Publications by authors named "Alipio Mangas"

26 Publications

  • Page 1 of 1

Plasma microrna expression profile for reduced ejection fraction in dilated cardiomyopathy.

Sci Rep 2021 Apr 6;11(1):7517. Epub 2021 Apr 6.

Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, Av/Ana de Viya 21, 11009, Cadiz, Spain.

The left ventricular (LV) ejection fraction (EF) is key to prognosis in dilated cardiomyopathy (DCM). Circulating microRNAs have emerged as reliable biomarkers for heart diseases, included DCM. Clinicians need improved tools for greater clarification of DCM EF categorization, to identify high-risk patients. Thus, we investigated whether microRNA profiles can categorize DCM patients based on their EF. 179-differentially expressed circulating microRNAs were screened in two groups: (1) non-idiopathic DCM; (2) idiopathic DCM. Then, 26 microRNAs were identified and validated in the plasma of ischemic-DCM (n = 60), idiopathic-DCM (n = 55) and healthy individuals (n = 44). We identified fourteen microRNAs associated with echocardiographic variables that differentiated idiopathic DCM according to the EF degree. A predictive model of a three-microRNA (miR-130b-3p, miR-150-5p and miR-210-3p) combined with clinical variables (left bundle branch block, left ventricle end-systolic dimension, lower systolic blood pressure and smoking habit) was obtained for idiopathic DCM with a severely reduced-EF. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. Bioinformatics analysis revealed that miR-150-5p and miR-210-3p target genes might interact with each other with a high connectivity degree. In conclusion, our results revealed a three-microRNA signature combined with clinical variables that highly discriminate idiopathic DCM categorization. This is a potential novel prognostic biomarker with high clinical value.
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http://dx.doi.org/10.1038/s41598-021-87086-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024336PMC
April 2021

Ischemic dilated cardiomyopathy pathophysiology through microRNA-16-5p.

Rev Esp Cardiol (Engl Ed) 2020 Oct 10. Epub 2020 Oct 10.

Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario de Puerta del Mar, Universidad de Cádiz, Cádiz, Spain; Departamento de Medicina, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.

Introduction And Objectives: The expression levels of microRNA-16-5p (miR-16) are upregulated in ischemic cardiomyopathy and in animal models of ischemic dilated cardiomyopathy (iDCM), inducing myocardial apoptosis. We investigated the role of miR-16 in the adaptive cellular response associated with endoplasmic reticulum (ER) stress and autophagy in the apoptotic iDCM environment.

Methods: We quantified the miR-16 plasma levels of 168 participants-76 controls, 60 iDCM patients, and 32 familial DCM patients with the pathogenic variant of BAG3-by quantitative real-time polymerase chain reaction and correlated the levels with patient variables. The effects of intracellular miR-16 overexpression were analyzed in a human cardiac cell line. Apoptosis and cell viability were measured, as well as the levels of markers associated with ER stress, cardiac injury, and autophagy.

Results: Plasma miR-16 levels were upregulated in iDCM patients (P=.039). A multivariate logistic regression model determined the association of miR-16 with iDCM clinical variables (P <.001). In vitro, miR-16 overexpression increased apoptosis (P=.02) and reduced cell viability (P=.008). Furthermore, it induced proapoptotic components of ER stress, based on upregulation of the PERK/CHOP pathway. However, we observed augmentation of autophagic flux (P <.001) without lysosomal blockade by miR-16 as a possible cytoprotective mechanism.

Conclusions: MiR-16 is specifically associated with iDCM. In an ischemic setting, miR-16 activates ER stress and promotes inflammation followed by autophagy in human cardiac cells. Thus, autophagy may be an attempt to maintain cellular homeostasis in response to misfolded/aggregated proteins related to ER stress, prior to apoptosis.
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http://dx.doi.org/10.1016/j.rec.2020.08.012DOI Listing
October 2020

Evaluation of the chylomicron-TG to VLDL-TG ratio for type I hyperlipoproteinemia diagnostic.

Eur J Clin Invest 2020 Dec 11;50(12):e13345. Epub 2020 Aug 11.

Lipids and Atherosclerosis Laboratory, Department of Medicine and Dermatology, Centro de Investigaciones Médico Sanitarias (CIMES), Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Málaga, Spain.

Background: The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low-density lipoproteins triglycerides (CM/VLDL-TG) ratio, the triglycerides to cholesterol ratio (TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS).

Methods: Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL-TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cut-offs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort.

Results: Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL-TG, TG/TC and TG/APOB ratios, whereas their HDL-C, LDL-C and APOB levels were lower than in non-FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL-TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cut-off of 3.8 and 4.5.

Conclusions: Our results suggest that in subjects at high risk of FCS a total serum TG/TC ratio or TG/APOB ratio are feasible to initially screen for HLPI; however, a CM/VLDL-TG ratio ≥4.5 is a better diagnostic criterion for HPLI.
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http://dx.doi.org/10.1111/eci.13345DOI Listing
December 2020

Peripheral microRNA panels to guide the diagnosis of familial cardiomyopathy.

Transl Res 2020 04 29;218:1-15. Epub 2020 Jan 29.

Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital University of Cádiz, Spain; Medicine Department, School of Medicine, University of Cádiz, Cádiz, Spain. Electronic address:

Etiology-based diagnosis of dilated cardiomyopathy (DCM) is challenging. We evaluated whether peripheral microRNAs (miRNAs) could be used to characterize the DCM etiology. We investigated the miRNA plasma profiles of 254 subjects that comprised 5 groups: Healthy subjects (n = 70), idiopathic DCM patients (n = 55), ischemic DCM patients (n = 60) and 2 groups of patients with pathogenic variants responsible for familial DCM in the LMNA (LMNA, n = 37) and BAG3 (BAG3, n = 32) genes. Diagnostic performance was assessed using receiver operating characteristic curves. In a screening study (n = 30), 179 miRNAs robustly detected in plasma samples were profiled in idiopathic DCM and carriers of pathogenic variants. After filtering, 26 miRNA candidates were selected for subsequent quantification in the whole study population. In the validation study, a 6-miRNA panel identified familial DCM with an AUC (95% confidence interval [CI]) of 87.8 (82.0-93.6). The 6-miRNA panel also distinguished between specific DCM etiologies with AUCs ranging from 85.9 to 89.9. Only 1 to 10 of the subjects in the first and second tertiles of the 6-miRNA panel were patients with familial DCM. Additionally, a 5-miRNA panel showed an AUC (95% CI) of 87.5 (80.4-94.6) for the identification of carriers with pathogenic variants who were phenotypically negative for DCM. The 5-miRNA panel discriminated between carriers and healthy controls with AUCs ranging from 83.2 to 90.8. Again, only 1 to 10 of the subjects in the lowest tertiles of the 5-miRNA panel were carriers of pathogenic variants. In conclusion, miRNA signatures could be used to rule out patients with pathogenic variants responsible for DCM.
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http://dx.doi.org/10.1016/j.trsl.2020.01.003DOI Listing
April 2020

Emerging role of microRNAs in dilated cardiomyopathy: evidence regarding etiology.

Transl Res 2020 01 23;215:86-101. Epub 2019 Aug 23.

Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain; Department of Internal Medicine, Puerta del Mar Universitary Hospital, Cádiz, Spain; Department of Medicine, School of Medicine, University of Cádiz, Cádiz, Spain. Electronic address:

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease. This cardiac disorder is a major health problem due to its high prevalence, morbidity, and mortality. DCM is a complex disease with a common phenotype but heterogeneous pathological mechanisms. Early etiological diagnosis and prognosis stratification is crucial for the clinical management of the patient. Advances in imaging technology and genetic tests have provided useful tools for clinical practice. Nevertheless, the assessment of the disease remains challenging. Novel noninvasive indicators are still needed to assist in decision-making. microRNAs (miRNAs), a group of small noncoding RNAs, have been identified as key mediators of cell biology. They are found in a stable form in body fluids and their concentration is altered in response to stress. Previous research has suggested that the miRNA signature constitutes a novel source of noninvasive biomarkers for a wide array of cardiovascular diseases. Specifically, several studies have reported the potential role of miRNAs as clinical indicators among the etiologies of DCM. However, this field has not been reviewed in detail. Here, we summarize the evidence of intracellular and circulating miRNAs in DCM and their usefulness in the development of novel diagnostic, prognostic and therapeutic approaches, with a focus on DCM etiology. Although the findings are still preliminary, due to methodological and technical limitations and the lack of robust population-based studies, miRNAs constitute a promising tool to assist in the clinical management of DCM.
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http://dx.doi.org/10.1016/j.trsl.2019.08.007DOI Listing
January 2020

Differential expression of circulating miRNAs as a novel tool to assess BAG3-associated familial dilated cardiomyopathy.

Biosci Rep 2019 03 15;39(3). Epub 2019 Mar 15.

Univ Puerta del Mar, School of Medicine, Cadiz, Spain

A new familial dilated cardiomyopathy (FDCM) was found related to mutations in gene. MicroRNAs (miRNAs) represent new targets of FDCM, although no studies have assessed clinical association between Bcl2-associated athanogene 3 (BAG3)-related DCM and miRNAs. Here, we studied whether a clinical association between BAG3-related FDCM and circulating miRNAs may have diagnostic and prognostic value in a small cohort of familial related individuals carrying a BAG3 mutation (BAG3+) and/or diagnosed of dilated cardiomyopathy (DCM) (DCM+). The analysis of 1759 circulating miRNAs showed significant differences between BAG3+ and BAG3- individuals for miRNAs mir-3191-3p, 6769b-3p, 1249-ep, 154-5p, 6855-5p, and 182-5p, while comparisons between BAG3+/DCM+ versus BAG3+/DCM- were restricted to miRNAs mir-154-5p, 6885-5p, and 182-5p, showing significant correlation with systolic and diastolic blood pressure, A wave, left atrium length, and left atrium area. Additionally, when stratified by gender and age, miRNAs were statistically correlated with critical parameters, including left ventricle ejection fraction (LVEF) and ventricular diameter, in women and young men. Likewise, 56% of BAG3+/DCM+, significantly co-expressed mir-154-5p and mir-182-5p, and a slight 4% did not express such combination, suggesting that co-expression of mir-154-5p and mir-182-5p may potentially show diagnostic value. Further studies will require long-term follow-up, and validation in larger populations.
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http://dx.doi.org/10.1042/BSR20180934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418398PMC
March 2019

Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society.

J Clin Lipidol 2018 Nov - Dec;12(6):1482-1492.e3. Epub 2018 Aug 1.

Department of Medicine and Dermatology, Lipids and Atherosclerosis Laboratory, Centro de Investigaciones Médico Sanitarias (CIMES), Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Spain; Internal Medicine Unit, University Hospital Virgen de la Victoria, Málaga, Spain.

