Nuestros investigadores

Susana Ravassa Albéniz

Publicaciones científicas más recientes (desde 2010)

Autores: Treibel, T. A.; López, B; González, A; et al.
ISSN 0195-668X  Vol. 39  Nº 8  2018  págs. 699 - 709
Aims To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n=80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyo-cardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P<0.001) compared with controls, and higher (P<0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P<0.001) but not ECV. Both LGE and ECV correlated independently (P<0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.
Autores: Moreno, MU; Gavira, Juan José; et al.
ISSN 0025-7125  Vol. 101  Nº 1  2017  págs. 43-52
The chronic hemodynamic load imposed by hypertension on the left ventricle leads to lesions in the myocardium that result in structural remodeling, which provides support for alterations in cardiac function, perfusion, and electrical activity that adversely influence the clinical evolution of hypertensive heart disease. Management must include detecting, reducing, and reversing left ventricular hypertrophy, as well as the detection and repair of microscopic lesions responsible for myocardial remodeling. Reducing the burden associated with hypertensive heart disease can be targeted using personalized treatment. The noninvasive, biomarker-mediated identification of subsets of patients with hypertensive heart disease is essential to provide personalized treatment.
Autores: Ravassa, S; López, B; Querejeta, R.; et al.
ISSN 1473-5598  Vol. 35  Nº 4  2017  págs. 853 - 861
OBJECTIVE: Myocardial fibrosis is associated with alterations in the cross-linking and deposition of collagen type I (CCL and CD, respectively). We aimed to evaluate whether the combination of circulating biomarkers of CCL [the carboxy-terminal telopeptide of collagen type I to matrix metalloproteinase-1 ratio (CITP¿:¿MMP-1)] and CD [the carboxy-terminal propeptide of procollagen type I (PICP)] identifies myocardial fibrosis phenotypes with distinct clinical outcome in hypertensive patients with heart failure. METHODS: Endomyocardial biopsies and blood samples from 38 patients (small cohort), and blood samples from 203 patients (large cohort) were analyzed. Myocardial CCL and CD were assessed by histological methods. Serum PICP, CITP, and MMP-1 were determined by ELISA. RESULTS: Small cohort: CITP¿:¿MMP-1 cutoff 1.968 or less and PICP cutoff at least 110.8¿ng/ml were used for predicting high CCL and severe CD, respectively. Large cohort: as defined by the above thresholds, patients were categorized into four subgroups based on the presence (+) or absence (-) of high CCL and severe CD. Compared with CCL-CD-, the adjusted hazard ratios for a composite end point of heart failure hospitalization or cardiovascular death over 5 years in CCL-CD+, CCL+CD-, and CCL+CD+ were 1.11 (P¿=¿0.79), 1.99 (P¿=¿0.07), and 2.18 (P¿=¿0.04), respectively (P for trend¿=¿0.005). In addition, the categorization based on CCL and CD yielded integrated discrimination (P¿=¿0.03) and net reclassification..
Autores: Echegaray, K.; Andreu, I.; Lazkano, A.; et al.
ISSN 0300-8932  Vol. 70  Nº 10  2017  págs. 832 - 840
Introducción y objetivos Se ha estudiado la localización anatómica, las propiedades biomecánicas y el fenotipo molecular del colágeno miocárdico tisular en 40 pacientes con estenosis aórtica grave, fracción de eyección conservada y síntomas de insuficiencia cardiaca. Métodos Se obtuvieron 2 biopsias transmurales de la pared libre del ventrículo izquierdo. La fracción del volumen de colágeno (FVC) se cuantificó mediante rojo picrosirio y la rigidez, mediante el módulo elástico de Young (YEM) evaluado con microscopia de fuerza atómica en regiones misiales y no misiales. Las FVC de tipos I y III se cuantificaron mediante microscopia confocal en áreas con determinación del YEM. Resultados Comparados con sujetos de control, la FVC misial y no misial y el cociente FVC no misial:misial (p < 0,05) estaban incrementados en los pacientes. El cociente entre la velocidad pico de la onda E mitral y la velocidad E del anillo lateral mitral de los pacientes se correlacionaba con la FVC no misial (r = 0,330; p = 0,046) y con el cociente FVC no misial:misial (r = 0,419; p = 0,012). El cociente FVCI:FVCIII y el YEM aumentaban (p ¿ 0,001) en regiones no misiales respecto de las misiales, con correlación entre ellos (r = 0,895; p < 0,001). Conclusiones En la estenosis aórtica grave con fracción de eyección conservada y síntomas de insuficiencia cardiaca, la disfunción diastólica se asocia con un depósito no misial de colágeno aumentado, predominantemente de tipo I y con mayor rigidez. Las características del colágeno tisular pueden contribuir a la disfunción diastólica en estos pacientes.
