Publications by authors named "María G Barderas"

93 Publications

TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension.

Antioxidants (Basel) 2021 Jul 9;10(7). Epub 2021 Jul 9.

Immunology Department, IIS-Fundación Jiménez Díaz-UAM, 28040 Madrid, Spain.

Moderately increased albuminuria, defined by an albumin to creatinine ratio (ACR) > 30 mg/g, is an indicator of subclinical organ damage associated with a higher risk of cardiovascular and renal disease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecular changes underlying early development are unclear. To decipher subjacent mechanisms, we stratified the normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin-angiotensin system (RAS) suppression with ACR values in the normoalbuminuria range were included and classified as control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10-30 mg/g). Target metabolomic analysis was carried out by liquid chromatography and mass spectrometry to investigate the role of the cardiorenal risk urinary metabolites previously identified. Besides this, urinary free fatty acids (FFAs), fatty acid binding protein 1 (FABP1) and nephrin were analyzed by colorimetric and ELISA assays. A Mann-Whitney test was applied, ROC curves were calculated and Spearman correlation analysis was carried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAs and FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycle and fatty acids β-oxidation. We showed here how cardiorenal metabolites associate with albuminuria, already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggesting increased β-oxidation to potentially counteract fatty acids overload in the HN range.
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http://dx.doi.org/10.3390/antiox10071100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301016PMC
July 2021

Subclinical Liver Disease is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.

J Invest Dermatol 2021 Jul 19. Epub 2021 Jul 19.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n=76 psoriasis participants and 76 controls), non-alcoholic fatty liver disease (NAFLD), assessed by the sonographic hepatorenal index (SHRI), was more prevalent in psoriasis than controls (61% vs 45%; p=.04). Psoriasis participants with NAFLD had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than psoriasis without NAFLD (61% vs 23%; p=.006) and controls with NAFLD (61% vs 32%; p<.05). SHRI was a determinant of subclinical atherosclerosis in psoriasis (OR, 3.5; p=.01). In the United States cohort, (n=162 psoriasis participants who underwent positron emission tomography and coronary CT angiography), those with high hepatic F-FDG uptake had higher noncalcified (1.3 (0.49 mm) vs 1.0 (0.40 mm)), fibrofatty (0.23 (0.15 mm) vs 0.11 (0.087 mm)), and lipid rich necrotic core (4.3 (2.3 mm) vs 3.0 (1.7 mm)) coronary burden (all p<.001,). Hepatic F-FDG uptake associated with noncalcified (β=0.28; p<.001), fibrofatty (β=0.49; p<.001) and lipid rich necrotic core (β=0.28; p=.003) burden. These results demonstrate the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2021.05.034DOI Listing
July 2021

Early renal and vascular damage within the normoalbuminuria condition.

J Hypertens 2021 Jul 13. Epub 2021 Jul 13.

Immunoallergy and Proteomics Laboratory, Department of Immunology, IIS-Fundación Jiménez Díaz, UAM Laboratory of Cardiovascular Proteomics, CNIC CIBER de Enfermedades Cardiovasculares (CIBERCV) Pathology Department, Fundación Jiménez Díaz, UAM Department of Allergy and Immunology, IIS-Fundación Jiménez Díaz, UAM Red de asma, reacciones adversas y alérgicas (ARADyAL) Faculty of Medicine and Biomedicine, Alfonso X El Sabio University Department of Cardiac Surgery, Fundación Jiménez Díaz, UAM Cardiorenal Translational Laboratory, Hospital Universitario 12 de Octubre, Madrid Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos SESCAM, Toledo Hypertension Unit, Hospital Universitario 12 de Octubre Red de Investigación Renal (REDINREN), Madrid, Spain Institute for Tumor Immunology, Philipps University of Marburg, Marburg, Germany.

Objective: A continuous association between albuminuria and cardiorenal risk exists further below moderately increased albuminuria ranges. If only based in albumin to creatinine ratio (ACR) higher than 30 mg/g, a significant percentage of individuals may be out of the scope for therapeutic management. Despite epidemiological outcomes, the identification of biochemical changes linked to early albuminuria is underexplored, and normoalbuminuric individuals are usually considered at no risk in clinical practice. Here, we aimed to identify early molecular alterations behind albuminuria development.

Methods: Hypertensive patients under renin-angiotensin system (RAS) suppression were classified as control, (ACR < 10 mg/g) or high-normal (ACR = 10-30 mg/g). Urinary protein alterations were quantified and confirmed by untargeted and targeted mass spectrometry. Coordinated protein responses with biological significance in albuminuria development were investigated. Immunohistochemistry assays were performed in human kidney and arterial tissue to in situ evaluate the associated damage.

Results: A total of 2663 identified proteins reflect inflammation, immune response, ion transport and lipids metabolism (P value ≤ 0.01). A1AT, VTDB and KNG1 varied in high-normal individuals (P value < 0.05), correlated with ACR and associated with the high-normal condition (odds ratio of 20.76, 6.00 and 7.04 were found, respectively (P value < 0.001)). After 12 months, protein variations persist and aggravate in progressors to moderately increased albuminuria. At tissue level, differential protein expression was found in kidney from individuals with moderately increased albuminuria and atherosclerotic aortas for the three proteins, confirming their capacity to reflect subclinical organ damage.

Conclusion: Early renal and vascular damage is molecularly evidenced within the normoalbuminuria condition.
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http://dx.doi.org/10.1097/HJH.0000000000002936DOI Listing
July 2021

Diabetes Mellitus and Its Implications in Aortic Stenosis Patients.

Int J Mol Sci 2021 Jun 9;22(12). Epub 2021 Jun 9.

Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos (HNP), SESCAM, 45071 Toledo, Spain.