Background: Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex.

Objective: This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry.

Methods: Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5).

Results: Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326_327insC; p.Tyr110Leufs*158).

Conclusion: We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS.
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http://dx.doi.org/10.1016/j.jacl.2018.07.013DOI Listing
October 2019

Plasma microRNAs as biomarkers for Lamin A/C-related dilated cardiomyopathy.

J Mol Med (Berl) 2018 08 14;96(8):845-856. Epub 2018 Jul 14.

CIBER Cardiovascular, Institute of Health Carlos III, Madrid, Spain.

Lamin A/C gene (LMNA)-related familial dilated cardiomyopathy (fDCM) is an aggressive heart disease that often leads to transplantation and sudden death. The aim of our study was to evaluate the circulating microRNA (miRNA) profiles of patients with LMNA pathogenic mutations. The study population (N = 75) included (i) patients with pathogenic LMNA mutations responsible for fDCM (LMNA), (ii) age- and sex-matched LMNA wild-type controls (LMNA control), and (iii) LMNA wild-type idiopathic DCM (iDCM) patients (LMNA iDCM). Detailed clinical information was obtained from each participant. A panel of 179 plasma miRNAs was evaluated using RT-qPCR. An initial screening study was performed in LMNA carriers and age-matched LMNA controls (N = 16). Forty-four miRNAs were specifically deregulated in LMNA carriers. Ten miRNA candidates were selected for subsequent validation after coexpression analyses and filtered for expression levels and statistical significance. Among the candidates, let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p levels were significantly increased in LMNA carriers compared to LMNA controls and iDCM patients (P < 0.050). These circulating miRNAs, and their combination, were also associated with the presence of pathogenic mutations in regression and ROC analyses. This signature also discriminates between LMNA healthy subjects and LMNA carriers who are phenotypically negative for DCM and between LMNA iDCM and LMNA-related DCM patients. Correlation and functional enrichment analyses supported their association with the pathophysiology of the disease. We demonstrated for the first time that a specific miRNA signature could serve as a novel non-invasive tool to assist in the diagnosis of patients with fDCM caused by LMNA pathogenic mutations. KEY MESSAGES: Let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p are differentially expressed in LMNA carriers. A composite score based on these miRNAs is a biomarker of mutations in the LMNA gene. This miRNA signature can be associated with the pathophysiology of familial DCM. The circulating miRNA profile can assist in the diagnosis of familial DCM.
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http://dx.doi.org/10.1007/s00109-018-1666-1DOI Listing
August 2018

Proteomic identification of putative biomarkers for early detection of sudden cardiac death in a family with a LMNA gene mutation causing dilated cardiomyopathy.

J Proteomics 2016 10 22;148:75-84. Epub 2016 Jul 22.

Medicine Department, School of Medicine, Universidad de Cádiz, Spain. Electronic address:

Unlabelled: Dilated cardiomyopathy (DCM) is a severe heart disease characterized by progressive ventricular dilation and impaired systolic function of the left ventricle. We recently identified a novel pathogenic mutation in the LMNA gene in a family affected by DCM showing sudden death background. We now aimed to identify potential biomarkers of disease status, as well as sudden death predictors, in members of this family. We analysed plasma samples from 14 family members carrying the mutation, four of which (with relevant clinical symptoms) were chosen for the proteomic analysis. Plasma samples from these four patients and from four sex- and age-matched healthy controls were processed for their enrichment in low- and medium-abundance proteins (ProteoMiner™) prior to proteomic analysis by 2D-DIGE and MS. 111 spots were found to be differentially regulated between mutation carriers and control groups, 83 of which were successfully identified by MS, corresponding to 41 different ORFs. Some proteins of interest were validated either by turbidimetry or western blot in family members and healthy controls. Actin, alpha-1-antytripsin, clusterin, vitamin-D binding protein and antithrombin-III showed increased levels in plasma from the diseased group. We suggest following these proteins as putative biomarkers for the evaluation of DCM status in LMNA mutation carriers.

Biological Significance: We developed a proteomic analysis of plasma samples from a family showing history of dilated cardiomyopathy caused by a LMNA mutation, which may lead to premature death or cardiac transplant. We identified a number of proteins augmented in mutation carriers that could be followed as potential biomarkers for dilated cardiomyopathy on these patients.
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http://dx.doi.org/10.1016/j.jprot.2016.07.020DOI Listing
October 2016

Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene.

PLoS One 2016 8;11(7):e0158730. Epub 2016 Jul 8.

Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain.

Background: Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.

Methods And Results: Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.

Conclusions: We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938129PMC
August 2017

[Performance of entero-insular axis in an athletic population: diet and exercise influence].

Nutr Hosp 2015 May 1;31(5):2187-94. Epub 2015 May 1.

Departamento de Medicina, Facultad de Medicina, Cádiz..

Introduction: The relationship between physical exercise and appetite regulation can lead to improved competitive performance of athletes. Mediators of the entero-insular axis generate neurohumoral signals that influence on the appetite regulation and energy homeostasis.

Aim: Determine the influence of diet and prolonged exercise on intestinal peptide, ghrelin, resistin, leptin, and incretins (GLP-1 and GIP) in an athlete population.

Methods: It is a prospective intervention study, conducted from October 2012 to March 2013. 32 healthy semiprofessional rugby players, aged 13-39 years were included. Anthropometric measurements and blood samples were taken at time 0 and after six months of study. Athletes were randomized to a protein diet (PD) or Mediterranean diet (MD) and plasma levels of intestinal peptide, ghrelin, resistin, leptin, and incretins were calculated.

Results: In the PD group, GLP-1 and GIP plasmatic levels showed a significant decrease (p <0.03; p <0.01 respectively). GLP-1 and ghrelin plasmatic concentration demonstrated a significant decrease (p <0.03 respectively) in those who experienced gain of muscle mass (MM). Finally, the athletes related to the PD who showed increased total weight and muscle mass presented significantly decreased GLP-1 concentration (p <0.03 and p<0.002, respectively).

Conclusion: GLP-1 plasmatic concentration was decreased, with the PD suggesting to be more beneficial for the athletes in order to avoid hypoglycemia. Furthermore, muscle mass and total weight gain, linked to the PD, could enhance athletic performance in certain sport modalities.
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http://dx.doi.org/10.3305/nh.2015.31.5.8828DOI Listing
May 2015

Relationship between lipoprotein (a) and micro/macro complications in type 2 diabetes mellitus: a forgotten target.

J Geriatr Cardiol 2015 Mar;12(2):93-9

Department of Medicine, Cádiz University, School of Medicine, Cádiz 11002, C/ Dr Marañon S/N, Cádiz, Spain ; Department of Internal Medicine, University Hospital Puerta del Mar, Cádiz 11002, Ana de Viya S/N, Cádiz, Spain.

Objectives: Increased lipoprotein (a) serum concentrations seems to be a cardiovascular risk factor; this has not been confirmed in extracoronary atherosclerosis complications. We therefore wished to gain a deeper insight into relationship between the plasma concentrations of lipoprotein (a) and the micro- and macro-vascular complications of type 2 diabetes mellitus and to identify possible differences in this association.

Methods: This is a descriptive observational cross-sectional study. Two-hundred and seventeen elderly patients with type 2 diabetes mellitus were included from the internal medicine outclinic. Anthropometric data, analytical data (insulin reserve, basal and postprandial peptide C, glycosylated hemoglobin, renal parameters, lipid profile and clinical data as hypertension, obesity, micro- and macrovascular complications were collected.

Results: Patients were grouped according to the type 2 diabetes mellitus time of evolution. The mean plasma concentration of lipoprotein (a) was 22.2 ± 17.3 mg/dL (22.1 ± 15.9 mg/dL for males, and 22.1 ± 18.4 mg/dL for females). Patients with hypertension, coronary heart disease, cerebrovascular accident, microalbuminuria and proteinuria presented a statistically significant increased level of lipoprotein (a). Similarly, the patients with hyperlipoprotein (a) (≥ 30 mg/dL) presented significantly increased levels of urea and total cholesterol. In the multivariate regression model, the level of lipoprotein (a) is positively correlated with coronary heart disease and diabetic nephropathy (P < 0.01 and P < 0.005, respectively).

Conclusions: The elevation of plasma levels of lipoprotein (a) are associated with the development of coronary heart disease and diabe tic nephropathy. Therefore, we consider that the determination of lipoprotein (a) may be a prognostic marker of vascular complications in patients with type 2 diabetes mellitus.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2015.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394322PMC
March 2015

A novel mutation in lamin a/c causing familial dilated cardiomyopathy associated with sudden cardiac death.

J Card Fail 2015 Mar 9;21(3):217-25. Epub 2014 Dec 9.

Cardiovascular Genetics Center, IDIBGI, University of Girona, Girona, Spain; Department of Medical Science, School of Medicine, University of Girona, Girona, Spain; Cardiomyopathy Unit, Hospital Josep Trueta, University of Girona, Girona, Spain. Electronic address:

Background: Dilated cardiomyopathy (DCM), a cardiac heterogeneous pathology characterized by left ventricular or biventricular dilatation, is a leading cause of heart failure and heart transplantation. The genetic origin of DCM remains unknown in most cases, but >50 genes have been associated with DCM. We sought to identify the genetic implication and perform a genetic analysis in a Spanish family affected by DCM and sudden cardiac death.

Methods And Results: Clinical assessment and genetic screening were performed in the index case as well as family members. Of all relatives clinically assessed, nine patients showed clinical symptoms related to the pathology. Genetic screening identified 20 family members who carried a novel mutation in LMNA (c.871 G>A, p.E291K). Family segregation analysis indicated that all clinically affected patients carried this novel mutation. Clinical assessment of genetic carriers showed that electrical dysfunction was present previous to mechanical and structural abnormalities.

Conclusions: Our results report a novel pathogenic mutation associated with DCM, supporting the benefits of comprehensive genetic studies of families affected by this pathology.
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http://dx.doi.org/10.1016/j.cardfail.2014.12.003DOI Listing
March 2015

Relationship between endothelin-1 levels and pulmonary arterial hypertension in HIV-infected patients.

AIDS 2014 Nov;28(18):2693-9

aCardiology Department, Hospital Carlos III, Madrid bDepartment of Medicine, School of Medicine, Cadiz cInfectious Diseases Department, Hospital Carlos III dCardiology Department, Hospital Clínico San Carlos, Madrid, Spain. *Maribel Q. Feijoo and Rocío Toro contributed equally to this paper.

Objective: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with average survival of less than 3 years if left untreated. It is most common in patients infected with HIV. Although the pathogenesis in this population is not fully understood, it is thought that HIV infection, through the immune response and release of different inflammatory mediators such as endothelin-1, may contribute directly to endothelial damage. Our objective was to quantify endothelin-1 levels in HIV-infected patients and determine whether or not there is an association between this marker and PAH.

Design: A case-control study in patients attending an infectious diseases clinic.

Methods: The sample was composed of 79 patients divided into three groups: 23 HIV patients with PAH (HIV+/PAH+), 45 HIV patients without PAH (HIV+/PAH-) and a control group of 11 healthy individuals. The ratio between the HIV+/PAH- and HIV+/PAH+ groups was 2 : 1. Patients were matched by age, sex, risk group and viral load; the control group by age and sex. All patients had blood taken for endothelin-1 plasma quantification.

Results: We found lower endothelin-1 levels in the controls than in the HIV+/PAH- group [0.71 pg/ml (interquartile range, IQR 0.54-0.94) vs. 1.13 pg/ml (IQR 0.87-1.38); P = 0.005] and the HIV+/PAH+ cohort [1.16 pg/ml (IQR 0.86-2.37); P = 0.003]. Patients with severe PAH had higher endothelin-1 levels [2.94 pg/ml (IQR 1.81-6.33)] than patients with mild and moderate PAH.

Conclusion: Plasma endothelin-1 levels are higher in HIV patients with PAH than in the HIV-noninfected population and levels increase with the severity of the PAH.
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http://dx.doi.org/10.1097/QAD.0000000000000470DOI Listing
November 2014

[Diet and exercise influence on the proteomic profile of an athlete population].

Nutr Hosp 2014 Nov 1;30(5):1110-7. Epub 2014 Nov 1.

Departamento de Salud Pública y Biotecnología, Facultad de Medicina, Cádiz. España..

Introduction: Nutrition has emerged as a fundamental tool included in the training program of athletes. Body composition seeks different objectives depending on type of sport, position, or time of the season. Furthermore, analysis proteomics allows us to know the structure and function of proteins.

Aims: To study, using proteomics, the influence of two different diets on the anthropometric profile in a rugby players group.

Methods: It is a prospective and interventionist study. Thirty-two rugby players were included. Two groups were defined, one followed proteic diet (PD) and, the other group subscribed the Mediterranean diet (MD). All participants were evaluated anthropometrically at the beginning and after six months. A blood sample was taken to twenty -two players, half of each group, used for the proteomic analysis.

Results: MD highlight more benefit for these athletes. Two groups were defined based on their anthropometric behavior, G1 and G2. The proteomic analysis related significantly some TGF-family mediators with these groups.

Conclusions: MD improves the muscular mass without increasing the total body weight, so this data could be determinant to define profiles for athletes. Some TGF-members could be implicated in the adipose tissue and muscular mass balance.
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http://dx.doi.org/10.3305/nh.2014.30.5.7697DOI Listing
November 2014

Impaired right and left ventricular mechanics in adults with pulmonary hypertension and congenital shunts.

J Cardiovasc Med (Hagerstown) 2016 Mar;17(3):209-16

aDepartment of Medicine, Cadiz University School of Medicine, CadizbAdult Congenital Heart Disease Unit, Clinical Management Area of the Heart, University Hospital 'Virgen del Rocio', SevillecCardiology Department, Hospital Carlos III, Madrid, Spain.

Aims: To assess left ventricle mechanics in Eisenmenger physiology patients with congenital shunts, and their relationship with the right ventricle, and to consider the clinical usefulness of this information.

Methods: The study involved 28 patients with pulmonary artery hypertension (PAH) and congenital shunt, matched with 28 healthy participants. Standard echocardiography and pulsed wave tissue Doppler imaging were employed to analyze systolic and diastolic ventricular function, the myocardial performance index (MPI) of ventricles, and the strain and strain rate along the left ventricle lateral wall, septum, and right ventricle free wall.

Results: The left ventricle ejection fraction was similar in the two groups. However, despite normal standard left ventricle measures, patients presented parameters of defective myocardial mechanics: mitral peak systolic velocity (S') (cm/s) (8.6 (7.6-10.9) vs. 10.7 (8.6-12.5); P = 0.002) was higher, whereas left ventricle-MPI was lower (0.54 ± 01 vs. 0.32 ± 0.07, P < 0.001). Right ventricle-MPI and right ventricle global strain were correlated significantly with left ventricle-MPI and left ventricle global strain (r = 0.74, P < 0.001; r = 0.442, P < 0.001, respectively). Clinically, the six-minute walking test results were correlated negatively with left ventricle-MPI (r = -0.69, P < 0.001), whereas the functional class was positively correlated (r = 0.36, P < 0.001). In conclusion, left ventricle mechanics and geometry are impaired in Eisenmenger syndrome patients, although conventional evaluation is in the normal range. Our results highlight the significance of ventricular interdependence in PAH and provide a useful tool for improving the clinical management of these patients.
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http://dx.doi.org/10.2459/JCM.0000000000000172DOI Listing
March 2016

Influence of the interaction between the adiponectin G276T polymorphism and body mass index on lipid levels in healthy children.

Mol Biol Rep 2012 Apr 22;39(4):4831-5. Epub 2011 Sep 22.

Lipid Metabolism Laboratory, IIS-Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040, Madrid, Spain.

Adiponectin is an adipose tissue-specific hormone which is inversely associated with metabolic alterations related to atherosclerosis. Polymorphisms in the adiponectin gene (AdipoQ) have been related to low adiponectin levels as well as several cardiovascular risk factors, but this association remains controversial. In our study we investigated the relationship between the AdipoQ T45G (rs: 2241766) and G276T (rs: 1501299) polymorphisms and adiponectin concentrations, blood pressure, and lipid and insulin levels, in a population-based sample of 12- to 16-year-old children. The study included 815 healthy Spanish children (388 boys and 427 girls). Plasma glucose and lipid levels were determined by standard methods. Insulin concentrations were measured by RIA, and serum adiponectin levels were determined by ELISA. The AdipoQ T45G and AdipoQ G276T polymorphisms were determined by TaqMan(®) allelic discrimination assays. ANOVA or t test allowed for comparison of the studied parameters across genotypes or genotype groups, respectively. A linear regression analysis was performed to examine the independent relationships of the lipid variables with BMI (body mass index), AdipoQ G276T polymorphism and the interaction between the two. When independently comparing the effect of these polymorphisms in normal-weight and overweight children, we observed that overweight boys carriers of the minor allele T had significantly lower TC, LDL-C and apo A-I levels than non-carriers, but these differences were not apparent in normal-weight boys. Furthermore, linear regression analysis demonstrated that interaction between the BMI and the AdipoQ G276T polymorphism is a significant factor explaining the variations of TC and LDL-C levels. To our knowledge, this is the first study to report an association between the AdipoQ G276T polymorphism and lipid levels in overweight boys alone, thereby suggesting that the influence of the AdipoQ polymorphisms on cardiovascular risk factors may be dependent on BMI.
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http://dx.doi.org/10.1007/s11033-011-1276-2DOI Listing
April 2012

[Prevalence of metabolic syndrome and its components in patients with acute coronary syndrome].

Rev Esp Cardiol 2011 Jul 2;64(7):579-86. Epub 2011 Jun 2.

Servicio de Endocrinología, Hospital Universitario Dr. Peset y Fundación para la Investigación Hospital Universitario Dr. Peset, Valencia, Spain.

Introduction And Objectives: A large proportion of patients with coronary disease have metabolic syndrome, although the frequency and association of its different components are not well understood. The aim of this study was to determine the prevalence of metabolic syndrome and the combination of its components in a Spanish cohort of patients with acute coronary syndrome.

Methods: Clinical histories of 574 inpatients with acute coronary syndrome in 6 tertiary hospitals were reviewed and the presence of metabolic syndrome and its components determined by applying Adult Treatment Panel III criteria. In a second step, the components of the metabolic syndrome were analyzed, excluding those patients with diabetes mellitus.

Results: The metabolic syndrome was present in 50.9% of patients and was more frequent in women than in men (66.3% vs. 47.3%; P<.001). The most prevalent component was carbohydrate metabolism disorder (85.3%), followed by low high-density lipoprotein cholesterol (HDLc) levels (80.5%). In nondiabetic patients, 34.6% had metabolic syndrome and the most prevalent component was low HDLc levels (86%), followed by high blood pressure and hypertriglyceridemia and, in fourth place, impaired fasting serum glucose levels.

Conclusions: The metabolic syndrome has a high prevalence in patients with an acute coronary syndrome, especially in women. The most frequent components are hyperglycemia and low HDLc levels. After excluding diabetic patients, the most prevalent diagnostic criterion of metabolic syndrome was low HDLc levels. Full English text available from: www.revespcardiol.org.
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http://dx.doi.org/10.1016/j.recesp.2011.03.010DOI Listing
July 2011

[Residual lipid profile in recurrent ischemic cardiopathy].

Med Clin (Barc) 2012 Mar 22;138(6):238-41. Epub 2011 Mar 22.

Unidad de Riesgo Vascular y Lípidos, Servicio de Medicina Interna, Hospital Universitario Gregorio Marañón, Madrid, España.

Background And Objectives: In this paper we analyze the lipid profile of a cohort of patients attended in different tertiary hospitals with acute coronary syndrome (angor pectoris or acute myocardial infarction).

Patients And Methods: We have analysed different variables of patients with acute coronary syndrome, related with the prevalence and grade of main cardiovascular risk factors, and related with different treatments. We have analysed the lipid profile, and stratified the results according with the status of the first acute coronary event or recurrent coronary event.

Results: Patients with recurrent disease showed lower levels of total cholesterol and LDL-c, and similar levels of HDL-c and triglycerides in relation with patients with a first event.

Conclusions: We found similar HDL-c and triglycerides levels in both groups of patients meaning that, despite a standard statins treatment, patients with a first coronary event did not modify such a lipid profile. It is necessary to do a more intensive therapeutic effort over all the lipid fractions with the aim to reduce the recurrences of coronary events.
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http://dx.doi.org/10.1016/j.medcli.2011.01.010DOI Listing
March 2012

A very high prevalence of low HDL cholesterol in Spanish patients with acute coronary syndromes.

Clin Cardiol 2010 Jul;33(7):418-23

Unitat de Lípids i Risc Vascular, Servei de Medicina Interna, Hospital Universitari de Bellvitge, Barcelona, Spain.

Background: Total and low-density lipoprotein cholesterol (LDL-C) concentrations in coronary artery disease have progressively declined, although high-density lipoprotein cholesterol (HDL-C) has not always been evaluated. The prevalence and related factors of low HDL-C in a cohort of Spanish patients with acute coronary syndromes (ACS) were assessed.

Methods: Clinical and laboratory data registered at admission and at discharge of 648 patients admitted to coronary care units of 6 Spanish hospitals for ACS between January 2004 and September 2007 were analyzed.

Results: Low HDL-C (HDL-C < 1.04 mmol/L) was observed in 367 (56.6%) patients. Male gender, smoking, hypertension, diabetes, high body mass index, and triglycerides were related to low HDL-C. Female gender was the strongest protective factor against low HDL-C (0.619; 95% confidence interval [CI]: 0.410-0.934; P = 0.022), whereas high triglycerides (1.653; 95% CI: 1.323-2.064; P < 0.001) followed by previous ischemic disease (1.504; 95% CI: 1.073-2.110; P = 0.018) were the strongest factors associated with low HDL-C. One-third of patients were taking statins at admission, but only 2% were on fibrate therapy. A large increase in statin therapy, but not in other hypolipemiant drug therapy, between admission and discharge was noted in the whole cohort and among patients with low HDL-C.

Conclusion: Spanish patients with ACS have a very high prevalence of low HDL-C. Male gender, high triglycerides, and previous ischemic disease are strong, independent factors associated with this disorder. As low HDL-C remains almost completely untreated in ACS, strategies to enhance the treatment of this lipoprotein abnormality are urgently required.
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http://dx.doi.org/10.1002/clc.20774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653221PMC
July 2010

[Calcified aortic valve disease: association with atherosclerosis].

Med Clin (Barc) 2011 May 24;136(13):588-93. Epub 2010 Apr 24.

Unidad de Cardiología, Hospital Virgen de la Montaña, Cáceres, España.

Calcified aortic valve disease (CAVD) is a prevalent condition, affecting 25% of people older than 65 years. CAVD and atherosclerosis share common risk factors and pathogenic mechanisms. Nevertheless, they present different pathologic lesions. The main factors involved in the pathogenesis of CAVD are genetic predisposition, the process of valvular calcification, deposition of lipoproteins, and chronic inflammation. Studies have suggested a potential benefit from early treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor blockers, and particularly with statins. Observational studies on risk factors for the CAVD, and randomized clinical trials on primary and secondary prevention in subjects with high risk for the disease, would be necessary to improve the clinical management of CAVD.
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http://dx.doi.org/10.1016/j.medcli.2010.02.019DOI Listing
May 2011

Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.

Vasc Health Risk Manag 2009 18;5:757-65. Epub 2009 Sep 18.

Hospital Universitario Gregorio Marañón, Madrid, Spain.

Low-density lipoprotein (LDL) cholesterol concentration has been the prime index of cardiovascular disease risk and the main target for therapy. However, several lipoprotein ratios or "atherogenic indices" have been defined in an attempt to optimize the predictive capacity of the lipid profile. In this review, we summarize their pathophysiological aspects, and highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy. Total/high-density lipoprotein (HDL) cholesterol and LDL/HDL cholesterol ratios are risk indicators with greater predictive value than isolated parameters used independently, particularly LDL. Future recommendations regarding the diagnosis and treatment of dyslipidemia, including instruments for calculating cardiovascular risk or action guidelines, should include the lipoprotein ratios with greater predictive power which, in view of the evidence-based results, are none other than those which include HDL cholesterol.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747394PMC
December 2009

Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy.

Int J Cardiol 2009 Feb 8;132(1):38-44. Epub 2008 Aug 8.

Hospital Clínico San Carlos, Madrid, Spain.

Unlabelled: Fabry cardiomyopathy (FC) is characterized by left ventricular hypertrophy (LVH). The aim of this study is to determine whether early changes revealed by tissue Doppler imaging (TDI) are useful for detecting preclinical cardiac abnormalities in patients with this X-linked genetic disorder. If so, this tool could help in deciding whether to begin enzymatic therapy earlier than otherwise.

Methods And Results: 59 consecutive patients with confirmed Fabry disease (FD) underwent conventional and TD echocardiography. FD patients with and without LVH had significantly lower early diastolic tissue Doppler velocities (Ea) compared with the control group (P<0.001); The isovolumic relaxation time (IVRT) was significantly longer in the FD group with LVH (P<0.001). Isovolumic contraction time (IVCT) was significantly shorter in the FD group without LVH compared with the control group (P<0.001). Additionally, peak systolic wall motion velocity (Sa) was significantly lower in patients with LVH, compared with those without LVH (P<0.001). The systolic myocardial velocity correlates inversely with septum and posterior wall thickness (r: -0.74 and r: -0.90; P<0.001 respectively). In respect of predicting preclinical cardiac impairment, the area under the ROC curve of 0.83 suggests an optimal IVRT cut-off point of 60 ms for separating early cardiac impairment from the established condition. This gives a 96.6% specificity rate for the early detection of cardiac involvement. The best parameter for detecting preclinical FC is the IVCT, with a cut-off point of 105 ms, which shows high sensitivity and specificity (100% and 91%, respectively; AUC: 0.97).

Conclusions: Myocardial contraction and relaxation evaluation confirms that TDI is a reliable method for early identification of preclinical FC, even before FC patients develop LVH.
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http://dx.doi.org/10.1016/j.ijcard.2008.04.075DOI Listing
February 2009

Dehydroepiandrosterone sulfate and high-density lipoprotein-cholesterol levels in overweight children.