Autores: Beaumont Javier; San José, Gorka; Moreno, MU; et al.
ISSN 2045-2322  Vol. 7  2017  págs. 41865
Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-beta(1)-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.
Autores: Maloberti A; Meani, P.; Vallerio, P.; et al.
ISSN 1473-5598  Vol. 35  Nº 1  2017  págs. 154 - 161
OBJECTIVE: Annexin A5 (AnxA5) has been previously linked to the presence of carotid and cardiac target organ damage (TOD) in the context of heart failure and rheumatologic patients. However, information is scant in the context of hypertension. Aim of our study was to evaluate AnxA5 in treated hypertension patients compared with normotensive controls and to determine whether it is associated with vascular and heart TOD evaluated as arterial stiffness, carotid plaque and left ventricular hypertrophy. METHODS: We enrolled 123 consecutive treated hypertension and 124 normotensive controls. TOD was evaluated as pulse wave velocity (PWV, complior), left ventricular hypertrophy (echocardiography) and intima-media thickness and carotid plaque presence (ecographic methods). AnxA5 levels was dosed and compared in patients with and without hypertension and with and without TOD. RESULTS: With similar age hypertension patients showed higher SBP, DBP and AnxA5 levels (13.9¿±¿11.1 vs 10.1¿±¿8.4¿ng/ml, P¿<¿0.001) compared with controls. Regarding TOD hypertension showed higher PWV (8.5¿±¿1.8 vs 7.6¿±¿1.5¿m/s, P¿<¿0.001) and LVMI (121.7¿±¿29.3 vs 113.5¿±¿21.1¿g/m, P¿<¿0.05), whereas carotid intima-media thickness was superimposable. AnxA5 correlates with PWV (r¿=¿0.13, P¿<¿0.05) and DBP (r¿=¿0.15, P¿<¿0.01), whereas it has never been found as a significant independent predictor of TOD in linear regression analysis. CONCLUSION: Our data have shown that AnxA5 levels are increased in treated hypertension patients. In this condition, it is probably released in the plasma as a defensive mechanism through its anti-inflammatory and anticoagulants effects. We found a significant association with arterial stiffness, but AnxA5 was not found to be a significant predictor of TOD.
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
ISSN 2045-2322  Vol. 7  2017  págs. 40696
This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF.
Autores: Ravassa, S; Gallego, C. ; Querejeta, R.; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 587 - 588
Autores: González, A; Pueyo, Jesús Ciro; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 123
Autores: González, A; López, B; Ravassa, S; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 9 - 10
Autores: Díez, J; González, A; Ravassa, S;
ISSN 0735-1097  Vol. 67  Nº 13  2016  págs. 1569 - 1571
Autores: Huerta, Ana; López, B; Ravassa, S; et al.