Aortic stenosis (AS) and diabetes mellitus (DM) are both progressive diseases that if left untreated, result in significant morbidity and mortality. Several studies revealed that the prevalence of DM is substantially higher in patients with AS and, thus, the progression from mild to severe AS is greater in those patients with DM. DM and common comorbidities associated with both diseases, DM and AS, increase patient management complexity and make aortic valve replacement the only effective treatment. For that reason, a better understanding of the pathogenesis underlying both these diseases and the relationships between them is necessary to design more appropriate preventive and therapeutic approaches. In this review, we provided an overview of the main aspects of the relationship between AS and DM, including common comorbidities and risk factors. We also discuss the established treatments/therapies in patients with AS and DM.
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http://dx.doi.org/10.3390/ijms22126212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227301PMC
June 2021

Cardiovascular Risk Stratification Based on Oxidative Stress for Early Detection of Pathology.

Antioxid Redox Signal 2021 Sep 5;35(8):602-617. Epub 2021 Jul 5.

Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain.

Current cardiovascular (CV) risk prediction algorithms are able to quantify the individual risk of CV disease. However, CV risk in young adults is underestimated due to the high dependency of age in biomarker-based algorithms. Because oxidative stress is associated with CV disease, we sought to examine CV risk stratification in young adults based on oxidative stress to approach the discovery of new markers for early detection of pathology. Young adults were stratified into (i) healthy controls, (ii) subjects with CV risk factors, and (iii) patients with a reported CV event. Plasma samples were analyzed using FASILOX, a novel approach to interrogate the dynamic thiol redox proteome. We also analyzed irreversible oxidation by targeted searches using the Uniprot database. Irreversible oxidation of cysteine (Cys) residues was greater in patients with reported CV events than in healthy subjects. These results also indicate that oxidation is progressive. Moreover, we found that glutathione reductase and glutaredoxin 1 proteins are differentially expressed between groups and are proteins involved in antioxidant response, which is in line with the impaired redox homeostasis in CV disease. This study, for the first time, describes the oxidative stress (reversible and irreversible Cys oxidation) implication in human plasma according to CV risk stratification. The identification of redox targets and the quantification of protein and oxidative changes might help to better understand the role of oxidative stress in CV disease, and aid stratification for CV events beyond traditional prognostic and diagnostic markers. . 35, 602-617.
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http://dx.doi.org/10.1089/ars.2020.8254DOI Listing
September 2021

Impact of Biological Agents on Imaging and Biomarkers of Cardiovascular Disease in Patients with Psoriasis: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

J Invest Dermatol 2021 Apr 21. Epub 2021 Apr 21.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Background: The effect of biologics on the risk for cardiovascular disease in patients with psoriasis is still unclear despite their widespread use.

Objective: The objective of this study was to examine the impact of licensed biological therapies on imaging and biomarkers of cardiovascular disease risk in patients with psoriasis by a systematic review and meta-analysis of placebo-controlled trials.

Methods: A comprehensive search of studies published before 1 June 2020 was performed in Medline-Ovid, EMBASE, and CENTRAL using a predefined strategy to identify relevant articles.

Results: Five studies were included for the final examination, and two studies were included in the meta-analysis. We did not find a significant reduction in aortic vascular inflammation in patients treated with adalimumab compared with those who received placebo at weeks 12-16. There was no beneficial effect on imaging biomarkers (aortic vascular inflammation or flow-mediated dilatation) of cardiovascular disease risk in patients exposed to biological therapies (adalimumab and secukinumab) compared with those exposed to placebo, except for ustekinumab showing a reduction in aortic vascular inflammation at week 12 but not at week 52 after the open-label extension period. The strongest reduction in blood-based cardiometabolic risk biomarkers was observed with adalimumab (CRP, TNF-α, IL-6, and GlycA) and phototherapy (CRP and IL-6) compared with that observed with placebo.

Conclusions: Randomized controlled trials show that ustekinumab reduces aortic vascular inflammation and that TNF-α inhibitors and phototherapy reduce CRP and IL-6. These surrogate marker findings require randomized controlled trials evaluating cardiovascular events to inform clinical practice.
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http://dx.doi.org/10.1016/j.jid.2021.03.024DOI Listing
April 2021

Underperformance of clinical risk scores in identifying imaging-based high cardiovascular risk in psoriasis: results from two observational cohorts.

Eur J Prev Cardiol 2020 Nov 9. Epub 2020 Nov 9.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Clinical Research Center, Room 5-5140, Bethesda, MD 20892, USA.

Aims: We aimed to evaluate whether traditional risk scores [short-term, 'psoriasis-modified' (multiplied by 1.5) and lifetime] were able to capture high cardiovascular disease (CVD) risk as defined by the presence of atherosclerotic plaques in coronary, femoral, or carotid arteries in psoriasis.

Methods And Results: We used two prospectives obseravational cohorts. European cohort: femoral and carotid atherosclerotic plaques were evaluated by ultrasound in 73 psoriasis patients. Lifetime CVD risk (LTCVR) was evaluated with QRISK-LT; short-term CVD risk was evaluated with SCORE and psoriasis-modified SCORE. American cohort: 165 patients underwent coronary computed tomography angiography to assess presence of coronary plaques. LTCVR was evaluated with atherosclerotic cardiovascular disease (ASCVD-LT) lifetime; short-term CVD risk was evaluated with ASCVD and psoriasis-modified ASCVD. European cohort: subclinical atherosclerosis was present in 51% of patients. QRISK-LT identified 64% of patients with atherosclerosis missing a high proportion (35%) with atheroma plaque (P < 0.05). The percentage of patients with atherosclerosis identified by QRISK-LT was significantly higher than those detected by SCORE (0%) and modified SCORE (10%). American cohort: subclinical atherosclerosis was present in 54% of patients. ASCVD-LT captured 54% of patients with coronary plaques missing a high proportion (46%) with coronary plaque (P < 0.05). The percentage of patients with atheroma plaques detected with ASCVD and modified ASCVD were only 20% and 45%, respectively.

