Antonio García-Honrubia

University of Murcia, Murcia, Murcia, Spain

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Publications (14)61.3 Total impact

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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis. HCM is an autosomal dominant disease caused by more than 400 mutations in sarcomeric genes. Changes in non-sarcomeric genes contribute to its phenotypic heterogeneity. Cardiac fibrosis can be studied using late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We evaluated the potential role of two polymorphisms in non-sarcomeric genes on interstitial fibrosis in HCM. Two polymorphisms in non-sarcomeric genes [ACE (deletion of 287-bp in the 16(th) intron) and RETN (-420C>G)] were analysed in 146 HCM patients. Cardiac fibrosis was assessed using LGE to determine the number of affected segments. Allelic frequencies in ACE and RETN polymorphisms were consistent with the Hardy-Weinberg equilibrium (both P > 0.05). We found that the presence of the polymorphic allele in the -420C>G RETN polymorphism was independently associated with the number of affected segments of LGE (P = 0.034). Increased circulating resistin concentration, measured by enzyme-linked immunosorbent assay, was associated with a higher degree of cardiac fibrosis. Myocardial fibrosis, assessed by Masson's trichrome staining, was associated with the -420C>G RETN polymorphism in 46 tissue samples obtained by septal myectomy (P = 0.044). The -420C>G RETN polymorphism was independently associated with the degree of cardiac fibrosis, assessed by LGE, in patients with HCM. In addition, there was an association between the polymorphism and circulating resistin levels as well as with myocardial fibrosis in tissues obtained by myectomy. Investigating the physiological implication of the RETN polymorphism in HCM in combination with the use of imaging technologies might help to establish the severity of disease in patients with HCM. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 12/2014; · 6.46 Impact Factor
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    ABSTRACT: Several non-sarcomeric genes have been postulated to act as modifiers in the phenotypic manifestations of hypertrophic cardiomyopathy (HCM). The development of atrial fibrillation (AF) in HCM has adverse prognostic implications with increased thromboembolism and functional class impairment. We tested the hypothesis that 2 non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] are associated with the development of AF. Prospective study.Methods: Two polymorphisms in non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] were analyzed in 159 HCM patients (49.3±14.9 years, 70.6% male) and 136 controls. All subjects were clinically stable and in sinus rhythm at entry in the study, without ischemic heart disease or other significant co-morbidities that could mask the effect of the analyzed polymorphisms (i.e. previous AF). Thirty-nine patients (24.4%) developed AF during a median follow-up of 49.5 months.Results: Patients with the -344T>C polymorphism in CYP11B2 gene had a higher risk for AF development (HR: 3.31(95%CI 1.29-8.50); p=0.008). In a multivariate analysis, the presence of the C allele in CYP11B2 gene [HR: 3.02(1.01-8.99); p=0.047], previous AF [HR: 2.81(1.09-7.23) p=0.033] and a left atrial diameter of ≥42mm [HR: 2.69(1.01-7.18) p=0.048] were independent predictors of AF development. The presence of the polymorphic allele was associated with higher aldosterone serum levels. We have shown for the first time that the CYP11B2 polymorphism is an independent predictor for AF development in HCM patients. This highlights the importance of non-sarcomeric genes in the phenotypic heterogeneity of HCM. The association with higher aldosterone serum levels could relate to greater fibrosis and cardiac remodelling.