ISSN 0263-6352  Vol. 34  Nº 1  2016  págs. 130 - 138
OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P¿<¿0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P¿<¿0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P¿<¿0.01), TIMP-1 and osteopontin (P¿<¿0.001) and inversely correlated with MMP-1:TIMP-1 (P¿<¿0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P¿<¿0.01) and TIMP-1 (P¿<¿0.0
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
ISSN 0143-5221  Vol. 130  Nº 23  2016  págs. 2139 - 2149
MicroRNAs have been associated with cardiomyocyte apoptosis, a process involved in myocardial remodelling in aortic valve (Av) stenosis (AS). Our aim was to analyse whether the dysregulation of myocardial microRNAs was related to cardiomyocyte apoptosis in AS patients. Endomyocardial biopsies were obtained from 28 patients with severe AS (based on pressure gradients and Av area) referred for Av replacement and from necropsies of 10 cardiovascular disease-free control subjects. AS patients showed an increased (P<0.001) cardiomyocyte apoptotic index (CMAI) compared with controls. Two clusters of patients were identified according to the CMAI: group 1 (CMAI ¿ 0.08%; n=16) and group 2 (CMAI > 0.08%; n=12). Group 2 patients presented lower cardiomyocyte density (P<0.001) and ejection fraction (P<0.05), and higher troponin T levels (P<0.05), prevalence of heart failure (HF; P<0.05) and NT-proBNP levels (P<0.05) than those from group 1. miRNA expression profile analysed in 5 patients randomly selected from each group showed 64 microRNAs down-regulated and 6 up-regulated (P<0.05) in group 2 compared with group 1. Those microRNAs with the highest fold-change were validated in the full two groups corroborating that miR-10b, miR-125b-2* and miR-338-3p were down-regulated (P<0.05) in group 2 compared with group 1 and control subjects. These three microRNAs were inversely correlated (P<0.05) with the CMAI. Inhibition of miR-10b induced an increase (P<0.05) of apoptosis and increased expression (P<0.05) of apoptosis protease-activating factor-1 (Apaf-1) in HL-1 cardiomyocytes. In conclusion, myocardial down-regulation of miR-10b may be involved in increased cardiomyocyte apoptosis in AS patients, probably through Apaf-1 up-regulation, contributing to cardiomyocyte damage and to the development of HF.
Autores: López, B; Ravassa, S; González, A; et al.
ISSN 0735-1097  Vol. 67  Nº 3  2016  págs. 251 - 260
BACKGROUND: Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function. OBJECTIVES: This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded. METHODS: Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples. RESULTS: Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ¿1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (¿1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death. CONCLUSIONS: Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.
Autores: Zhang, Z. Y. ; Ravassa, S; Yang, W. Y.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 11  Nº 12  2016  págs. e0167582
Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e' decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e' increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e' decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p <= 0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure.
Autores: López, B; González, A; Ravassa, S; et al.
ISSN 0735-1097  Vol. 65  Nº 22  2015  págs. 2449 - 2456
Myocardial fibrosis impairs cardiac function, in addition to facilitating arrhythmias and ischemia, and thus influences the evolution and outcome of cardiac diseases. Its assessment is therefore clinically relevant. Although tissue biopsy is the gold standard for the diagnosis of myocardial fibrosis, a number of circulating biomarkers have been proposed for the noninvasive assessment of this lesion. A review of the published clinical data available on these biomarkers shows that most of them lack proof that they actually reflect the myocardial accumulation of fibrous tissue. In this "call to action" article, we propose that this absence of proof may lead to misinterpretations when considering the incremental value provided by the biomarkers with respect to traditional diagnostic tools in the clinical handling of patients. We thus argue that strategies are needed to more strictly validate whether a given circulating biomarker actually reflects histologically proven myocardial fibrosis before it is applied clinically.
Autores: Ravassa, S; Beaumont Javier; Huerta, Ana; et al.
ISSN 0891-5849  Vol. 81  2015  págs. 1 - 12
Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.
Autores: Ravassa, S; Kuznetsova, T.; Varo, N; et al.
ISSN 0167-5273  Vol. 185  2015  págs. 177 - 185
BACKGROUND/OBJECTIVES: The validation of effective screening tools for the identification of patients with subclinical myocardial remodelling is a major clinical need. Thus, we explored the associations of circulating biomarkers of cardiomyocyte injury and stress with subclinical cardiac remodelling and dysfunction, and with biomarkers reflecting collagen turnover. METHODS: We randomly recruited 727 subjects from a general population (51.2% women; mean age 51.3 years). Measurements included echocardiographic left atrial (LA) and left ventricular (LV) structure and function, quantification of high sensitivity cardiac Troponin T (hs-cTnT), NT-proBNP, and biomarkers of collagen types I and III turnover. RESULTS: In unadjusted and adjusted analyses, the prevalence of LA enlargement (LAE), LV hypertrophy (LVH) and LV diastolic dysfunction (LVDD) increased with higher hs-cTnT (P ¿ 0.031). NT-proBNP was independently associated with LVDD (P=0.009). Both biomarkers combined yielded significant integrated discrimination and net reclassification improvements (P ¿ 0.014 and P ¿ 0.009, respectively) for LAE, LVH and LVDD, over the conventional risk factors, and were independently and positively associated with biomarkers of collagen type I turnover. In a sensitivity analysis, after excluding participants with previous cardiac diseases, our findings remained consistent. CONCLUSIONS: Our population-based study suggested that subclinical LV and LA remodelling were associated with hs-cTnT, and that, in combination with NT-proBNP, hs-cTnT showed incremental diagnostic utility over the conventional risk factors. Both biomarkers were associated with biomarkers of collagen type I turnover. Thus, biomarkers of cardiomyocyte microinjury and hemodynamic stress may stimulate fibrosis-related mechanisms and facilitate the diagnosis of subclinical LA and LV remodelling and dysfunction in the general population.
