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1.
Int J Mol Sci ; 24(5)2023 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-36901846

RESUMEN

Previous studies have reported an association between ABO type blood group and cardiovascular (CV) events and outcomes. The precise mechanisms underpinning this striking observation remain unknown, although differences in von Willebrand factor (VWF) plasma levels have been proposed as an explanation. Recently, galectin-3 was identified as an endogenous ligand of VWF and red blood cells (RBCs) and, therefore, we aimed to explore the role of galectin-3 in different blood groups. Two in vitro assays were used to assess the binding capacity of galectin-3 to RBCs and VWF in different blood groups. Additionally, plasma levels of galectin-3 were measured in different blood groups in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2571 patients hospitalized for coronary angiography) and validated in a community-based cohort of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (3552 participants). To determine the prognostic value of galectin-3 in different blood groups, logistic regression and cox regression models were used with all-cause mortality as the primary outcome. First, we demonstrated that galectin-3 has a higher binding capacity for RBCs and VWF in non-O blood groups, compared to blood group O. Additionally, LURIC patients with non-O blood groups had substantially lower plasma levels of galectin-3 (15.0, 14.9, and 14.0 µg/L in blood groups A, B, and AB, respectively, compared to 17.1 µg/L in blood group O, p < 0.0001). Finally, the independent prognostic value of galectin-3 for all-cause mortality showed a non-significant trend towards higher mortality in non-O blood groups. Although plasma galectin-3 levels are lower in non-O blood groups, the prognostic value of galectin-3 is also present in subjects with a non-O blood group. We conclude that physical interaction between galectin-3 and blood group epitopes may modulate galectin-3, which may affect its performance as a biomarker and its biological activity.


Asunto(s)
Galectina 3 , Factor de von Willebrand , Humanos , Factor de von Willebrand/metabolismo , Pronóstico , Sistema del Grupo Sanguíneo ABO , Riñón/metabolismo
2.
Pflugers Arch ; 473(8): 1301-1313, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34142210

RESUMEN

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.


Asunto(s)
Adaptación Fisiológica , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Biogénesis de Organelos , Condicionamiento Físico Animal/fisiología , Receptores de Eritropoyetina/metabolismo , Animales , Cardiomegalia Inducida por el Ejercicio , Masculino , Ratones Noqueados , Neovascularización Fisiológica
3.
Am Heart J ; 226: 60-68, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32512291

RESUMEN

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Betacoronavirus , