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Maria Micaela Molina-Navarro, Esther Roselló-Lletí,
Estefanía Tarazón,
Ana Ortega,
Dolors Sánchez-Izquierdo,
Francisca Lago,
José Ramón González-Juanatey,
Pablo García-Pavía,
Antonio Salvador,
José Anastasio Montero,
Manuel Portolés,
Miguel Rivera
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ABSTRACT: BACKGROUND: Heart failure (HF) induces alterations in nucleocytoplasmic transport, which is essential to the cardiomyocyte biology. The objective of this study was to analyze the changes in gene expression in human HF, particularly focusing on nucleocytoplasmic transport-related genes. METHODS AND RESULTS: 29 RNA heart samples from dilated cardiomyopathy (DCM, n=12) and ischemic cardiomyopathy (ICM, n=12) patients undergoing heart transplantation and control donors (CNT, n=5) were extracted to perform a microarray profiling using Affymetrix Human Gene® 1.0 ST arrays. We focused on the study of 5 nucleocytoplasmic transport-related genes, since this functional category has not previously been studied in HF. XPO1, GABPB2, and RANBP17 were upregulated, while KALRN was downregulated in both DCM and ICM, and XPO5 only in DCM. Validation of the results by RT-qPCR increasing the total heart samples up to 41 showed a high degree of consistency with microarray results. Moreover, we observed a strong relationship between the XPO1 mRNA and robust left ventricular function parameters in ICM: left ventricular end-systolic (r=0.81, p<0.0001) and end-diastolic diameters (r=0.80, p<0.0001), and ejection fraction (r=-0.57, p<0.05). CONCLUSIONS: We show that the expression of nucleocytoplasmic transport-related genes is altered in HF. Furthermore, XPO1 mRNA level is closely related with robust left ventricular function parameters in ICM patients. These changes may help to distinguish DCM and ICM in HF at the level of the transcriptome and provide a base for novel therapeutic approaches.
International journal of cardiology 05/2013; · 7.08 Impact Factor
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Esther Roselló-Lletí,
Jana Alonso,
Raquel Cortés,
Luis Almenar,
Luis Martínez-Dolz,
Ignacio Sánchez-Lázaro,
Francisca Lago,
Inmaculada Azorín,
Jose R González Juanatey,
Manuel Portolés,
Miguel Rivera
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ABSTRACT: The development of heart failure (HF) is characterized by progressive alteration of left ventricle structure and function. Previous works on proteomic analysis in cardiac tissue from patients with HF remain scant. The purpose of our study was to use a proteomic approach to investigate variations in protein expression of left ventricle tissue from patients with ischaemic (ICM) and dilated cardiomyopathy (DCM). Twenty-four explanted human hearts, 12 from patients with ICM and 12 with DCM undergoing cardiac transplantation and six non-diseased donor hearts (CNT) were analysed by 2DE. Proteins of interest were identified by mass spectrometry and validated by Western blotting and immunofluorescence. We encountered 35 differentially regulated spots in the comparison CNT versus ICM, 33 in CNT versus DCM, and 34 in ICM versus DCM. We identified glyceraldehyde 3-phophate dehydrogenase up-regulation in both ICM and DCM, and alpha-crystallin B down-regulation in both ICM and DCM. Heat shock 70 protein 1 was up-regulated only in ICM. Ten of the eleven differentially regulated proteins common to both aetiologies are interconnected as a part of a same network. In summary, we have shown by proteomics analysis that HF is associated with changes in proteins involved in the cellular stress response, respiratory chain and cardiac metabolism. Although we found altered expression of eleven proteins common to both ischaemic and dilated aetiology, we also observed different proteins altered in both groups. Furthermore, we obtained that seven of these eleven proteins are involved in cell death and apoptosis processes, and therefore in HF progression.
Journal of Cellular and Molecular Medicine 03/2012; 16(10):2471-86. · 4.13 Impact Factor
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ABSTRACT: Background
Ca2+ handling machinery modulates the activation of cardiac transcription pathways involved in heart failure (HF). The present study investigated the effect of HF aetiology on Ca+2 handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue.
