV controls (p = 0.004). Furthermore, miR-130a expression in plasma was inversely correlated with ascending aorta (r = 0.318, p = 0.004) and aortic root z scores (r = 0.322; p = 0.004). Enrichment analysis showed that miR-130a target genes are related to the TGFß signalling pathway. CONCLUSIONS: miR-130a expression in plasma is decreased in aortic-dilated BAV children compared to nondilated BAV children, helping differentiate low- to high-risk patients. IMPACT: miR-130a expression in plasma is related to aortic dilation in bicuspid aortic valve (BAV) children. To our knowledge, this is the first study that analyses miRNA patterns in bicuspid aortic valve children with aortic dilation. miR-130a expression in plasma could be a biomarker in order to help differentiate low-to high-risk BAV children, which is vitally important for advanced care planning.

Lipidomics Reveals Myocardial Lipid Composition in a Murine Model of Insulin Resistance Induced by a High-Fat Diet.

Ectopic fat accumulation in non-adipose tissues is closely related to diabetes-related myocardial dysfunction. Nevertheless, the complete picture of the lipid metabolites involved in the metabolic-related myocardial alterations is not fully characterized. The aim of this study was to characterize the specific lipid profile in hearts in an animal model of obesity/insulin resistance induced by a high-fat diet (HFD). The cardiac lipidome profiles were assessed via liquid chromatography-mass spectrometry (LC-MS)/MS-MS and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging in hearts from C57BL/6J mice fed with an HFD or standard-diet (STD) for 12 weeks. Targeted lipidome analysis identified a total of 63 lipids (i.e., 48 triacylglycerols (TG), 5 diacylglycerols (DG), 1 sphingomyelin (SM), 3 phosphatidylcholines (PC), 1 DihydroPC, and 5 carnitines) modified in hearts from HFD-fed mice compared to animals fed with STD. Whereas most of the TG were up-regulated in hearts from animals fed with an HFD, most of the carnitines were down-regulated, thereby suggesting a reduction in the mitochondrial ß-oxidation. Roughly 30% of the identified metabolites were oxidated, pointing to an increase in lipid peroxidation. Cardiac lipidome was associated with a specific biochemical profile and a specific liver TG pattern. Overall, our study reveals a specific cardiac lipid fingerprint associated with metabolic alterations induced by HFD.

FABP4 inhibitor BMS309403 decreases saturated-fatty-acid-induced endoplasmic reticulum stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.

AIMS: Fatty acid binding protein 4 (FABP4) inhibitors have been proposed as potential therapeutic approaches against insulin resistance-related inflammation and type 2 diabetes mellitus. However, the underlying molecular mechanisms by which these molecules drive these effects in skeletal muscle remain unknown. Here, we assessed whether the FABP4 inhibitor BMS309403 prevented lipid-induced endoplasmic reticulum (ER) stress-associated inflammation in skeletal muscle. MATERIALS AND METHODS: The BMS309403 treatment was assessed both in the skeletal muscle of high-fat diet (HFD)-fed mice and in palmitate-stimulated C2C12 myotubes. RESULTS: HFD feeding promoted insulin resistance, which is characterized by increased plasma levels of glucose, insulin, non-esterified fatty acids, triglycerides, resistin, and leptin and reduced plasma levels of adiponectin compared with control mice fed a standard diet. Additionally, insulin-resistant animals showed increased FABP4 plasma levels. In line with this evidence, recombinant FABP4 attenuated the insulin-induced AKT phosphorylation in C2C12 myotubes. Treatment with BMS309403 reduced lipid-induced ER stress and inflammation in both mouse skeletal muscle and C2C12 myotubes. The effects of the FABP4 inhibitor reducing lipid-induced ER stress-associated inflammation were related to the reduction of fatty acid-induced intramyocellular lipid deposits, ROS and nuclear factor-kappaB (NF-κB) nuclear translocation. Accordingly, BMS309403 reduced lipid-induced p38 MAPK phosphorylation, which is upstream of NF-κB activation. CONCLUSION: Overall, these findings indicate that BMS309403 reduces fatty acid-induced ER stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.