    QJM: monthly journal of the Association of Physicians 03/2014; · 2.36 Impact Factor
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    ABSTRACT: Introduction. Aiming at identifying biomarkers for hypertrophic cardiomyopathy (HCM), the serum proteome was explored through a two-dimensional gel-based proteomic approach (2D-DIGE) coupled with mass spectrometry and database interrogation. Methods. Serum samples from 20 male HCM patients and their sex- and age-matched controls were cleaned from interfering components. Patients and controls were pooled in five matched groups with the same age, and proteins extracts from each pool were labelled with cyanine dyes. Then, gel images were analysed using a fluorescence scanner and proteins were identified. Tryptic peptides were analysed by capillary reversed-phase liquid chromatography coupled online with tandem mass spectrometry (MS/MS). Results. Four different proteins were observed to be differentially expressed between HCM patients and their matched controls. Of them, decreases in haptoglobin levels were confirmed to be associated with HCM in an independent set of 181 consecutive HCM patients from our monographic clinic and 114 controls with similar age and sex using a nephelometer-based technique. Moreover, a significant negative correlation was observed between haptoglobin and subaortic gradient, thus highlighting the role of haptoglobin in HCM. Conclusion. All these observations point out the utility of the 2D-DIGE proteomic strategy for the identification of serum proteins indicative of the presence of cardiac injury.
    Annals of Medicine 05/2013; · 4.73 Impact Factor
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    ABSTRACT: The growth differentiation factor 15 (GDF-15) has been shown up-regulated in stress conditions and to have regulatory actions in myocyte hypertrophy. We hypothesized that GDF-15 could be related to disease severity and functional status in patients with hypertrophic cardiomyopathy (HCM). We performed a study which includes 102 consecutive outpatient HCM subjects, 73% males, aged 47.1±14.6 years. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, symptom-limited treadmill exercise, 24-hour ECG-Holter monitoring, and magnetic resonance with Gadolinium. Several biomarkers, associated with myocardial remodeling and damage, were compared to GDF-15 levels. The assays were performed with commercial ELISAs or standardized methods when available. There was a significant association between GDF-15 levels and comorbidities, being higher in hypertension (p=0.001), diabetes (p=0.030), atrial fibrillation (p=0.012), dyspnea (p=0.020) and NYHA≥II functional class (p=0.037). GDF-15 levels were positively correlated with clinical variables (age, worse exercise capacity and mild renal dysfunction) and biomarkers of interstitial remodeling, such as metalloproteinase-2 (r: 0.40; p=0.009), N-terminal pro-B-type natriuretic peptide (r: 0.28; p=0.049), high-sensitivity troponin T (r: 0.30; p=0.003) and von Willebrand factor (r: 0.33; p=0.001). Multivariate analysis was assessed to estimate the involvement of these different factors in the GDF-15 levels, confirming the independent implication of severe dyspnea and functional status. The present results show that higher levels of GDF-15 are associated to conditions of severe disease in HCM. Hence, GDF-15 is suggested as a novel marker related to the severity and could represent a further useful tool in monitoring functional capacity of HCM patients.
    European Journal of Internal Medicine 03/2012; 23(2):169-74. · 2.30 Impact Factor
  • Clinical Chemistry and Laboratory Medicine 06/2011; 49(9):1569-71. · 3.01 Impact Factor
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate hypertrophy, small-vessel coronary artery disease, myocyte disarray, and increased interstitial fibrosis. High-sensitivity troponin T (hs-TnT) could be a reliable indicator of myocardial remodeling, a proposed prognostic marker in HCM. Therefore we hypothesized that increased hs-TnT levels are related to different variables associated with myocardial remodeling, such as the presence of fibrosis assessed with cardiac magnetic resonance imaging (MRI). We included 95 hemodynamically stable HCM patients, 72 male, aged 45.7 ± 14.2 years, and 45 healthy control subjects with similar age and gender. A complete history and clinical examination was performed, including 12-lead electrocardiogram (ECG), echocardiography, 24-hour ECG-Holter monitoring, symptom-limited treadmill exercise test, and late gadolinium enhancement in cardiac MRI. Risk factors for sudden death were evaluated. A blinded cardiac MRI was performed with late gadolinium enhancement study. Serum hs-TnT levels were assayed. A high proportion (42%) of hemodynamically stable patients studied showed increased levels of hs-TnT. The hs-TnT levels were raised in patients with severe dyspnea: New York Heart Association (NYHA) functional class ≥3 (P = .020), outflow obstruction (P = .013), systolic dysfunction (P = .037), abnormal blood pressure response (P = .036), and presence of gadolinium enhancement (P = .021). The hs-TnT levels correlated positively with the maximum left ventricular wall thickness (r = 0.47; P < .001), left atrial diameter (r = 0.36, P = .014), and outflow gradient (r = 0.28; P = .008). A high proportion of hemodynamically stable patients show increased levels of hs-TnT. We observed that raised hs-TnT serum levels are associated with different conditions related to the severity of the disease.