Methodology and Principal Findings
A total of 83 hearts from ischemic (ICM, n = 43) and dilated (DCM, n = 31) patients undergoing heart transplantation and controls (CNT, n = 9) were analyzed by western blotting. Subcellular distribution was analyzed by fluorescence and electron microscopy. When we compared Ca+2 handling proteins according to HF aetiology, ICM showed higher levels of calmodulin (24%, p
PLoS ONE 02/2012; 7(2). · 4.09 Impact Factor
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Esther Roselló-Lletí,
Miguel Rivera,
Raquel Cortés,
Inmaculada Azorín,
Rafael Sirera,
Luis Martínez-Dolz,
Leif Hove,
Juan Cinca,
Francisca Lago,
José R González-Juanatey,
Antonio Salvador,
Manuel Portolés
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ABSTRACT: We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n=38) and DCM (n=27) patients, undergoing heart transplantation and control donors (n=6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p<0.05) and DCM (141%, p<0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p<0.05) and DCM (1.70-fold, p<0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p<0.0001), and it was increased in pathological hearts (p<0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p<0.05 and 131%, p<0.001) and DCM (56%, p<0.01 and 69%, p<0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p<0.001), perinucleolar chromatin (p<0.01) and dense fibrillar components (p<0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p<0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein.
Biochemical and Biophysical Research Communications 02/2012; 418(2):222-8. · 2.48 Impact Factor
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ABSTRACT: B-type natriuretic peptide (BNP) and its inactive amino-terminal fragment (NT-proBNP) are diagnostic tools for heart failure (HF), but less is understood regarding the effects of renal function on their urinary concentrations. The objective was to analyze the influence of renal function, as estimated glomerular filtration rate (eGFR), on BNP and NT-proBNP concentrations in 90 HF outpatients (65 ± 12 years; 73% men), grouped according to eGFR below or above 60 mL/min. Patients with worse eGFR had higher serum NT-proBNP (p < 0.01) and BNP (p < 0.01) than patients with higher eGFR: NT-proBNP, but urinary levels did not reach statistical differences. In addition, a direct significant correlation between filtered load of serum NT-proBNP or BNP with their concentrations in urine was found in patients with eGFR above 60 mL/min (r = 0.66, p < 0.001 and r = 0.338, p < 0.05) and below 60 mL/min (r = 0.63, p < 0.001 and r = 0.406, p < 0.01). However, after normalizing urinary natriuretic peptide concentrations by their filtered load, we obtained a significant inverse and exponential relation in patients with worse renal function for NT-proBNP and BNP (r = -0.87, p = 0.001; and r = -0.71, p < 0.001, respectively) and in patients with eGFR>60 mL/min (r = -0.84, p < 0.001; and r = -0.72, p < 0.001, respectively). In conclusion, similar urinary NT-proBNP and BNP excretion was obtained in patients with high or low eGFR. Furthermore, despite the direct correlation between filtered load of serum natriuretic peptides with their urinary levels, an inverse an exponential relationship was obtained after normalizing urinary concentrations. Therefore, glomerular filtration does not seem to be the major determinant of both urinary peptide concentrations.
Peptides 02/2012; 33(2):354-8. · 2.43 Impact Factor
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ABSTRACT: Ca(2+) handling machinery modulates the activation of cardiac transcription pathways involved in heart failure (HF). The present study investigated the effect of HF aetiology on Ca(+2) handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue.
A total of 83 hearts from ischemic (ICM, n = 43) and dilated (DCM, n = 31) patients undergoing heart transplantation and controls (CNT, n = 9) were analyzed by western blotting. Subcellular distribution was analyzed by fluorescence and electron microscopy. When we compared Ca(+2) handling proteins according to HF aetiology, ICM showed higher levels of calmodulin (24%, p<0.01), calcineurin (26%, p<0.01) and Ca(2+)/Calmodulin-dependent kinase II (CaMKIIδ(b) nuclear isoform 62%, p<0.001) than the CNT group. However, these proteins in DCM did not significantly increase. Furthermore, ICM showed a significant elevation in MEF2C (33%, p<0.01), and GATA4 (49%, p<0.05); also NFAT1 (66%, p<0.001) was increased, producing the resultant translocation of this transcriptional factor into the nuclei. These results were supported by fluorescence and electron microscopy analysis. Whereas, DCM only had a significant increase in GATA4 (52%, p<0.05). Correlations between NFAT1 and MEF2C in both groups (ICM r = 0.38 and DCM r = 0.59, p<0.05 and p<0.01, respectively) were found; only ICM showed a correlation between GATA4 and NFAT1 (r = 0.37, p<0.05).