Conclusions: Application of lifetime, short-term and 'psoriasis-modified' risk scores did not accurately capture psoriasis patients at high CVD risk.
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http://dx.doi.org/10.1093/eurjpc/zwaa033DOI Listing
November 2020

Analysis of Global Oxidative Status Using Multimarker Scores Reveals a Specific Association Between Renal Dysfunction and Diuretic Therapy in Older Adults.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1198-1205

Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.

Aging and chronic kidney disease (CKD) are important interrelated cardiovascular risk (CVR) factors linked to oxidative stress, but this relationship has not been well studied in older adults. We assessed the global oxidative status in an older population with normal to severely impaired renal function. We determined the oxidative status of 93 older adults (mean age 85 years) using multimarker scores. OxyScore was computed as index of systemic oxidative damage by analyzing carbonyl groups, oxidized low-density lipoprotein, 8-hydroxy-2'-deoxyguanosine, and xanthine oxidase activity. AntioxyScore was computed as index of antioxidant defense by analyzing catalase and superoxide dismutase (SOD) activity and total antioxidant capacity. OxyScore and AntioxyScore were higher in subjects with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 than in peers with eGFR >60 mL/min/1.73 m2, with protein carbonyls, catalase, and SOD activity as major drivers. Older adults with a recent cardiovascular event had similar OxyScore and AntioxyScore as peers with eGFR >60 mL/min/1.73 m2. Multivariate linear regression analysis revealed that both indices were associated with decreased eGFR independently of traditional CVR factors. Interestingly, AntioxyScore was also associated with diuretic treatment, and a more pronounced increase was seen in subjects receiving combination therapy. The associations of AntioxyScore with diuretic treatment and eGFR were mutually independent. In conclusion, eGFR is the major contributor to the imbalance in oxidative stress in this older population. Given the association between oxidative stress, CKD, and CVR, the inclusion of renal function parameters in CVR estimators for older populations, such as the SCORE-OP, might improve their modest performance.
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http://dx.doi.org/10.1093/gerona/glab012DOI Listing
June 2021

Oxidized Low-Density Lipoprotein Associates with Ventricular Stress in Young Adults and Triggers Intracellular Ca Alterations in Adult Ventricular Cardiomyocytes.

Antioxidants (Basel) 2020 Dec 1;9(12). Epub 2020 Dec 1.

Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.

Oxidized low-density lipoprotein (oxLDL) is associated with cardiac damage and causes injury to multiple cell types. We aimed to investigate the role of oxLDL in ventricular stress. We first examined the association between circulating oxLDL and N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stress, in young subjects (30-50 years) with or without stable coronary artery disease (SCAD). oxLDL and NT-proBNP were significantly higher in subjects at high cardiovascular risk (CVR) than in subjects at low CVR and were associated independently of traditional CVR factors and C-reactive protein. Furthermore, the levels of oxLDL and NT-proBNP were significantly lower in subjects with SCAD than in peers at high CVR. To determine the intracellular mechanisms involved in the cardiac effects of oxLDL, we analyzed the in vitro effect of oxLDL on intracellular Ca handling in adult rat ventricular cardiomyocytes using confocal microscopy. Acute challenge of adult ventricular cardiomyocytes to oxLDL reduced systolic Ca transients and sarcoplasmic reticulum Ca load. Moreover, diastolic spontaneous Ca leak increased significantly after acute exposure to oxLDL. Thus, we demonstrate that oxLDL associates with NT-proBNP in young subjects, and can directly induce Ca mishandling in adult ventricular cardiomyoyctes, predisposing cardiomyocytes to cardiac dysfunction and arrhythmogenicity.
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http://dx.doi.org/10.3390/antiox9121213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761043PMC
December 2020

Effects of Growth Hormone Treatment and Rehabilitation in Incomplete Chronic Traumatic Spinal Cord Injury: Insight from Proteome Analysis.

J Pers Med 2020 Oct 21;10(4). Epub 2020 Oct 21.

Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos (HNP), SESCAM, 45071 Toledo, Spain.

Despite promising advances in the medical management of spinal cord injury (SCI), there is still no available effective therapy to repair the neurological damage in patients who experience this life-transforming condition. Recently, we performed a phase II/III placebo-controlled randomized trial of safety and efficacy of growth hormone (GH) treatment in incomplete chronic traumatic spinal cord injury. The main findings were that the combined treatment of GH plus rehabilitation treatment is feasible and safe, and that GH but not placebo slightly improves the SCI individual motor score. Moreover, we found that an intensive and long-lasting rehabilitation program per se increases the functional outcome of SCI individuals. To understand the possible mechanisms of the improvement due to GH treatment (motor score) and due to rehabilitation (functional outcome), we used a proteomic approach. Here, we used a multiple proteomic strategy to search for recovery biomarkers in blood plasma with the potential to predict response to somatropin treatment and to delayed intensive rehabilitation. Forty-six patients were recruited and followed for a minimum period of 1 year. Patients were classified into two groups based on their treatment: recombinant somatropin (0.4 mg) or placebo. Both groups received rehabilitation treatment. Our strategy allowed us to perform one of the deepest plasma proteomic analyses thus far, which revealed two proteomic signatures with predictive value: (i) response to recombinant somatropin treatment and (ii) response to rehabilitation. The proteins implicated in these signatures are related to homeostasis, inflammation, and coagulation functions. These findings open novel possibilities to assess and therapeutically manage patients with SCI, which could have a positive impact on their clinical response.
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http://dx.doi.org/10.3390/jpm10040183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720149PMC
October 2020

Why Does COVID-19 Affect Patients with Spinal Cord Injury Milder? A Case-Control Study: Results from Two Observational Cohorts.

J Pers Med 2020 Oct 21;10(4). Epub 2020 Oct 21.

Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos (HNP), SESCAM, 45071 Toledo, Spain.