Specific circulating microRNA signature of bicuspid aortic valve disease.

BACKGROUND: We aimed to determine the circulating miRNA expression profile associated with BAV and aortic dilation to provide diagnostic and prognostic biomarkers for BAV and/or aortic dilation. METHODS AND RESULTS: We applied a miRNome-wide microarray approach using plasma samples (n = 24) from healthy tricuspid aortic valve individuals, BAV patients and BAV patients with aortic dilation to compare and identify the specific miRNAs associated with BAV and aortic dilation. In a second stage, the expression patterns of the miRNA candidates were validated by RT-qPCR in an independent cohort (n = 43). The miRNA microarray data and RT-qPCR analyses revealed that the expression levels of circulating miR-122, miR-130a and miR-486 are significantly influenced by the morphology of the aortic valve (bicuspid/tricuspid) and could be functionally involved in the regulation of TGF-ß1 signalling. Furthermore, the expression pattern of miR-718 in the plasma was strongly influenced by dilation of the ascending aorta. miR-718 expression was inversely correlated with the aortic diameter (R = -0.63, p = 3.1 × 10-5) and was an independent predictor of aortic dilation (ß = -0.41, p = 0.022). The genes targeted by miR-718 are involved in the regulation of vascular remodelling. CONCLUSIONS: We propose that miR-122, miR-130a, miR-486 and miR-718 are new molecular features associated with BAV and aortic dilation principally by the activation of TGF-ß1 pathway and vascular remodelling mediated by VEGF signalling pathways.

Acute effect of static exercise in patients with aortic regurgitation assessed by cardiovascular magnetic resonance: role of left ventricular remodelling.

OBJECTIVE: In patients with aortic regurgitation (AR), the effect of static exercise (SE) on global ventricular function and AR severity has not been previously studied. METHODS: Resting and SE cardiovascular magnetic resonance (CMR) were prospectively performed in 23 asymptomatic patients with AR. RESULTS: During SE, we observed a decrease in regurgitant volume in both end-diastolic (EDV) and end-systolic (ESV) volume in both ventricles, as well as a slight decrease in LV ejection fraction (EF). Interestingly, responses varied depending on the degree of LV remodelling. Among patients with a greater degree of LV remodelling, we observed a decrease in LVEF (56 ± 4 % at rest vs 48 ± 7 % during SE, p = 0.001) as a result of a lower decrease in LVESV (with respect to LVEDV. Among patients with a lower degree of LV remodelling, LVEF remained unchanged. RVEF remained unchanged in both groups. CONCLUSIONS: In patients with AR, SE provoked a reduction in preload, LV stroke volume, and regurgitant volume. In those patients with higher LV remodelling, we observed a decrease in LVEF, suggesting a lower LV contractile reserve. KEY POINTS: • In patients with aortic regurgitation, static exercise reduced preload volume. • In patients with aortic regurgitation, static exercise reduced stroke volume. • In patients with aortic regurgitation, static exercise reduced regurgitant volume. • In patients with greater remodelling, static exercise unmasked a lower contractile reserve. • Effect of static exercise on aortic regurgitation was assessed by cardiac MR.

Grape-seed procyanidins modulate cellular membrane potential and nutrient-induced GLP-1 secretion in STC-1 cells.

Grape-seed procyanidin extracts (GSPE) modulate glucose homeostasis, and it was suggested that GSPE may achieve this by enhancing the secretion of incretin hormones such as glucagon-like peptide-1 (GLP-1). Therefore, the aim of the present study is to examine in detail the effects of GSPE on intestinal endocrine cells (STC-1). GSPE was found to modulate plasma membrane potential in enteroendocrine cells, inducing depolarization at low concentrations (0.05 mg/l) and hyperpolarization at high concentrations (50 mg/l), and surprisingly this was also accompanied by suppressed GLP-1 secretion. Furthermore, how GSPE affects STC-1 cells under nutrient-stimulated conditions (i.e., glucose, linoleic acid, and l-proline) was also explored, and we found that the higher GSPE concentration was effective in limiting membrane depolarization and reducing GLP-1 secretion. Next, it was also examined whether GSPE affected mitochondrial membrane potential, and it was found that this too is altered by GSPE; however, this does not appear to explain the observed effects on plasma membrane potential and GLP-1 secretion. In conclusion, our results show that grape-seed procyanidins modulate cellular membrane potential and nutrient-induced enteroendocrine hormone secretion in STC-1 cells.