This study shows an increase of Ca(2+) handling machinery synthesis and their cardiac transcription pathways in HF, being more markedly increased in ICM. Furthermore, there is a significant association between MEF2, NFAT1 and GATA4. These proteins could be therapeutic targets to improve myocardial function.
PLoS ONE 01/2012; 7(2):e30915. · 4.09 Impact Factor
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ABSTRACT: AIMS: The objectives of this study were to analyse the effect of heart failure (HF) on several proteins of nuclear pore complex (NPC) and their relationship with the human ventricular function. METHODS AND RESULTS: A total of 88 human heart samples from ischemic (ICM, n = 52) and dilated (DCM, n = 36) patients undergoing heart transplant and control donors (CNT, n = 9) were analyzed by Western blot. Subcellular distribution of nucleoporins was analysed by fluorescence and immunocytochemistry. When we compared protein levels according to etiology, ICM showed significant higher levels of NDC1 (65%, p<0.0001), Nup160 (88%, p<0.0001) and Nup153 (137%, p = 0.004) than those of the CNT levels. Furthermore, DCM group showed significant differences for NDC1 (41%, p<0.0001), Nup160 (65%, p<0.0001), Nup153 (155%, p = 0.006) and Nup93 (88%, p<0.0001) compared with CNT. However, Nup155 and translocated promoter region (TPR) did not show significant differences in their levels in any etiology. Regarding the distribution of these proteins in cell nucleus, only NDC1 showed differences in HF. In addition, in the pathological group we obtained good relationship between the ventricular function parameters (LVEDD and LVESD) and Nup160 (r = -0382, p = 0.004; r = -0.290, p = 0.033; respectively). CONCLUSIONS: This study shows alterations in specific proteins (NDC1, Nup160, Nup153 and Nup93) that compose NPC in ischaemic and dilated human heart. These changes, related to ventricular function, could be accompanied by alterations in the nucleocytoplasmic transport. Therefore, our findings may be the basis for a new approach to HF management.
PLoS ONE 01/2012; 7(11):e48957. · 4.09 Impact Factor
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Núria Carpena, Esther Roselló-Lletí,
Jose R Calabuig,
Estefanía Tarazón,
Jose R González-Juanatey,
Luis Martínez-Dolz,
Antonio Salvador,
Lilian Grigorian,
Plácido Orosa,
Manuel Portolés,
Miguel Rivera
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ABSTRACT: The aim of this study is to analyze MMP-2 and sTNF-R1 variability, potent predictors of cardiovascular events, in stable hypertensive patients during a 12-month followup. 234 asymptomatic patients (age 60 ± 13, 136 male) out of 252 patients with essential hypertension were followed up. MMP-2 and sTNF-R1 were measured at baseline and after 12 months (stage I). To compare MMP-2 and sTNF-R1 levels over time interval, we used the statistical method of Bland-Altman. MMP-2 and sTNF-R1 reproducibility was good in our patients for the two intervals with a coefficient of reproducibility of 8.2% and 11.3%, respectively. The percentages of patients within 1.96 × standard deviation of the mean were 93.6% and 92.7%. An elevated coefficient of correlation was obtained for MMP-2, basal versus stage I (r = 0.55, P < 0.0001) and for sTNF-R1 (r = 0.75, P < 0.0001). There is good stability in MMP-2 and sTNF-R1 levels in a followup study of patients with stable hypertension. As a consequence, assessment of its concentrations may be a useful tool for monitoring the follow-up of these patients. Measured variations in MMP-2 and sTNF-R1 levels, exceeding 8.2% and 11.3%, respectively, may indicate an increase in cardiovascular risk, thus, could be used to optimizing treatment than blood pressure control alone.
ISRN cardiology. 01/2012; 2012:501894.
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Esther Roselló-Lletí,
Jose R Calabuig,
Pedro Morillas,
Raquel Cortés,
Luis Martínez-Dolz,
Luis Almenar,
Jose R González-Juanatey,
Catheline Lauwers,
Antonio Salvador,
Manuel Portolés,
Vicente Bertomeu,
Miguel Rivera
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ABSTRACT: The variability of NT-proBNP levels has been studied in heart failure, yet no data exist on these changes over time in hypertensive patients. Furthermore, studies on the relationship between natriuretic peptides and inflammatory status are limited.
220 clinically and functionally asymptomatic stable patients (age 59 ± 13, 120 male) out of 252 patients with essential hypertension were followed up, and NT-proBNP was measured at baseline, 12 and 24 months. No differences in NT-proBNP were found with respect to the basal stage in the hypertrophic group, but significant changes were found in non-hypertrophic subjects. The reproducibility of NT-proBNP measurements was better in patients with hypertrophy than in the non-hypertrophic group for the three intervals (stage I-basal; stage II-stage I; stage II-basal) with a reference change value of 34%, 35% and 41%, respectively, in the hypertrophic group. A more elevated coefficient of correlation was obtained in the hypertrophic group than in patients without hypertrophy: basal versus stage I (r = 0.79, p < 0.0001 and r = 0.59, p < 0.0001) and stage I versus stage II (r = 0.86, p < 0.0001 and r = 0.56, p < 0.0001). Finally, levels of NT-proBNP significantly correlated with sTNF-R1 (p < 0.0001) and IL-6 (p < 0.01) during follow-up. A multivariate linear regression analysis showed that sTNF-R1 is an independent factor of NT-proBNP.
This work shows that there is good stability in NT-proBNP levels in a follow-up study of asymptomatic patients with stable hypertension and left ventricular hypertrophy. As a consequence, assessment of NT-proBNP concentrations may be a useful tool for monitoring the follow-up of hypertensive patients with hypertrophy. Measured variations in peptide levels, exceeding 35% in a 12-month follow-up and 41% in a 24-month follow-up, may indicate an increase in cardiovascular risk, and therefore implies adjustment in the medical treatment. In addition, this study shows a link between neurohormonal and inflammatory activation in these patients.
PLoS ONE 01/2012; 7(2):e31189. · 4.09 Impact Factor
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Esther Roselló-Lletí,
Fernando García de Burgos,
Pedro Morillas,
Raquel Cortés,
Luis Martínez-Dolz,
Luis Almenar,
Lilian Grigorian,
Plácido Orosa,
Manuel Portolés,
Vicente Bertomeu,
Miguel Rivera
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ABSTRACT: The urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) reflect the oxidation status of hypertensive subjects and it can be used for monitoring oxidative stress changes. However, the influence of cardiovascular risk factors and inflammation on the urinary levels of this marker in hypertension (HT) has never evaluated. The purpose of this study was to analyze the impact of cardiovascular risk factors, and established inflammatory markers on 8-OHdG in essential HT.
We studied 149 asymptomatic hypertensive patients (61 ± 14 years). A routine physical examination, laboratory analyses, and echo-Doppler study were performed. Urinary 8-OHdG and plasma tumor necrosis factor-α (TNF-α), soluble TNF receptor 1 (sTNF-R1), soluble TNF receptor 2 (sTNF-R2), and interleukin-6 (IL-6) were determined.
8-OHdG/creatinine levels were higher in hypertrophic patients (P = 0.022) and correlated with left ventricular mass index (P < 0.01). When 8-OHdG/creatinine was compared according to obesity and diabetes in our hypertensive subjects, no significant differences were found. 8-OHdG/creatinine was increased in hypertensive smokers (P = 0.032) and women (P = 0.006). Furthermore, 8-OHdG/creatinine correlated with TNF-α, sTNF-R1, sTNF-R2 (P < 0.0001), and with IL-6 (P < 0.05). A multivariate linear regression analysis showed that gender, smoking, and TNF-α were independent factors of 8-OHdG/creatinine.