The COVID-19 pandemic represents an unprecedented global challenge in this century. COVID-19 is a viral respiratory infection, yet the clinical characteristics of this infection differ in spinal cord injury patients from those observed in the general population. Cough and asthenia are the most frequent symptoms in this population. Moreover, infected spinal cord injury patients rarely present complications that require admission to an Intensive Care Unit, in contrast to the general population. Thus, there is a clear need to understand how COVID-19 affects spinal cord injury patients from a molecular perspective. Here, we employed an -omics strategy in order to identify variations in protein abundance in spinal cord injury patients with and without COVID-19. After a quantitative differential analysis using isobaric tags and mass spectrometry and a verification phase, we have found differences mainly related to coagulation and platelet activation. Our results suggest a key role of heparin in the response of spinal cord injury patients to COVID-19 infection, showing a significant correlation between these proteins and heparin dose. Although the number of patients is limited, these data may shed light on new therapeutic options to improve the management these patients and, possibly, those of the general population as well.
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http://dx.doi.org/10.3390/jpm10040182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712183PMC
October 2020

Urinary metabolic signatures reflect cardiovascular risk in the young, middle-aged, and elderly populations.

J Mol Med (Berl) 2020 11 11;98(11):1603-1613. Epub 2020 Sep 11.

Department of Immunology, Immunoallergy and Proteomics Laboratory, IIS-Fundación Jiménez Díaz, UAM, Avenida Reyes Católicos 2, 28040, Madrid, Spain.

The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30-50 years (cohort I, young), 50-70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention. KEY MESSAGES: • Cardiovascular risk in the young and elderly is underestimated. • The urinary metabolome reflects cardiovascular risk across all age groups. • Six metabolites constitute a metabolic signature of cardiovascular risk in young adults. • Middle-aged and elderly adults share a cardiovascular risk metabolic signature. • TMAO and glucuronate levels reflect cardiovascular risk across all age groups.
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http://dx.doi.org/10.1007/s00109-020-01976-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591416PMC
November 2020

Patient Management in Aortic Stenosis: Towards Precision Medicine Through Protein Analysis, Imaging and Diagnostic Tests.

J Clin Med 2020 Jul 28;9(8). Epub 2020 Jul 28.

Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos (HNP), SESCAM, 45071 Toledo, Spain.

Aortic stenosis is the most frequent valvular disease in developed countries. It progresses from mild fibrocalcific leaflet changes to a more severe leaflet calcification at the end stages of the disease. Unfortunately, symptoms of aortic stenosis are unspecific and only appear when it is too late, complicating patients' management. The global impact of aortic stenosis is increasing due to the growing elderly population. The disease supposes a great challenge because of the multiple comorbidities of these patients. Nowadays, the only effective treatment is valve replacement, which has a high cost in both social and economic terms. For that reason, it is crucial to find potential diagnostic, prognostic and therapeutic indicators that could help us to detect this disease in its earliest stages. In this article, we comprehensively review several key observations and translational studies related to protein markers that are promising for being implemented in the clinical field as well as a discussion about the role of precision medicine in aortic stenosis.
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http://dx.doi.org/10.3390/jcm9082421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463596PMC
July 2020

Prediction of the early response to spironolactone in resistant hypertension by the combination of matrix metalloproteinase-9 activity and arterial stiffness parameters.

Eur Heart J Cardiovasc Pharmacother 2020 Jul 14. Epub 2020 Jul 14.

Cardiorenal Translational Laboratory, Institute of Research i + 12, Hospital Universitario 12 de Octubre, Madrid, Spain.

Aims: The aim of present study was to determine whether arterial stiffness assessed with the biochemical parameter active matrix metalloproteinase (MMP)-9 and the clinical parameters pulse pressure (PP) and pulse wave velocity predicts the response to spironolactone in resistant hypertension (RH).

Methods And Results: Ambulatory blood pressure (BP) and active MMP-9 (measured by zymography and ELISA) were measured at baseline, and patients were classified as having pseudo-RH or RH. Patients with RH received spironolactone and the response was determined after 8 weeks by ambulatory BP monitoring: those who achieved BP goals were considered controlled (CRH) and those who did not were considered uncontrolled (UCRH). Plasma active MMP-9 was significantly higher in patients with RH than with pseudo-RH, and correlated with 24-hour systolic BP and PP. Receiver operating characteristic analysis indicated that active MMP-9 could predict the response to spironolactone, and its combination with 24-hour PP and pulse wave velocity significantly improved this prediction. Moreover, plasma of patients with UCRH induced the MMP-9 expression pathway.

Conclusion: We propose active MMP-9 as a useful biomarker to identify patients with RH who will not respond to spironolactone. Combining MMP-9 activity with classical arterial stiffness parameters improves the prediction of the clinical response to spironolactone and might contribute to guide the most appropriate therapeutic decisions for patients with RH.
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http://dx.doi.org/10.1093/ehjcvp/pvaa086DOI Listing
July 2020

Novel molecular plasma signatures on cardiovascular disease can stratify patients throughout life.

J Proteomics 2020 06 8;222:103816. Epub 2020 May 8.

Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain. Electronic address:

Several models are available to calculate the risk of developing cardiovascular complications in mid-life. The estimation of lifetime risk in the long-term remains an unmet clinical need. We previously identified new molecular plasma signatures for cardiovascular risk stratification in a young population (30-50-years old). The aim of the present study was to determine if the specific signature found in young population changes with age. Proteomic analysis was performed in plasma samples obtained from different age groups, middle-age (50-70-years old, n = 63) and elderly (>70-years old, n = 61), which, in turn were classified into 3 subgroups according to cardiovascular risk. Our previous results in a young population clearly showed two different proteomic signatures. Building on these findings, targeted-mass spectrometry and turbidimetry analyses were used to test these signatures in middle-age and elderly populations. This strategy identified three common proteomic signatures between young and adult patients related to cardiovascular stratification, organ damage and risk prediction. Furthermore, receiver operating characteristic analysis revealed the potential value of these novel markers for lifetime risk stratification. Our results provide new insight into altered molecular mechanisms in the pathogenesis of cardiovascular disease and, more importantly, identify novel protein panels that can stratify patients throughout life. SIGNIFICANCE: Our results revealed three common proteomic signatures between young and adult patients related to cardiovascular stratification, organ damage and risk prediction. The results obtained provide a deeper insight into the pathogenesis of CV diseases and allow the identification of novel protein panels to stratify patients according to CV risk throughout life. While current estimators calculate the risk of having a CV event considering age as the most important factor to CV disease, our results represent an alternative to traditional CV risk factors, allowing the stratification of CV risk regardless of the age. Using a combination of traditional markers and established algorithms with these findings as a future preventive strategy, could facilitate an adequate assessment of CV risk.
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http://dx.doi.org/10.1016/j.jprot.2020.103816DOI Listing
June 2020

Comprehensive Proteomic Profiling of Pressure Ulcers in Patients with Spinal Cord Injury Identifies a Specific Protein Pattern of Pathology.

Adv Wound Care (New Rochelle) 2020 05 19;9(5):277-294. Epub 2020 Mar 19.

Department of Vascular Physiopathology, National Hospital for Paraplegics (HNP), SESCAM, Toledo, Spain.

Severe pressure ulcers (PUs) do not respond to conservative wound therapy and need surgical repair. To better understand the pathogenesis and to advance on new therapeutic options, we focused on the proteomic analysis of PU, which offers substantial opportunities to identify significant changes in protein abundance during the course of PU formation in an unbiased manner. To better define the protein pattern of this pathology, we performed a proteomic approach in which we compare severe PU tissue from spinal cord injury (SCI) patients with control tissue from the same patients. We found 76 proteins with difference in abundance. Of these, 10 proteins were verified as proteins that define the pathology: antithrombin-III, alpha-1-antitrypsin, kininogen-1, alpha-2-macroglobulin, fibronectin, apolipoprotein A-I, collagen alpha-1 (XII) chain, haptoglobin, apolipoprotein B-100, and complement factor B. This is the first study to analyze differential abundance protein of PU tissue from SCI patients using high-throughput protein identification and quantification by tandem mass tags followed by liquid chromatography tandem mass spectrometry. Differential abundance proteins are mainly involved in tissue regeneration. These proteins might be considered as future therapeutic options to enhance the physiological response and permit cellular repair of damaged tissue.
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http://dx.doi.org/10.1089/wound.2019.0968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099418PMC
May 2020

Differential metabolic profile associated with the condition of normoalbuminuria in the hypertensive population.

Nefrologia (Engl Ed) 2020 Jul - Aug;40(4):440-445. Epub 2020 Mar 3.

Laboratorio de Inmunoalergia y Proteómica, Departamento de Inmunología, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, España; REDINREN. Electronic address:

Background And Aim: Albuminuria is an indicator of sub-clinical organ damage and a marker of cardiovascular risk and renal disease. A percentage of hypertensive patients develop albuminuria despite being under chronic suppression of the renin-angiotensin system (RAS). We previously identified urinary metabolites associated with the development of albuminuria. In this study, we searched for metabolic alterations which reflect different levels within the condition of normoalbuminuria.

Patients, Materials And Methods: Urine from 48 hypertensive patients under chronic RAS suppression was analysed. They were classified according to the albumin/creatinine ratio (ACR) into 3groups: Normoalbuminuria (<10mg/g); high-normal (10-30mg/g in men, or 20-40mg/g in women); and moderately high albuminuria (microalbuminuria, 30-200mg/g or 40-300mg/g, respectively). The metabolome was analysed by mass spectrometry and a correlation analysis was performed between altered metabolite levels and ACR.

Results: Oxaloacetate, 3-ureidopropionate, guanidoacetate and malate show significant variation between the normo and micro groups. Additionally, these metabolites are able to differentiate between patients in the normo and high-normal range. A significant correlation between metabolites and ACR was found. Observed variations point to alterations in the energy metabolism already in patients with albuminuria in the high-normal range.

Conclusions: The association between the molecular panel consisting of 3-ureidopropionate, oxaloacetate, malate and guanidoacetate and different levels of albuminuria is confirmed. A metabolic fingerprint was also identified showing variations within the condition of normoalbuminuria allowing an earlier molecular stratification of patients.
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http://dx.doi.org/10.1016/j.nefro.2019.10.007DOI Listing
September 2021

Plasma CD5L and non-invasive diagnosis of acute heart rejection.

J Heart Lung Transplant 2020 03 21;39(3):257-266. Epub 2019 Nov 21.

Myocardial Dysfunction and Cardiac Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain; CIBERCV, Madrid, Spain.

Background: Acute rejection is one of the most important direct contributors to mortality after heart transplantation. Advances in the development of novel non-invasive approaches for the early identification of allograft rejection are necessary. We conducted a non-targeted proteome characterization focused on identifying multiple plasmatic protein differences to evaluate their diagnostic accuracy for rejection episodes.

Methods: We included consecutive plasma samples from transplant recipients undergoing routine endomyocardial biopsies. A liquid chromatography-tandem mass spectrometry analysis using isobaric tags (tandem mass tag 10-plex) was performed and concentrations of CD5L were validated using a specific sandwich enzyme-linked immunosorbent assay.

Results: A total of 17 altered proteins were identified as potential markers for detecting heart transplant rejection, most involved in inflammation and immunity. CD5L, an apoptosis inhibitor expressed by macrophages, showed the best results in the proteomic analysis (n = 30). We confirm this finding in a larger patient cohort (n = 218), obtaining a great diagnostic capacity for clinically relevant rejection (≥Grade 2R: area under the curve = 0.892, p < 0.0001) and preserving the accuracy at mild rejection (Grade 1R: area under the curve = 0.774, p < 0.0001). CD5L was a strong independent predictor, with an odds ratio of 14.74 (p < 0.0001), for the presence of rejection.