    Journal of cardiac failure 12/2010; 16(12):950-6. · 3.25 Impact Factor
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is characterised by inappropriate hypertrophy, small-vessel coronary artery disease, myocyte disarray and increased interstitial fibrosis. Microvascular dysfunction is a common finding in HCM and its extent has been proposed as an important prognostic marker. Plasma von Willebrand factor (vWf) is an established marker of endothelial damage or dysfunction; however it has scarcely been studied in HCM. We hypothesised that vWf could be raised in patients with HCM and be related to different variables associated with severity of HCM. We included 124 HCM patients, 93 males, aged 48+/-15 years, 59 healthy control subjects with similar age and sex and 20 patients with ischemic heart disease but clinical stability for the last 6 months. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, 24 hours ECG-Holter monitoring, and symptom limited treadmill exercise test. Risk factors for sudden death were evaluated. A blinded cardiac MRI was performed with late enhanced study with Gadolinium. Plasma vWf levels were assayed by commercial ELISA. Patients showed higher levels of vWf (140.0+/-65.0 UI/ml vs 105.0+/-51.0 UI/ml, p<0.001) even after adjusting for ABO blood group. vWf levels were found raised in patients with severe functional class (168.4+/-65.9 UI/mL vs 132.4+/-60.7 UI/mL, p=0.020), atrial fibrillation (175.8+/-69.4 UI/mL vs 133.0+/-59.0 UI/mL, p=0.005), hypertension (161.4+/-60.8 vs 128.9+/-60.5, p=0.010) obstruction (153.9+/-67.9 vs 128.2+/-57.4 UI/mL, p=0.046) and non sustained ventricular tachycardia (159.3+/-59.1 vs 133.0+/-63.0, p=0.049). vWf correlated with age (r:0.26; p=0.006) and obstruction (r:0.22; p=0.021). We show, for the first time, patients with HCM present significantly raised levels of vWf. These are associated with different conditions related to the severity of the disease.
    Thrombosis Research 02/2010; 126(1):e46-50. · 3.13 Impact Factor
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    ABSTRACT: Using gadolinium-enhanced cardiovascular magnetic resonance, it is possible to evaluate the presence of myocardial fibrosis in hypertrophic cardiomyopathy. Classical disease markers are weak predictors of functional disability in affected patients. Our objective was to study the relationship between the degree of myocardial fibrosis observed by cardiac magnetic resonance and exercise capacity. We performed cardiac magnetic resonance, echocardiography, exercise testing and Holter monitoring, along with the usual clinical assessments, in 98 patients (age, 46.3+/-15.4 years, 71.4% male) referred from two specialist hypertrophic cardiomyopathy clinics. Cardiac magnetic resonance assessment included quantifying the degree of fibrosis (i.e., the percentage of the myocardium showing enhancement) 10 min after gadolinium infusion. Symptom-limited exercise testing was used to determine exercise capacity (in metabolic equivalent [MET] units). In 71 patients, the basal N-terminal probrain natriuretic peptide (NT-proBNP) level was also measured. Late enhancement was observed on cardiac magnetic resonance in 67 (68.4%) patients. These patients had a lower exercise capacity (8.04+/-3.56 MET vs. 10.41+/-3.57 MET; P=.003). There was an inverse correlation between the percentage of fibrosis and exercise capacity (r=-0.21; P=.044). The best predictor of exercise capacity was the logarithm of the NT-proBNP level (r=-0.5; P< .0001). Multivariate analysis confirmed that age, a history of atrial fibrillation, the basal NT-proBNP level and the presence of fibrosis were independent predictors of exercise capacity (r2 for the model=0.47). The observation of areas of late gadolinium enhancement on cardiac magnetic resonance was independently associated with poor exercise capacity in patients with hypertrophic cardiomyopathy.