Urinary 8-OHdG was increased in hypertensive patients with hypertrophy even under medical treatment. The presence of other cardiovascular risk factors on top of HT do not alter the concentrations of this oxidative stress marker, only smoking increasing its levels. TNF-α is an independent factor of 8-OHdG. These data suggest that this urinary marker gives specific additional information, further than blood pressure control alone, when evaluating hypertensive patients.
American Journal of Hypertension 11/2011; 25(2):236-42. · 3.18 Impact Factor
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Raquel Cortés, Esther Roselló-Lletí,
Manuel Portolés,
Luis Almenar,
Luis Martínez-Dolz,
Lilian Grigorian,
Fernando García de Burgos,
Nuria Carpena,
Antonio Salvador,
Vicente Bertomeu,
Miguel Rivera
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ABSTRACT: To analyze the relationship between sFas and soluble TNF receptor 1 (sTNF-R1) with type iii (PIIINP) and i (PINP) amino-terminal propeptide procollagens, and diastole in hypertension (HT).
A group of 253 Caucasian asymptomatic hypertensive patients (age 60±13 years, 139 males) were studied, in whom a physical examination, laboratory analyses (determination of serum PIIINP, PINP, sFas and by radioimmunoassay and ELISA, respectively), and echo-Doppler study were performed.
Serum PINP and PIIINP were increased in left ventricular hypertrophy compared to non-hypertrophy [41 (31-52) vs. 35 (28-47) μg/l, P=.010; and 4.33 (3.71-5.29) vs. 3.98 (3.49-4.58) μg/l, P=.005, respectively]. Furthermore, sFas and sTNF-R1 were also elevated [1.47 (1.2-1.77) vs. 1.37 (1.1-1.59), P=.012; and 466 (331-657) vs. 317 (260-427) μg/l, P<.0001, respectively]. Moreover, serum PIIINP was associated with sFas (r=.386, P<.0001) and sTNF-R1 (r=.298, P<.001); PINP was also associated with these cytokines (r=0.158, P=.011 and r=.241, P<.0001, respectively). Multivariable analyses included sFas (P<.0001) and sTNF-R1 (P<.0001) as independent factors related with serum PIIINP. Finally, marker concentrations were significantly related with left ventricular diastolic function parameters.
Procollagen and anti-apoptotic cytokine levels were increased in our hypertrophic patients. Furthermore, sFas and sTNF-R1 are independent related factors of serum PIIINP. Diastolic parameters were associated with myocardial fibrosis and anti-apoptotic cytokines.
Medicina Clínica 10/2011; 139(8):325-30. · 1.38 Impact Factor
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ABSTRACT: This study sought to determine pro-B-type natriuretic peptide (proBNP), BNP, N-terminal proBNP (NT-proBNP) and GATA-4 in the same cardiac tissue, the correlation among them, and the influence of ischemic etiology on their levels.
Protein levels were analyzed by Western blot techniques and mRNA expression was quantified by quantitative real-time polymerase chain reaction (RT-PCR) in a total of 33 human samples from ischemic (ICM), and control hearts.
Tissue protein level of proBNP is 1.5- and 12-fold higher than BNP or NT-proBNP respectively (p<0.0001), and BNP protein level was 8-fold higher than that of NT-proBNP (p<0.0001) in ICM hearts. Furthermore, proBNP mRNA expression was also increased in ICM (4-fold) compared to control hearts (p<0.05), but there was not a significant increase in GATA-4 mRNA. Then, tissue NP forms showed a high correlation among them (proBNP vs. BNP r=0.74, p<0.0001; proBNP vs. NT-proBNP r=0.43, p=0.03; and BNP vs. NT-proBNP r=0.61, p=0.001, respectively). Furthermore, GATA-4 with proBNP (r=0.536, p=0.007) and BNP (r=0.610, p=0.001) in ischemic samples. Finally, we found that proBNP, BNP, NT-proBNP and GATA-4 were increased in our ICM hearts (by 14%, p=0.004; 46%, p=0.024, 33%, p=0.002, and 49%, p=0.026, respectively) compared with controls.