Conclusions: Episodes of acute cardiac allograft rejection are related to significant changes in a key inhibitor of apoptosis in macrophages, CD5L. Because of its precision to detect acute cellular rejection, even at mild grade, we propose CD5L as a potential candidate to be included in the studies of molecule combination panel assays. This finding could contribute to improving the diagnostic and preventive methods for the surveillance of cardiac transplanted patients.
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http://dx.doi.org/10.1016/j.healun.2019.11.004DOI Listing
March 2020

Lifetime cardiovascular risk is associated with a multimarker score of systemic oxidative status in young adults independently of traditional risk factors.

Transl Res 2019 10 29;212:54-66. Epub 2019 Jun 29.

Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain; CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address:

Cardiovascular risk (CVR) tends to be estimated in the short-term, which underestimates lifetime (LT)-CVR of young subjects. We determined whether LT-CVR is associated with a multimarker score of oxidative status in young adults and whether this association is independent of traditional CVR factors. Seventy-two young adults were stratified into: (1) low or (2) high LT-CVR, and (3) stable coronary artery disease (SCAD). CVR was estimated with QRisk and atherosclerotic CV disease (ASCVD) risk estimators, or second manifestations of arterial disease (SMART). Risk score. oxidative damage was determined by measuring carbonyls, oxidized LDL (oxLDL), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and xanthine oxidase activity. Antioxidant defence was determined by total antioxidant capacity (TAC), catalase (CAT) activity and superoxide dismutase (SOD) activity. Multimarker scores of systemic oxidative damage (OxyScore) and antioxidant defence (AntioxyScore) were computed as standardized variables. Subjects with high LT-CVR had significantly higher levels of oxLDL, 8-OHdG, TAC, and CAT activity than subjects with low LT-CVR or with SCAD. QRisk and ASCVD estimators correlated positively with oxLDL, TAC, and CAT activity, while SMART Risk Score correlated with carbonyls and SOD activity. OxyScore and AntioxyScore were significantly higher in subjects with high LT-CVR than with low LT-CVR or with SCAD. OxyScore, but not AntioxyScore, was associated with LT-CVR independently of each traditional CVR factor. This study for the first time demonstrates a positive association between oxidative stress and the risk of first and recurrent CV events in young adults.
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http://dx.doi.org/10.1016/j.trsl.2019.06.002DOI Listing
October 2019

Frequency and Prognosis of Treated Hypertensive Patients According to Prior and New Blood Pressure Goals.

Hypertension 2019 07 28;74(1):130-136. Epub 2019 May 28.

Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/IdiPAZ and CIBERESP, Spain (L.M.R., J.d.l.C., J.R.B.).

United States and European guidelines have recommended new treatment goals for office blood pressure (BP). We examined 9784 hypertensives of the Spanish Ambulatory BP Monitoring (ABPM) registry with office BP treated to the prior goal (<140/90 mm Hg); and evaluated the frequency and all-cause mortality of 4 BP strata depending on whether or not they attained more conservative or new office BP goal (130-139/80-89 and <130/80 mm Hg, respectively) and whether or not BP was controlled according to ABPM criteria in the European and US guidelines (24-hour ambulatory BP <130/80 and <125/75 mm Hg, respectively). Whether achieving or not the new office BP goal, the total-mortality risk during a 5-year follow-up was only significantly higher than the reference (normal office BP and ABPM) when 24-hour ambulatory BP was above goal (hazard ratio from multivariable Cox models was in the range of 2.4-2.9; P<0.001). The frequency of patients achieving the new office BP goal was 34.4%, and the frequencies of those not achieving the ABPM goal were 31.6% and 53.7% using the 130/80 or the 125/75 ABPM goal, respectively. Mean office systolic BP was 129 mm Hg for patients not achieving the ABPM goal. In hypertensive patients controlled under prior office BP goal, the frequency of those achieving new office BP goal <130/80 was high, suggesting this goal can be attained. In addition, patients had a higher mortality risk only when ABPM was above goal despite having mean office systolic BP under control, a condition that was also common.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12921DOI Listing
July 2019

Urine Haptoglobin and Haptoglobin-Related Protein Predict Response to Spironolactone in Patients With Resistant Hypertension.

Hypertension 2019 04;73(4):794-802

From the Laboratory of Immunoallergy and Proteomics, Department of Immunology (M.M.-L., P.J.M., A.S.-H., G.A.-L.), IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain.

Resistant hypertension prevalence is progressively increasing, and prolonged exposure to suboptimal blood pressure control results in higher cardiovascular risk and end-organ damage. Among various antihypertensive agents, spironolactone seems the most effective choice to treat resistant hypertension once triple therapy including a diuretic fails. However success in blood pressure control is not guaranteed, adverse effects are not negligible, and no clinical tools are available to predict patient's response. Complementary to our previous study of resistant hypertension metabolism, here we investigated urinary proteome changes with potential capacity to predict response to spironolactone. Twenty-nine resistant hypertensives were included. A prospective study was conducted and basal urine was collected before spironolactone administration. Patients were classified in responders or nonresponders in terms of blood pressure control. Protein quantitation was performed by liquid chromatography-mass spectrometry; ELISA and target mass spectrometry analysis were performed for confirmation. Among 3310 identified proteins, HP (haptoglobin) and HPR (haptoglobin-related protein) showed the most significant variations, with increased levels in nonresponders compared with responders before drug administration (variation rate, 5.98 and 7.83, respectively). Protein-coordinated responses were also evaluated by functional enrichment analysis, finding oxidative stress, chronic inflammatory response, blood coagulation, complement activation, and regulation of focal adhesions as physiopathological mechanisms in resistant hypertension. In conclusion, protein changes able to predict patients' response to spironolactone in basal urine were here identified for the first time. These data, once further confirmed, will support clinical decisions on patients' management while contributing to optimize the rate of control of resistant hypertensives with spironolactone.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12242DOI Listing
April 2019

Identification of six cardiovascular risk biomarkers in the young population: A promising tool for early prevention.

Atherosclerosis 2019 03 14;282:67-74. Epub 2019 Jan 14.

Immunoallergy and Proteomics Laboratory, Department of Immunology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain; REDINREN, Madrid, Spain. Electronic address:

Background And Aims: The predictive value of traditional CV risk calculators is limited. Novel indicators of CVD progression are needed particularly in the young population. The main aim of this study was the identification of a molecular profile with added value to classical CV risk estimation.

Methods: Eighty-one subjects (30-50 years) were classified in 3 groups according to their CV risk: healthy subjects; individuals with CV risk factors; and those who had suffered a previous CV event. The urine proteome was quantitatively analyzed and significantly altered proteins were identified between patients' groups, either related to CV risk or established organ damage. Target-MS and ELISA were used for confirmation in independent patients' cohorts. Systems Biology Analysis (SBA) was carried out to identify functional categories behind CVD.

Results: 4309 proteins were identified, 75 of them differentially expressed. ADX, ECP, FETUB, GDF15, GUAD and NOTCH1 compose a fingerprint positively correlating with lifetime risk estimate (LTR QRISK). Best performance ROC curve was obtained when ECP, GDF15 and GUAD were combined (AUC = 0.96). SBA revealed oxidative stress response, dilated cardiomyopathy, signaling by Wnt and proteasome, as main functional processes related to CV risk.

Conclusions: A novel urinary protein signature is shown, which correlates with CV risk estimation in young individuals. Pending further confirmation, this six-protein-panel could help in CV risk assessment.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.01.003DOI Listing
March 2019

Association between renal dysfunction and metalloproteinase (MMP)-9 activity in hypertensive patients.

Nefrologia (Engl Ed) 2019 Mar - Apr;39(2):184-191. Epub 2018 Dec 1.

Laboratorio Traslacional Cardiorrenal, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, España; Unidad de Hipertensión, Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España. Electronic address:

Background And Objective: Matrix metalloproteinases (MMPs) are involved in deleterious tissue remodeling associated with target organ damage in renal disease. The aim of this study was to study the association between renal dysfunction and activity of the inflammatory metalloproteinase MMP-9 in hypertensive patients with mild-moderate chronic kidney disease (CKD).

Material And Methods: Plasmatic active MMP-9, total MMP-9, tissue inhibitor of MMP-9 (TIMP-1), MMP-9/TIMP-1 ratio and MMP-9-TIMP-1 interaction were analyzed in 37 hypertensive patients distributed by estimated glomerular filtration rate (eGFR) in 3 groups:>90, 90-60 y 60-30mL/min/1.73 m.

Results: Total MMP-9 was not different as eGFR declines. TIMP-1 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m (P<.01 versus>90mL/min/1.73 m). This relates to the significant decrease in the interaction between MMP-9-TIMP-1 observed in patients with eGFR 60-30mL/min/1.73 m (P<.01 versus>90mL/min/1.73 m). Despite the systemic elevation of TIMP-1, active MMP-9 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m (P<.05 and P<0.01 versus>90 and 90-60mL/min/1.73 m, respectively). TIMP-1, active MMP-9 and MMP-9-TIMP-1 interaction significantly correlate with the decline in renal function, which was not observed with total MMP-9.

Conclusions: The progression of CKD, even in stages where the decline of renal function is still moderate, is associated with an increase in MMP-9 activity, which could be considered as a potential therapeutic target.
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http://dx.doi.org/10.1016/j.nefro.2018.08.009DOI Listing
January 2020

Translational science in albuminuria: a new view of albuminuria under chronic RAS suppression.

Clin Sci (Lond) 2018 04 6;132(7):739-758. Epub 2018 Apr 6.

Cardiorenal Translational Laboratory, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain

The development of albuminuria during chronic renin-angiotensin system (RAS) suppression is a clinical entity that remains poorly recognized in the biomedical literature. It represents a clear increment in global cardiovascular (CV) and renal risk that cannot be counteracted by RAS suppression. Although not specifically considered, it is clear that this entity is present in most published and ongoing trials dealing with the different forms of CV and renal disease. In this review, we focus on the mechanisms promoting albuminuria, and the predictors and new markers of albuminuria, as well as the potential treatment options to counteract the excretion of albumin. The increase in risk that accompanies albuminuria supports the search for early markers and predictors that will allow practising physicians to assess and prevent the development of albuminuria in their patients.
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http://dx.doi.org/10.1042/CS20180097DOI Listing
April 2018

Potential role of new molecular plasma signatures on cardiovascular risk stratification in asymptomatic individuals.

Sci Rep 2018 03 19;8(1):4802. Epub 2018 Mar 19.

Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos (HNP), SESCAM, Toledo, Spain.

The evaluation of cardiovascular (CV) risk is based on equations derived from epidemiological data in individuals beyond the limits of middle age such as the Framingham and SCORE risk assessments. Lifetime Risk calculator (QRisk), estimates CV risk throughout a subjects' lifetime, allowing those. A more aggressive and earlier intervention to be identified and offered protection from the consequences of CV and renal disease. The search for molecular profiles in young people that allow a correct stratification of CV risk would be of great interest to adopt preventive therapeutic measures in individuals at high CV risk. To improve the selection of subjects susceptible to intervention with aged between 30-50 years, we have employed a multiple proteomic strategy to search for new markers of early CV disease or reported CV events and to evaluate their relationship with Lifetime Risk. Blood samples from 71 patients were classified into 3 groups according to their CV risk (healthy, with CV risk factors and with a previously reported CV event subjects) and they were analyzed using a high through quantitative proteomics approach. This strategy allowed three different proteomic signatures to be defined, two of which were related to CV stratification and the third one involved markers of organ damage.
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http://dx.doi.org/10.1038/s41598-018-23037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859270PMC
March 2018

Author Correction: Immune system deregulation in hypertensive patients chronically RAS suppressed developing albuminuria.