Obesity (Silver Spring) 2007 May;15(5):1147-54

Lipid Unit, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040 Madrid, Spain.

Objective: The association of childhood overweight with cardiovascular risk factors seems to change by sex and age, which may indicate that hormonal status could be the cause of this different association. In this study, we analyzed the relationship of dehydroepiandrosterone sulfate (DHEA-S) with the alterations associated with overweight by analyzing the influence of this hormone in the differences found in biochemical variables between normal-weight and overweight prepubertal children. RESEARCH METHODS AND DESIGN: The study included 684 6- to 8-year-old children (350 boys and 334 girls) categorized by the presence or absence of overweight, according to the age- and sex-specific cut-off points proposed for children. Lipid levels were determined by standard methods. DHEA-S and insulin levels were measured by radioimmunoassay. Biochemical variables were compared between normal-weight and overweight children by tertiles of DHEA-S.

Results: We observed that plasma high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein (apo)-AI levels were significantly lower in overweight than in normal-weight boys only in the highest tertile of DHEA-S. No significant differences in plasma glucose levels, total cholesterol, low-density lipoprotein-cholesterol, or apo B were found between overweight and normal-weight children in any DHEA-S tertile. In a Spearman correlation analysis, we observed a significant and negative correlation for weight and BMI with HDL-C and for weight and apo-AI levels only in the highest tertile of DHEA-S.

Discussion: Our study showed that, in our prepubertal population, the association of overweight with decreased HDL-C and apo-AI levels was present only in boys within the highest levels of DHEA-S, supporting the importance of hormonal influences on the association of metabolic alterations with overweight.
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http://dx.doi.org/10.1038/oby.2007.625DOI Listing
May 2007

[Waist circumference as a predictor of insulin resistance in young men].

Med Clin (Barc) 2005 Jun;125(2):46-50

Departamento de Medicina, Universidad de Cádiz, Cádiz, Spain.

Background And Objective: Waist circumference (WC) is a measure of upper body fat and so should be useful for identifying overweight and obese men at risk of developing metabolic complications. The objective was to determine the relations of WC to cardiovascular risk factors in a sample of young men and to assess the clinical relevance of WC in identifying insulin resistance.

Subjects And Method: This study included 194 male Spanish subjects aged 26 (5) years who were divided in 3 groups according to the WC: Normal (< 94 cm), moderate risk (> or = 94 cm) and elevated risk (> or = 102 cm). Body mass index (BMI), WC, blood pressure, serum levels of total cholesterol, triglycerides (TG), HDL-cholesterol, LDL-cholesterol, glucose, uric acid and insulin were measured by standard methods. The homeostasis model assessment was applied to estimate the degree of insulin resistance (HOMAIR).

Results: The prevalence of overweight and obesity was 46.9% and 6.7% respectively. Men with moderate and elevated risk showed higher concentrations of glucose (p < 0.004), uric acid (p < 0.001), TG (p < 0.001), LDL-cholesterol/HDL-cholesterol index (p < 0.001), insulin (p < 0.001) and HOMAIR (p < 0.001). WC was significantly correlated with age (r = 0,282; p < 0.001), TG (r = 0.308; p < 0,001), insulin (r = 0.282; p < 0.001) and HOMAIR (r = 0.281; p < 0.001). A multivariate linear correlation analysis showed that HOMAIR was significantly associated with WC (p < 0.009) and TG (p < 0.003; r2 = 0.13).

Conclusions: WC of these young men was independently associated with certain cardiovascular risk factors, in particular insulin resistance. This suggests that WC may be reasonably included in clinical practice as a simple tool that may help identify sub-groups of overweight or obese young men at higher metabolic risk.
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http://dx.doi.org/10.1157/13076462DOI Listing
June 2005

Increased hospital expenditures in diabetic patients hospitalized for cardiovascular diseases.

J Diabetes Complications 2003 Nov-Dec;17(6):331-6

Endocrinology Service of the Puerta del Mar University Hospital, Cádiz, Spain.

Objectives: To measure the impact of diabetes on hospital resource use and expenditures in patients hospitalized for cardiovascular diseases (CVD).

Research Design And Methods: We conducted an observational study of 4865 hospitalizations for CVD over 2 years (January 1998 to December 1999). Information with respect of the presence of diabetes mellitus, length of stay, readmissions, mortality, and costs were obtained through retrospective chart review.

Results: Diabetic patients accounted for 35.1% of hospital admissions (1706 admissions), 40.8% of hospital stays (23,309 days), and 39% of direct medical cost (5,735,884 euros). On average, diabetic patients had longer hospital stay (13.6+/-13.2 vs. 10.7+/-11.2 days; P<.001) and direct in-patient cost (3438+/-4308 vs. 2513+/-3384 euros; P<.001) and experienced more readmissions (relative risk: 1.67; 95% CI: 1.45-1.91) compared with nondiabetic patients. However, despite the hospital mortality rate being higher in nondiabetic patients (6.3% vs. 5.8%), these results were not statistically significant (relative risk: 1.09; 95% CI: 0.86-1.40).

Conclusions: Diabetic patients hospitalized for CVD have longer hospital stay, greater risk of short-term readmission, and are more costly than nondiabetic patients. However, in-hospital mortality risk in patients hospitalized by CVD is no greater in diabetic than in nondiabetics.
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http://dx.doi.org/10.1016/s1056-8727(02)00219-2DOI Listing
July 2004