    Revista Espa de Cardiologia 09/2008; 61(8):853-60. · 3.20 Impact Factor
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    ABSTRACT: Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. An increase in extracellular matrix produces interstitial fibrosis, by raised amounts of collagen type I/III. Regions of myocardial late gadolinium enhancement by cardiac magnetic resonance (CMR) represented increased myocardial collagen. Regarding the role of matrix metalloproteinases (MMPs) in myocardial remodeling and subsequent fibrosis, the aim of our study was to explore the relation between MMP system and myocardial late gadolinium enhancement by CMR (as expression of image-documented fibrosis) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (as a marker of cardiac overload) in HCM. We included 67 HCM patients (44 men aged 49 +/- 14 years) and were compared to 58 controls with similar age and sex. Risk factors for sudden death were recorded. A blinded CMR was performed with gadolinium. Matrix metalloproteinase 1, MMP-2, and MMP-9 plasma levels were assayed by enzyme-linked immunosorbent assay. Serum samples were used for measurement of NT-proBNP. In patients, >50% of MMP-1 values were below the lowest limit of detection of the technique. Raised levels of MMP-2, MMP-9, and NT-proBNP were observed in HCM patients (all P < .01). Matrix metalloproteinase 2 was associated with dyspnea (P = .049) and correlated with MMP-9 (r = 0.28, P = .025) and NT-proBNP (r = 0.39, P = .001). Matrix metalloproteinase 9 was associated with the presence of gadolinium enhancement in CMR (P = .001) and correlated with NT-proBNP (r = 0.52, P < .001). NT-proBNP was also associated with gadolinium enhancement (P = .006). Both MMP-2 and MMP-9 correlated negatively with exercise capacity (metabolic equivalent units), (r = -0.36 and r = -0.42 respectively, both P < .01). On multivariate analysis (adjusted by sudden death risk factors and echocardiographic markers), only MMP-9 was associated with fibrosis (P = .011). Matrix metalloproteinase 9 is independently associated with gadolinium enhancement on CMR in patients with hypertrophic cardiomyopathy, suggesting that the MMP system has an important role in cardiac remodeling and fibrosis in this condition.
    American heart journal 07/2008; 156(1):85-91. · 4.65 Impact Factor
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    ABSTRACT: There are limited data on the influence of genetic polymorphisms in atrial fibrillation (AF) stroke risk. We hypothesized that a functional haemostatic polymorphism, that is, the factor VII -323 Del/Ins polymorphism, would influence the prothrombotic state associated with AF, as well as stroke risk. Other functional polymorphisms were also tested. We performed a cross-sectional study of 119 AF patients, who were compared to 96 patients with stroke secondary to AF. In the first patient group, we analysed plasma prothrombin fragment 1+2 levels (F1+2, an index of thrombin generation) to reflect the prothrombotic state of AF. AF patients carrying the -323 Ins allele had lower plasma F1+2 levels (P=0.015). After multivariate analysis adjusted by age, sex and clinical risk factors, advanced age and 807C/T polymorphism of glycoprotein Ia (GPIa) gene were associated with higher risk of ischaemic stroke (OR: 1.06; P=0.003 and OR: 1.91; P=0.025), whilst FVII Ins -323 allele was associated with lower stroke risk (OR: 0.41; P=0.017). FVII -323 Ins allele may modulate the prothrombotic state associated with AF. Despite the small sample size, we found that FVII Ins -323 allele could be associated with a lower stroke risk in AF, whereas the 807C/T polymorphism may increase the risk.