Autores: Ravassa, S; Barba, Joaquín; Coma, María Isabel; et al.
ISSN 1475-2840  Vol. 12  2013  págs. 143
Background: Patients with type 2 diabetes mellitus (T2DM) present subclinical left ventricular systolic and/or diastolic dysfunction (LVD). Dipeptidyl peptidase-4 (DPP4) inactivates peptides that possess cardioprotective actions. Our aim was to analyze whether the activity of circulating DPP4 is associated with echocardiographically defined LVD in asymptomatic patients with T2DM. Methods: In this cross-sectional study, we examined 83 T2DM patients with no coronary or valve heart disease and 59 age and gender-matched non-diabetic subjects. Plasma DPP4 activity (DPP4a) was measured by enzymatic assay and serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) was measured by enzyme-linked immunosorbent assay. LV function was assessed by two-dimensional echocardiographic imaging, targeted M-mode recordings and Doppler ultrasound measurements. Differences in means were assessed by t-tests and one-way ANOVA. Associations were assessed by adjusted multiple linear regression and logistic regression analyses. Results: DPP4a was increased in T2DM patients as compared with non-diabetic subjects (5855 +/- 1632 vs 5208 +/- 957 pmol/min/mL, p < 0.05). Clinical characteristics and echocardiographic parameters assessing LV morphology were similar across DPP4a tertiles in T2DM patients. However, prevalence of LVD progressively increased across incremental DPP4a tertiles (13%, 39% and 71%, all p < 0.001). Multivariate regression analysis confirmed the independent associations of DPP4a with LVD in T2DM patients (p < 0.05). Similarly, multiple logistic regression analysis showed that an increase of 100 pmol/min/min plasma DPP4a was independently associated with an increased frequency of LVD with an adjusted odds ratio of 1.10 (95% CI, 1.04 to 1.15, p = 0.001). Conclusions: An excessive activity of circulating DPP4 is independently associated with subclinical LVD in T2DM patients. Albeit descriptive, these findings suggest that DPP4 may be involved in the mechanisms of LVD in T2DM.
Autores: Ravassa, S; Beloqui, Óscar; Varo, N; et al.
ISSN 0263-6352  Vol. 31  Nº 3  2013  págs. 587 - 594
Objectives: Cardiotrophin-1 (CT-1) induces hypertrophic growth and contractile dysfunction in cardiomyocytes. This cross-sectional study was aimed to analyze CT-1 associations with echocardiographically assessed left ventricular systolic properties taking into account the influence of left ventricular growth [i.e. left ventricular hypertrophy (LVH) and inappropriate left ventricular mass (iLVM)] in asymptomatic hypertensive patients. Methods: Serum CT-1 was measured by ELISA in 278 asymptomatic hypertensive patients with a left ventricular ejection fraction more than 50% and in 25 age and sex-matched normotensive patients. Results: Serum CT-1 was increased in hypertensive patients as compared to normotensive patients. CT-1 was directly correlated with parameters of left ventricular mass (LVM) and inversely correlated with parameters assessing myocardial systolic function and left ventricular chamber contractility in hypertensive patients, these associations being independent of a number of potential confounding factors. Interestingly, the associations of CT-1 with myocardial systolic function were independent of LVM even in patients with LVH or iLVM. In addition, there was a significant increment of serum CT-1 in hypertensive patients with LVH or iLVM, especially in those in whom LVH or iLVM were accompanied by impaired myocardial systolic function, as compared to the remaining hypertensive patients and normotensive patients. Plasma amino-terminal pro-brain natriuretic peptide was not correlated with any of the assessed left ventricular systolic parameters in either group of patients. Conclusion: These findings suggest that serum CT-1 is associated with myocardial systolic dysfunction in asymptomatic hypertensive patients, independently of LVM, even in those patients with pathologic left ventricular growth.
Autores: López, B; González, A; Lindner, D.; et al.