Specific Multiomic Profiling in Aortic Stenosis in Bicuspid Aortic Valve Disease.

INTRODUCTION AND PURPOSE: Bicuspid aortic valve (BAV) disease is associated with faster aortic valve degeneration and a high incidence of aortic stenosis (AS). In this study, we aimed to identify differences in the pathophysiology of AS between BAV and tricuspid aortic valve (TAV) patients in a multiomics study integrating metabolomics and transcriptomics as well as clinical data. METHODS: Eighteen patients underwent aortic valve replacement due to severe aortic stenosis: 8 of them had a TAV, while 10 of them had a BAV. RNA sequencing (RNA-seq) and proton nuclear magnetic resonance spectroscopy (1H-NMR) were performed on these tissue samples to obtain the RNA profile and lipid and low-molecular-weight metabolites. These results combined with clinical data were posteriorly compared, and a multiomic profile specific to AS in BAV disease was obtained. RESULTS: H-NMR results showed that BAV patients with AS had different metabolic profiles than TAV patients. RNA-seq also showed differential RNA expression between the groups. Functional analysis helped connect this RNA pattern to mitochondrial dysfunction. Integration of RNA-seq, 1H-NMR and clinical data helped create a multiomic profile that suggested that mitochondrial dysfunction and oxidative stress are key players in the pathophysiology of AS in BAV disease. CONCLUSIONS: The pathophysiology of AS in BAV disease differs from patients with a TAV and has a specific RNA and metabolic profile. This profile was associated with mitochondrial dysfunction and increased oxidative stress.

Cardiovascular risk assessment in inflammatory bowel disease with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been reported to increase the risk of early atherosclerosis even in young patients. Moreover, metabolic dysfunction-associated steatotic liver disease (MASLD), which has been linked to IBD, is a well-recognized but underdiagnosis entity related to cardiovascular risk. We analyze the impact of MASLD in IBD patients' cardiovascular risk through both advanced lipoprotein profile sorted by nuclear magnetic resonance spectroscopy, and carotid artery intima-media thickness (CIMT). METHODS: Cross-sectional cohort study which involves 941 IBD adult outpatients. Of them, 50 patients with IBD who met criteria for MASLD and 50 with IBD without MASLD, matched by sex and age were included. Alterations in CIMT were evaluated considering abnormal measures above the 75th percentile adjusted for sex and age. Specific advanced lipoprotein profile was also carried out. RESULTS: Most of the patients had an abnormal CIMT (58%). MASLD (OR=5.05, CI 95%=1.71-14.92) and female sex (OR=3.32, CI 95%=1.03-10) were significantly associated with CIMT alterations. Dense LDL particles (with high cholesterol composition in general cohort (OR=3.62, 95% CI=1.07-12.19) and high triglycerides density in young subgroup (OR=6.25, 95% CI=1.04-50) but not total LDL cholesterol were associated with CIMT alterations. CONCLUSIONS: MASLD and female sex are associated with early atherosclerosis in IBD patients. Dense LDL particle in combination with vascular imaging findings should be evaluated as non-invasive tools in the management of cardiovascular risk in IBD patients.

Omega-3 docosahexaenoic acid and procyanidins inhibit cyclo-oxygenase activity and attenuate NF-κB activation through a p105/p50 regulatory mechanism in macrophage inflammation.