Sci Rep 2018 Mar 2;8(1):4154. Epub 2018 Mar 2.

Departament of Immunology, IIS-Fundacion JimenezDiaz, REDinREN, Madrid, Spain.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-22185-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834532PMC
March 2018

Progression of Renal Insufficiency in Patients with Essential Hypertension Treated with Renin Angiotensin Aldosterone System Blockers: An Electrocardiographic Correlation.

Diseases 2017 Dec 8;5(4). Epub 2017 Dec 8.

Hypertension Unit, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, 28220 Madrid, Spain.

Background: There is a frequent association between renal insufficiency and cardiovascular disease in patients with essential hypertension (HTN). The aim of this study was to analyze the relationship between ECG parameters and the progress of renal damage in patients with treated HTN.

Methods: 109 patients with HTN had their microalbuminuria monitored over a 3-year time frame. During the last 3 months of follow-up, an ECG was recorded. Patients were divided into 3 groups according to the deterioration of their renal function: normoalbuminuria during the study period (normo-normo; = 51); normoalbuminuria developing microalbuminuria (normo-micro; = 29); and microalbuminuria at baseline (micro-micro; = 29).

Results: There were no differences in presence of left ventricular hypertrophy between the 3 groups. RV6/RV5 >1 was observed more frequently as renal function declined ( = 0.025). The 12-lead QRS-complex voltage-duration product was significantly increased in patients without microalbuminuria at baseline who went on to develop microalbuminuria ( = 0.006). Patients who developed microalbuminuria during follow-up, with positive Cornell voltage criteria, showed a lesser degree of progression of microalbuminuria when compared with the rest of the subgroups ( = 0.044). Furthermore, patients with microalbuminuria at baseline treated with angiotensin receptor blockers and diuretics, and positive Cornell voltage criteria, showed a higher degree of microalbuminuria compared to those with negative Cornell voltage criteria ( = 0.016).

Conclusions: In patients with HTN, we identified some ECG parameters, which predict renal disease progression in patients with HTN, which may permit the identification of patients who are at risk of renal disease progression, despite optimal antihypertensive pharmacotherapy.
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http://dx.doi.org/10.3390/diseases5040033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750544PMC
December 2017

Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

Hypertension 2017 11 5;70(5):1049-1056. Epub 2017 Sep 5.

From the Department of Immunology, IIS-Fundacion Jimenez Diaz, REDinREN, Madrid, Spain (M.M.-L., P.J.M., F.V., G.A.-L.); Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos SESCAM, Toledo, Spain (M.B.-M., M.G.B.); Hypertension Unit, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain (G.R.-H., J.C.P., J.S., L.M.R.); Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, United Kingdom (F.d.l.C.); Department of Biochemistry and Molecular Biology I, Universidad Complutense, Madrid, Spain (F.V.); and Universidad Europea, Madrid, Spain (L.M.R.).

Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered (<0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to μg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09819DOI Listing
November 2017

Immune system deregulation in hypertensive patients chronically RAS suppressed developing albuminuria.

Sci Rep 2017 08 21;7(1):8894. Epub 2017 Aug 21.

Departament of Immunology, IIS-Fundacion JimenezDiaz, REDinREN, Madrid, Spain.

Albuminuria development in hypertensive patients is an indicator of higher cardiovascular (CV) risk and renal damage. Chronic renin-angiotensin system (RAS) suppression facilitates blood pressure control but it does not prevent from albuminuria development. We pursued the identification of protein indicators in urine behind albuminuria development in hypertensive patients under RAS suppression. Urine was collected from 100 patients classified in three groups according to albuminuria development: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Quantitative analysis was performed in a first discovery cohort by isobaric labeling methodology. Alterations of proteins of interest were confirmed by target mass spectrometry analysis in an independent cohort. A total of 2416 proteins and 1223 functional categories (coordinated protein responses) were identified. Immune response, adhesion of immune and blood cells, and phagocytosis were found significantly altered in patients with albuminuria compared to normoalbuminuric individuals. The complement system C3 increases, while Annexin A1, CD44, S100A8 and S100A9 proteins showed significant diminishment in their urinary levels when albuminuria is present. This study reveals specific links between immune response and controlled hypertension in patients who develop albuminuria, pointing to potential protein targets for novel and future therapeutic interventions.
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http://dx.doi.org/10.1038/s41598-017-09042-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566220PMC
August 2017

Rapid, Automated, and Specific Immunoassay to Directly Measure Matrix Metalloproteinase-9-Tissue Inhibitor of Metalloproteinase-1 Interactions in Human Plasma Using AlphaLISA Technology: A New Alternative to Classical ELISA.

Front Immunol 2017 24;8:853. Epub 2017 Jul 24.

Laboratorio de Hipertensión y Riesgo Cardiovascular y Unidad de Hipertensión, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.

The protocol describes a novel, rapid, and no-wash one-step immunoassay for highly sensitive and direct detection of the complexes between matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) based on AlphaLISA technology. We describe two procedures: (i) one approach is used to analyze MMP-9-TIMP-1 interactions using recombinant human MMP-9 with its corresponding recombinant human TIMP-1 inhibitor and (ii) the second approach is used to analyze native or endogenous MMP-9-TIMP-1 protein interactions in samples of human plasma. Evaluating native MMP-9-TIMP-1 complexes using this approach avoids the use of indirect calculations of the MMP-9/TIMP-1 ratio for which independent MMP-9 and TIMP-1 quantifications by two conventional ELISAs are needed. The MMP-9-TIMP-1 AlphaLISA assay is quick, highly simplified, and cost-effective and can be completed in less than 3 h. Moreover, the assay has great potential for use in basic and preclinical research as it allows direct determination of native MMP-9-TIMP-1 complexes in circulating blood as biofluid.
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http://dx.doi.org/10.3389/fimmu.2017.00853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523156PMC
July 2017
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