ISSN 0008-6363  Vol. 99  Nº 1  2013  págs. 111 - 120
We investigated whether the pro-fibrotic matricellular protein osteopontin (OPN) is associated with the enzymes involved in the extracellular synthesis of fibril-forming collagen type I (i.e. procollagen C-proteinase, PCP) and its cross-linking to form insoluble fibrils (i.e. lysyl oxidase, LOX) in heart failure (HF) of hypertensive origin. OPN, PCP, and LOX were assessed by histochemical and molecular methods in the myocardium of 21 patients with hypertensive heart disease (HHD) and HF. Whereas the myocardial expression of OPN was very scarce in control hearts (n 10), it was highly expressed in HF patients (P 0.0001). OPN was directly correlated with LOX (r 0.460, P 0.041), insoluble collagen (r 0.534, P 0.015), pulmonary capillary wedge pressure (r 0.558; P 0.009), and left-ventricular (LV) chamber stiffness (r 0.458, P 0.037), and inversely correlated with LV ejection fraction (r 0.513, P 0.017) in all patients. OPN did not correlate with PCP and other parameters assessing collagen synthesis by fibroblasts or degradation by matrix metalloproteinases. In vitro studies showed that OPN significantly (P 0.05) increases the expression and activity of LOX in human cardiac and dermal fibroblasts. An excess of OPN is associated with increased LOX and insoluble collagen, as well as with LV stiffness and systolic dysfunction in patients with HHD and HF. In addition, OPN up-regulates LOX in human fibroblasts. It is suggested that the OPNLOX axis might facilitate the formation of insoluble collagen (i.e. stiff and resistant to degradation) and the subsequent alteration in LV mechanical properties and function in patients with HHD and HF.
Autores: Ravassa, S; Díez, J;
ISSN 0008-6363  Vol. 94  Nº 2  2012  págs. 316 - 323
During myocardial infarction (MI), a variety of mechanisms contribute to the activation of cell death processes in cardiomyocytes, determining the final MI size, subsequent mortality, and post-MI remodelling. The deleterious mechanisms accompanying the ischaemic and reperfusion phases in MI include deprivation of oxygen, nutrients, and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration of the ischaemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of which contribute to the activation of apoptosis and necrosis in cardiomyocytes. During the last few years, glucagon-like peptide-1 (GLP-1) (7-36)-based therapeutic strategies have been incorporated into the treatment of patients with type 2 diabetes mellitus. Cytoprotection is among the pleiotropic actions described for GLP-1 in different cell types, including cardiomyocytes. This paper reviews the most relevant experimental and clinical studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in the cardioprotection induced by GLP-1, analysing in depth its potential role as a therapeutic target in the ischaemic and reperfused myocardium as well as in other pathologies that are associated with myocardial remodelling and heart failure.
Autores: Ravassa, S; Díez, J;
ISSN 0188-9796  Vol. 59  Nº 9  2012  págs. 561 - 569
La activación de diferentes procesos de muerte celular en los cardiomiocitos tras un infarto de miocardio (IM) contribuye al tamaño final del infarto, a la mortalidad subsecuente y al remodelado postinfarto en los supervivientes. Los diversos mecanismos deletéreos activados durante las fases de isquemia y reperfusión en el IM incluyen la privación de oxígeno, la disponibilidad reducida de nutrientes y factores de supervivencia, la acumulación de residuos, la generación de especies reactivas del oxígeno, la sobrecarga de calcio, la infiltración por neutrófilos en el área isquémica, la depleción energética, y la apertura del poro de transición de permeabilidad mitocondrial, todos ellos mecanismos de activación de apoptosis y necrosis en los cardiomiocitos. En los últimos años, las terapias basadas en el péptido similar al glucagón tipo 1 [GLP-1 (7-36) amida] han adquirido mayor relevancia como tratamiento metabólico de la diabetes mellitus tipo 2. Entre las acciones atribuidas a GLP-1 destaca la preservación de la viabilidad en diferentes tipos celulares, entre ellos los cardiomiocitos. Este artículo revisa los principales estudios experimentales que han contribuido a una mayor comprensión de la citoprotección inducida por GLP-1 en el miocardio y de sus efectos en la función cardiaca, ahondando en el estudio de su papel como diana terapéutica, no solo en el contexto de la diabetes mellitus sino también en otras patologías que cursan con remodelado cardiaco.