This study shows higher protein level of proBNP in human hearts than of BNP and NT-proBNP, increased proBNP mRNA expression in ICM samples, and a good correlation among tissue natriuretic peptide and GATA-4. Finally, ICM shows a high tissue protein level of proBNP, BNP, NT-proBNP and GATA-4.
International journal of cardiology 03/2011; 158(2):199-204. · 7.08 Impact Factor
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ABSTRACT: To calculate the relationship of E and P selectins with immunological changes in essential hypertension.
We included 261 patients with essential hypertension with or without left ventricular hypertrophy (LVH), in whom selectins and specific cytokines were quantified.
E-and P-selectins were increased in hypertension compared to controls [75(51) ng/mL versus 45(17) ng/mL, (p<0.0001) and 47(18) ng/mL versus 38(15) ng/mL, (p=0.049), respectively], as well as cytokine concentrations (p<0.0001). Furthermore, selectin values were significantly correlated with changes in immunological markers. The multivariate analysis showed that IL-1ra (p<0.0001) and P-selectin (p=0.013) were independent factors of E-selectin values. For P-selectin, IL-1ra (p=0.005), IL-8 (p<0.0001) and selectin-E (p=0.013) influenced on its concentration. Finally, selectin values were similar between patients with or without left ventricular hypertrophy.
Immunological activation influenced on selectin concentrations in cardiologic asymptomatic patients with essential hypertension. LVH did not induce significant changes.
Medicina Clínica 12/2010; 137(6):254-6. · 1.38 Impact Factor
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ABSTRACT: The amino-terminal pro-brain natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR) values are related to short prognosis in patients with heart failure (HF). This study evaluates the prognostic power of serum and urinary NT-proBNP levels, and eGFR values, in HF patients during a 60-month follow-up.
We studied 93 HF outpatients (66 males, age 65+/-12). Primary endpoint was defined as cardiovascular mortality and secondary endpoint as cardiovascular mortality or admissions.
Only serum NT-proBNP levels had a significant area under the curve for the prognosis of 60-month mortality and combined events, 0.70 (p=0.004) and 0.67 (p=0.019), respectively. Urinary NT-proBNP and eGFR did not have statistical significant areas under the curve. Patients with high serum NT-proBNP had the highest risk of cardiovascular death [44 (IC 95% 38-50) vs. 56 (IC 95% 53-59) months, p=0.0006] and combined events [33 (IC 95% 28-38) vs. 42 (IC 95% 28-38) months; p=0.027]. After the integration of serum NT-proBNP and renal function, patients with high peptide levels and low eGFR had the worst survival [42 (IC 95% 33-52) months; p=0.010]. Finally, only serum NT-proBNP concentration above 933 pg/mL was a predictor of poor survival (hazard ratio=2.81, p=0.033) and NT-proBNP above 550 pg/mL for combined events (hazard ratio=1.79, p=0.049).
Serum NT-proBNP levels were superior to urine NT-proBNP and eGFR values for predicting 60-month cardiovascular death and combined events in HF patients.
Medicina Clínica 03/2010; 134(7):296-302. · 1.38 Impact Factor
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ABSTRACT: The aim was to evaluate the usefulness of urinary N-terminal fragment of B-type natriuretic peptide (NT-proBNP) measurement for predicting the presence of left ventricular hypertrophy (LVH) in 160 asymptomatic patients with essential hypertension. The urinary NT-proBNP/creatinine ratio was higher in patients with LVH than in either those without LVH (P< .0001) or control subjects (P< .0001). Multivariate linear regression analysis identified age (P=.034), left ventricular mass index (P=.026) and serum NT-proBNP level (P=.001) as predictors of the urinary peptide level. The area under the curve for the NT-proBNP/creatinine ratio was 0.71+/-0.04 (P< .0001) for identifying LVH. Logistic regression analysis showed that the NT-proBNP: creatinine ratio was a predictor of LVH (odds ratio=4.074; P=.009). In conclusion, the urinary NT-proBNP concentration is a new marker that could be useful for identifying LVH in subjects with essential hypertension.