    Annals of Medicine 06/2008; 40(7):553-9. · 4.73 Impact Factor
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    ABSTRACT: Introduction and objectives Using gadoliniumenhanced cardiovascular magnetic resonance, it is possible to evaluate the presence of myocardial fibrosis in hypertrophic cardiomyopathy. Classical disease markers are weak predictors of functional disability in affected patients. Our objective was to study the relationship between the degree of myocardial fibrosis observed by cardiac magnetic resonance and exercise capacity. Methods We performed cardiac magnetic resonance, echocardiography, exercise testing and Holter monitoring, along with the usual clinical assessments, in 98 patients (age, 46.3±15.4 years, 71.4% male) referred from two specialist hypertrophic cardiomyopathy clinics. Cardiac magnetic resonance assessment included quantifying the degree of fibrosis (i.e., the percentage of the myocardium showing enhancement) 10 min after gadolinium infusion. Symptom-limited exercise testing was used to determine exercise capacity (in metabolic equivalent [MET] units). In 71 patients, the basal N-terminal probrain natriuretic peptide (NT-proBNP) level was also measured. Results Late enhancement was observed on cardiac magnetic resonance in 67 (68.4%) patients. These patients had a lower exercise capacity (8.04 ± 3.56 MET vs. 10.41 ± 3.57 MET; P=.003). There was an inverse correlation between the percentage of fibrosis and exercise capacity (r = –0.21; P = .044). The best predictor of exercise capacity was the logarithm of the NT-proBNP level (r = –0.5; P < 0001). Multivariate analysis confirmed that age, a history of atrial fibrillation, the basal NT-proBNP level and the presence of fibrosis were independent predictors of exercise capacity (r2 for the model = 0.47). Conclusions The observation of areas of late gadolinium enhancement on cardiac magnetic resonance was independently associated with poor exercise capacity in patients with hypertrophic cardiomyopathy.
    Revista Espanola de Cardiologia 01/2008; 61(8):853-860. · 3.20 Impact Factor
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    ABSTRACT: We aimed to study the prevalence of Fabry disease (FD) in patients with hypertrophic cardiomyopathy (HCM). There are limited and controversial data about the prevalence of FD in patients with HCM. We screened the plasma alpha-galactosidase A activity from 508 unrelated patients with HCM (328 men, 180 women, ages 58 +/- 16 years). Patients with low activity (0% to 30% of the normal control in men, and 0% to 50% in women) underwent genetic study of the GLA gene. We found low plasma activity in 15 patients (3%). Three men had GLA mutations (0.9%): S238N (novel) in 2 and E358del (described) in 1. Two women had described mutations (1.1%): L89P and A143T. Three unrelated men had the D313Y variant previously associated with enzyme pseudo-deficiency. Two women had polymorphisms that did not segregate with the disease in their families. Five women (activity 39% to 47%) had no sequence variants. The familial studies allowed the diagnosis of 14 carriers: 6 women without Fabry manifestations, 3 women with cardiomyopathy, 2 men with renal and cardiac disease, 1 man with microhematuria, 1 woman with first-degree atrioventricular block, and a 32-year-old woman with only renal disease. By means of a screening based on genotyping of patients with low plasma enzymatic activity, the prevalence of FD in our population of HCM is 1% (0.9% in men and 1.1% in women). This diagnosis is relevant, because it allows the identification of disease carriers that might benefit from enzyme replacement therapy.
    Journal of the American College of Cardiology 01/2008; 50(25):2399-403. · 14.09 Impact Factor
  • Clinical Therapeutics - CLIN THER. 01/2007; 29.
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    ABSTRACT: We have read with great interest a retrospective cohort study recently published by Blich and Gross. In our opinion, this article renews the controversy of the best antithrombotic therapy in patients with AF. The use of anticoagulant treatment to prevent the occurrence of stroke in patients with AF is supported by several randomized controlled clinical trials. Aspirin is also effective in preventing stroke in AF, but both direct and indirect comparisons with oral anticoagulation suggest less effectiveness. However, very probably these patients are quite different than those seen in the clinical practice. The role of antiplatelet therapy is not completely established, and the selection between aspirin or warfarin in advanced age remains an unfinished task.
    International Journal of Cardiology 07/2006; 110(2):271-2. · 6.18 Impact Factor