The inflammatory response has been implicated in the pathogenesis of many chronic diseases. Along these lines, the modulation of inflammation by consuming bioactive food compounds, such as ω-3 fatty acids or procyanidins, is a powerful tool to promote good health. In the present study, the administration of DHA (docosahexaenoic acid) and B1, B2 and C1 procyanidins, alone or in combination, prevented the inflammatory response induced by the LPS (lipopolysaccharide) endotoxin in human macrophages and brought them to the homoeostatic state. DHA and B1 were strong and selective negative regulators of cyclo-oxygenase 1 activity, with IC50 values of 13.5 µM and 8.0 µM respectively. Additionally, B2 and C1 were selective inhibitors of pro-inflammatory cyclo-oxygenase 2 activity, with IC50 values of 9.7 µM and 3.3 µM respectively. Moreover, DHA and procyanidins prevented the activation of the NF-κB (nuclear factor κB) cascade at both early and late stages with shared mechanisms. These included inhibiting IκBα (inhibitor of NF-κB α) phosphorylation, inducing the cytoplasmic retention of pro-inflammatory NF-κB proteins through p105 (NF-κB1) overexpression, favouring the nuclear translocation of the p50-p50 transcriptional repressor homodimer instead of the p50-p65 pro-inflammatory heterodimer, inhibiting binding of NF-κB DNA to κB sites and, finally, decreasing the release of NF-κB-regulated cytokines and prostaglandins. In conclusion, DHA and procyanidins are strong and selective inhibitors of cyclo-oxygenase activity and NF-κB activation through a p105/p50-dependent regulatory mechanism.

Biomarkers of stable and decompensated phases of heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a disorder related to patient comorbidities and aging. Whether mitochondrial dysfunction is present during HFpEF decompensation versus the stable phase is largely unknown. The aim of the present study was to identify mitochondrial and cell metabolism blood biomarkers in older patients with acute and stable HFpEF. METHODS: Peripheral blood biomarkers were investigated in a group of eight to 12 patients aged 80-96 years and diagnosed with HFpEF first when they were in decompensated phase and then at least three months later in stable phase. Their data were compared to two control groups with an equal number of participants and sex proportions. One group was age matched and the other included individuals aged between 22 and 44 years. RESULTS: Decompensated patients experienced an increased mitochondrial superoxide production and mitochondrial mass, lower mitochondrial DNA copy number and LDHB expression, and higher lactate level compared to the stable stage. The stable phase was characterized by a sharp reduction in formate level. Multivariate analysis indicated that formate, lactate, and histidine can distinguish both of the HFpEF phases. Many of these parameters, including LDHB, lactate, formate, and mitochondrial mass, followed an age-related pattern, with acute HFpEF at its apex or nadir, suggesting that it represents an exacerbation of an aging-related process. CONCLUSIONS: We identified distinct blood biomarkers of chronic and decompensated HFpEF phases. The data underlined the relationship between HFpEF and aging. These findings could be used to monitor patients and might be therapeutically targeted.

Different profiles of lipoprotein particles associate various degrees of cardiac involvement in adolescents with morbid obesity.

Introduction: Dyslipidemia secondary to obesity is a risk factor related to cardiovascular disease events, however a pathological conventional lipid profile (CLP) is infrequently found in obese children. The objective is to evaluate the advanced lipoprotein testing (ALT) and its relationship with cardiac changes, metabolic syndrome (MS) and inflammatory markers in a population of morbidly obese adolescents with normal CLP and without type 2 diabetes mellitus, the most common scenario in obese adolescents. Methods: Prospective case-control research of 42 morbidly obese adolescents and 25 normal-weight adolescents, whose left ventricle (LV) morphology and function had been assessed. The ALT was obtained by proton nuclear magnetic resonance spectroscopy, and the results were compared according to the degree of cardiac involvement - normal heart, mild LV changes, and severe LV changes (specifically LV remodeling and systolic dysfunction) - and related to inflammation markers [highly-sensitive C-reactive protein and glycoprotein A (GlycA)] and insulin-resistance [homeostatic model assessment for insulin-resistance (HOMA-IR)]. A second analysis was performed to compare our results with the predominant ALT when only body mass index and metabolic syndrome criteria were considered. Results: The three cardiac involvement groups showed significant increases in HOMA-IR, inflammatory markers and ALT ratio LDL-P/HDL-P (40.0 vs. 43.9 vs. 47.1, p 0.012). When only cardiac change groups were considered, differences in small LDL-P (565.0 vs. 625.1 nmol/L, p 0.070), VLDL size and GlycA demonstrated better utility than just traditional risk factors to predict which subjects could present severe LV changes [AUC: 0.79 (95% CI: 0.54-1)]. In the second analysis, an atherosclerotic ALT was detected in morbidly obese subjects, characterized by a significant increase in large VLDL-P, small LDL-P, ratio LDL-P/HDL-P and ratio HDL-TG/HDL-C. Subjects with criteria for MS presented overall worse ALT (specially in triglyceride-enriched particles) and remnant cholesterol values. Conclusions: ALT parameters and GlycA appear to be more reliable indicators of cardiac change severity than traditional CV risk factors. Particularly, the overage of LDL-P compared to HDL-P and the increase in small LDL-P with cholesterol-depleted LDL particles appear to be the key ALT's parameters involved in LV changes. Morbidly obese adolescents show an atherosclerotic ALT and those with MS present worse ALT values.

Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease.

INTRODUCTION: The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. METHODS: Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. RESULTS: Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. CONCLUSIONS: Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter.

Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients.

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10-4) and small HDL particles (p=6.0x10-5) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10-3) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10-3, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.

Relationship Between Fatty Acid Binding Protein 4 and Liver Fat in Individuals at Increased Cardiometabolic Risk.

Background: Liver steatosis is considered the onset of the non-alcoholic fatty liver disease (NAFLD), a major public health challenge. Nevertheless, NAFLD detection and diagnosis remain a difficult task. Fatty acid binding protein 4 (FABP4) has been proposed as potential biomarker for the ectopic fat accumulation in non-adipose tissues, although its role reflecting liver steatosis in metabolic patients is not fully explored. The aim of this study was to assess the relationship between FABP4 and the fatty liver index (FLI) in metabolic patients and to evaluate its potential role in the fatty liver disease. Methods: A cross-sectional study involving 389 participants at increased cardiometabolic risk was performed. FLI was calculated in order to assess liver fatty disease and a FLI ≥ 60 was considered to define liver steatosis. The serum FABP4 levels were assessed by using a sandwich enzyme-linked immunosorbent assay. Multivariable regression models were used to examine the associations of FABP4 with fatty liver after adjusting for demographic and clinical characteristics. Results: Both, FLI and serum FABP4 levels were upregulated in diabetic, obese, and metabolic syndrome patients. Serum FABP4 levels were higher in individuals with liver steatosis. Serum FABP4 were robustly associated with FLI in metabolic patients in both linear and logistic regression analyses. Conclusion: Our findings show that the serum FABP4 is associated to liver steatosis in metabolic patients.

Altered Serum Metabolic Profile Assessed by Advanced 1H-NMR in Breast Cancer Patients.

BACKGROUND: Altered lipid metabolism has been described in some types of cancer. To analyse in depth the metabolic modifications in breast cancer patients, advanced 1H-nuclear magnetic resonance was performed in these patients. The main objective of this paper was to define a specific lipidomic signature for these cancer patients. MATERIALS AND METHODS: Serum from 240 women (171 breast cancer patients and 69 control women) were studied and analysed by nuclear magnetic resonance. RESULTS: Triglyceride-enriched particles, specifically very low-density lipoprotein triglycerides, intermediate-density lipoprotein triglycerides, low-density lipoprotein triglycerides, and high-density lipoprotein triglycerides, were positively associated with breast cancer. Moreover, alanine, tyrosine, and branched amino acids were also associated with increased risk of breast cancer. CONCLUSIONS: Breast cancer patients showed a modified metabolome, giving a very interesting tool to draw different radar charts between control women and breast cancer patients. To our knowledge, this is the first time that advanced nuclear magnetic resonance profiling has been used to identify relevant and specifically altered lipid or amino acid metabolites in BC serum samples. The altered metabolic signature could be analysed for early and reliable BC patient diagnosis and prognosis.

Bicuspid Aortic Valve and Endothelial Dysfunction: Current Evidence and Potential Therapeutic Targets.