Revista Espa de Cardiologia 11/2009; 62(11):1322-5. · 2.53 Impact Factor
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ABSTRACT: The role of the cell nucleus in the development of heart failure (HF) is unknown, so the objectives of this study were to analyse the effect of HF on nucleocytoplasmic transport and density of the nuclear pore complex (NPC).
A total of 51 human heart samples from ischaemic (ICM, n = 30) and dilated (DCM, n = 16) patients undergoing heart transplantation and control donors (CNT, n = 5) were analysed by western blotting. Subcellular distribution of proteins and NPC were analysed by fluorescence and electron microscopy, respectively. When we compared nucleocytoplasmic machinery protein levels according to aetiology of HF, ICM showed higher levels of importins [(IMP-beta3) (150%, P < 0.0001), IMP-alpha2 (69%, P = 0.001)] and exportins [EXP-1 (178%, P < 0.0001), EXP-4 (81%, P = 0.006)] than those of the CNT group. Furthermore, DCM also showed significant differences for IMP-beta3 (192%, P < 0.0001), IMP-alpha2 (52%, P = 0.025), and EXP-1 (228%, P < 0.0001). RanGTPase-activating proteins (RanGAP1 and RaGAP1u) were increased in ICM (76%, P = 0.005; 51%, P = 0.012) and DCM (41%, P = 0.042; 50%, P = 0.029). Furthermore, subcellular distribution of nucleocytoplasmic machinery was not altered in pathological hearts. Finally, nucleoporin (Nup) p62 was increased in ICM (80%) and DCM (109%) (P < 0.001 and P = 0.024). Nuclear pore density was comparable in pathological and CNT hearts, and ICM showed a low diameter (P = 0.005) and different structural configuration of NPC.
This study shows the effect of HF on nucleocytoplasmic trafficking machinery, evidenced by higher levels of importins, exportins, Ran regulators and Nup p62 in ischaemic and dilated human hearts than those in the controls, with NPCs acquiring a different configuration and morphology in ICM.
Cardiovascular research 10/2009; 85(3):464-72. · 5.80 Impact Factor
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Esther Roselló-Lletí,
Miguel Rivera,
Luís Martínez-Dolz,
Jose R González Juanatey,
Raquel Cortés,
Alejandro Jordán,
Pedro Morillas,
Catheline Lauwers,
Jose R Calabuig,
Isabel Antorrena,
Beatriz de Rivas,
Manuel Portolés,
Vicente Bertomeu
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ABSTRACT: Inflammation is an independent risk factor for high blood pressure, and as a consequence inflammatory cytokines could be related with left ventricular hypertrophy (LVH). We sought to assess the association and predictive role of different cytokine levels with LVH in a group of patients with essential hypertension (HT).
We studied 251 asymptomatic hypertensive patients (142 with LVH and 109 without LVH), referred from 11 hospitals. A routine physical examination, laboratory analyses, and echo-Doppler study were performed. Plasma soluble tumor necrosis factor (TNF) receptors (sTNF-R1 and sTNF-R2), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were centrally determined.
Hypertensive patients with LVH had higher inflammatory cytokine levels than the group without hypertrophy (P < 0.001). Multivariate linear regression reported that sTNF-R1 (P < 0.01) was an independent predictor of left ventricular mass index (LVMI). All cytokines had significant area under the curves for detection of LVH, but sTNF-R1 has the highest area, 0.71 +/- 0.03 (P < 0.001). Finally, prevalence of LVH was increased in the group of patients with higher cytokine levels, and logistic regression analysis showed that sTNF-R1 (odds ratio = 2.59, 95% CI of 1.14-5.87) was an independent predictor of LVH.
Cytokine levels were significantly correlated with LVMI in hypertensive patients. The sTNF-R1 was an independent predictor of LVMI. Plasma sTNF-R1 concentrations could be a predictive factor of LVH in patients with essential HT.