Autores: González, A; López, B; Ravassa, S; et al.
ISSN 1355-008X  Vol. 42  Nº 1  2012  págs. 9 - 17
Hypertensive heart disease, here defined by the presence of pathologic left ventricular hypertrophy in the absence of a cause other than arterial hypertension, is characterized by complex changes in myocardial structure including enhanced cardiomyocyte growth and non-cardiomyocyte alterations that induce the remodeling of the myocardium, and ultimately, deteriorate left ventricular function and facilitate the development of heart failure. It is now accepted that a number of pathological processes mediated by mechanical, neurohormonal, and cytokine routes acting on the cardiomyocyte and the non-cardiomyocyte compartments are responsible for myocardial remodeling in the context of arterial hypertension. For instance, cardiotrophin-1 is a cytokine member of the interleukin-6 superfamily, produced by cardiomyocytes and non-cardiomyocytes in situations of biomechanical stress that once secreted interacts with its receptor, the heterodimer formed by gp130 and gp90 (also known as leukemia inhibitory factor receptor beta), activating different signaling pathways leading to cardiomyocyte hypertrophy, as well as myocardial fibrosis. Beyond its potential mechanistic contribution to the development of hypertensive heart disease, cardiotrophin-1 offers the opportunity for a new translational approach to this condition. In fact, recent evidence suggests that cardiotrophin-1 may serve as both a biomarker of left ventricular hypertrophy and dysfunction in hypertensive patients, and a potential target for therapies aimed to prevent and treat hypertensive heart disease beyond blood pressure control.
Autores: Beaumont Javier; González, A; López, B; et al.
ISSN 0263-6352  Vol. 30  Nº 1  2012  págs. 34 - 37
Autores: Ravassa, S; González, A; Díez, J;
ISSN 1131-3587  Vol. 11  Nº Supl. 4  2011  págs. 37 - 41
El sistema renina-angiotensina desempeña un papel determinante en la aparición de complicaciones cardiovasculares y renales en el contexto de la diabetes mellitus. Las acciones del sistema reninaangiotensina incluyen no sólo las dependientes de la producción de angiotensina II, sino también las resultantes de la activación del sistema renina-pro-renina/receptor de la pro-renina. En los últimos años, diversos estudios clínicos y experimentales señalan la implicación del sistema renina-pro-renina/receptor de la pro-renina en el daño de órganos diana en la diabetes mellitus. Este artículo revisa los principales estudios que han contribuido a una mayor comprensión de dicho sistema y de su papel como posible diana terapéutica en la diabetes mellitus.
Autores: González, A; Ravassa, S; Beaumont Javier; et al.
ISSN 0735-1097  Vol. 58  Nº 18  2011  págs. 1833 - 1843
Classical therapy of heart failure is based on treatment of its pre-disposing/triggering factors and of the neurohumoral activation secondary to the deterioration of cardiac function. A new view is emerging that proposes the direct intervention on the pathological structural remodeling of the myocardium as part of heart failure therapy. In fact, in conditions of chronic injury, the cardiomyocytic and the noncardiomyocytic components of the myocardium undergo a series of structural lesions (i.e., cardiomyocyte growth and death, inflammation, alterations of collagen matrix, and microvascular rarefaction) that are governed by a complex interplay of mechanisms. Our increasing knowledge of the role of these mechanisms in remodeling enables us not only to better understand how our more successful therapies work but also to explore novel therapies for the future. In this paper, we will examine recent insights from experimental and pilot clinical studies that have provided new targets for interventions to prevent or reverse inflammation, alterations of collagen matrix, and cardiomyocyte death.
Autores: Díez, J; López, B; Beaumont Javier; et al.
ISSN 0263-6352  Vol. 29  Nº 4  2011  págs. 660 - 662
Autores: Ravassa, S; Carr, R. D.; Díez, J;
ISSN 0363-6135  Vol. 300  Nº 4  2011  págs. H1361 - H1372
Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP-1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 ¿M), or ceramide (15 ¿M) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL-1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP-1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis.
Autores: Díez, J; González, A; Ravassa, S;
ISSN 0194-911X  Vol. 56  Nº 6  2010  págs. 1045 - 1046
Autores: Ravassa, S; Garcia-Bolao, I; et al.
ISSN 0008-6363  Vol. 88  Nº 2  2010  págs. 304 - 313