Bicuspid aortic valve (BAV), the most frequent congenital heart malformation, is characterized by the presence of a two-leaflet aortic valve instead of a three-leaflet one. BAV disease progression is associated with valvular dysfunction (in the form of stenosis or regurgitation) and aortopathy, which can lead to aneurysm and aortic dissection. This morphological abnormality modifies valve dynamics and promotes eccentric blood flow, which gives rise to alterations of the flow pattern and wall shear stress (WSS) of the ascending aorta. Recently, evidence of endothelial dysfunction (ED) in BAV disease has emerged. Different studies have addressed a reduced endothelial functionality by analyzing various molecular biomarkers and cellular parameters in BAV patients. Some authors have found impaired functionality of circulating endothelial progenitors in these patients, associating it with valvular dysfunction and aortic dilation. Others focused on systemic endothelial function by measuring artery flow-mediated dilation (FMD), showing a reduced FMD in BAV individuals. Novel biomarkers like increased endothelial microparticles (EMP), which are related to ED, have also been discovered in BAV patients. Finally, latest studies indicate that in BAV, endothelial-to-mesenchymal transition (EndoMT) may also be de-regulated, which could be caused by genetic, hemodynamic alterations, or both. Different hypothesis about the pathology of ED in BAV are nowadays being debated. Some authors blamed this impaired functionality just on genetic abnormalities, which could lead to a pathological aorta. Nevertheless, thanks to the development of new and high-resolution imaging techniques like 4D flow MRI, hemodynamics has gained great attention. Based on latest studies, alterations in blood flow seem to cause proper modification of the endothelial cells (ECs) function and morphology. It also seems to be associated with aortic dilation and decreased vasodilators expression, like nitric oxide (NO). Although nowadays ED in BAV has been reported by many, it is not clear which its main cause may be. Comprehending the pathways that promote ED and its relevance in BAV could help further understand and maybe prevent the serious consequences of this disease. This review will discuss the ED present in BAV, focusing on the latest evidence, biomarkers for ED and potential therapeutic targets (Figure 1).

Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity.

BACKGROUND: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV. METHODS: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism. RESULTS: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve. DISCUSSION: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.

Plasma glucose, triglycerides, VLDL, leptin and resistin levels as potential biomarkers for myocardial fat in mice. / Niveles plasmáticos de glucosa, triglicéridos, VLDL, leptina y resistina como potenciales biomarcadores de la grasa miocárdica en ratones.

INTRODUCTION: The increase in myocardial fat has been proposed as one of the main precursors of myocardial dysfunction due to diabetic aetiology, independently of coronary artery disease. However, biomarkers reflecting the myocardial fat content for the clinical detection of this pathology are currently lacking. METHODS: Correlations between cardiac triglyceride content and plasma levels of major altered molecules during diabetes and cardiac mRNA levels of genes involved in cardiac metabolism (Cd36 and Pdk4) have been explored in a murine model of insulin resistance induced by a high-fat diet. RESULTS: In insulin-resistant mice, the fatty diet increased myocardial triglyceride levels, compared to control animals fed with a standard diet. The content of cardiac triglycerides was directly associated with plasma levels of glucose, triglycerides, VLDL, resistin and leptin. In addition, an inverse correlation was observed between the content of cardiac triglycerides and the cardiac mRNA levels of Cd36 and Pdk4. CONCLUSIONS: Our data reveal that the cardiac triglyceride content is associated with altered plasma biochemical profile and reprogramming of gene expression aimed to mitigate the impact of ectopic lipid accumulation in the myocardium.

Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms.

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography-mass spectrometry (LC-MS) and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC-MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI-MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of ß-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.

Glycoprotein Profile Assessed by 1H-NMR as a Global Inflammation Marker in Patients with HIV Infection. A Prospective Study.

Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/µL. Patients with fewer than 200 cells/µL were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA); and N-acetylneuraminic acid signal (GlycB) associated with the sugar-protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with < 200 CD4+ T-cell/µL (Glyc A: 1040(917.9-1199.1) vs. 950.4(845.5-1050.9), p < 0.001, and Glyc B: 521(440.3-610.3) vs. 468.6(417.9-507.0) µ mol/L, p < 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.