American Journal of Hypertension 05/2009; 22(4):444-50. · 3.18 Impact Factor
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ABSTRACT: Several studies have analyzed big endothelin-1 as a marker of mortality in patients with severe heart failure (HF). However, it has not proven prognostic value in patients with moderately symptomatic functional class. Our objective was to evaluate, in a 24 months follow-up, the prognostic power of big endothelin-1 in patients with HF and moderately deteriorated functional class.
Big endothelin-1 levels were measured in a cohort of 90 outpatients (age 64 (13), 70% males) diagnosed with HF. Patients were functionally classified (NYHA).
For the whole population, big endothelin-1 was 0.86 (0.61-1.20)fmol/ml. We evaluated its predictive value in detecting cardiovascular mortality, obtaining an AUC of 0.68 (0.08) (P=.02), and a cut-off value of 0.98 fmol/ml (sensitivity 69%, specificity 75%). When a logistic regression analysis was performed, big endothelin-1 was also an independent predictor of mortality (OR=5.851, P=.009).
Big endothelin-1 predicts cardiovascular mortality in patients diagnosed of HF and moderately symptomatic functional class.
Medicina Clínica 05/2009; 133(5):173-6. · 1.38 Impact Factor
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Raquel Cortés,
Miguel R Otero,
Pedro Morillas, Esther Roselló-Lletí,
Lilian Grigorian,
Luís Martínez-Dolz,
Fernando G de Burgos,
Jose R Calabuig,
Federico Soria,
Teresa Lozano,
Manuel Portolés,
Vicente Bertomeu
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ABSTRACT: Multiple studies have focused on the influence of obesity on natriuretic peptide levels. However, the effect of obesity on amino-terminal propeptide of B-type natriuretic peptide (NT-proBNP) levels in hypertensive (HT) patients remains uncertain.
We studied 252 asymptomatic patients (60 +/- 13 years, 136 men) with essential HT. A routine physical examination, anthropometry, laboratory analyses, echo-Doppler study, and NT-proBNP level determination were performed.
NT-proBNP levels were similar in both obese and nonobese HT (median 56 (25-130) pg/ml vs. median 51 (26-129) pg/ml, P = 0.488). No significant differences were found in obese or nonobese patients with left ventricular hypertrophy (LVH) (median 135 (73-425) pg/ml vs. median 151 (64-274) pg/ml, P = 0.597). The area under the curve was 0.89 +/- 0.03 for NT-proBNP to diagnose LVH in the obese HT patients and 0.88 +/- 0.03 in the nonobese. A logistic regression analysis showed that age, gender, and left ventricular mass index (LVMI) were independent predictors of NT-proBNP levels. Body mass index (BMI) was not significantly associated with NT-proBNP in LVH HT patients.
Obesity is not statistically associated with NT-proBNP levels in HT asymptomatic patients. The same results were observed in our group of patients with LVH. These data are in contrast with those previously found in heart failure, and raise questions about the role of obesity per se as primary cause of decreased NT-proBNP levels in other pathophysiological conditions.
American Journal of Hypertension 08/2008; 21(7):820-5. · 3.18 Impact Factor
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ABSTRACT: The study's objectives were to investigate nuclear stereology and to determine the level of p62, a protein involved in nuclear transport, in human cardiomyocytes from patients with heart failure due to ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM). We studied 23 human hearts: 10 had ICM, 10 had DCM, and three were from control subjects. The size of the nucleus was significantly increased in ICM and DCM hearts compared with those from controls (by 60% and 66%, respectively, P=.03), as was the size of the nucleolus (by 59%, P=.02 and 75%, P=.03, respectively). In addition, the p62 level was significantly increased in both forms of cardiomyopathy compared with controls (ICM 110%, P=.01; and DCM 145%, P=.04). In the ICM group, there were correlations between the p62 level and nuclear size (r=0.615, P=.05) and between the p62 level and the heterochromatin percentage (r=-0.707; P=.02). In conclusion, cardiomyocytes from hearts affected by ICM and DCM showed changes in nuclear and nucleolar morphology. The p62 level had doubled in both forms of cardiomyopathy and, in ICM hearts, there was a correlation with nuclear changes.
Revista Espa de Cardiologia 01/2008; 60(12):1319-23. · 2.53 Impact Factor
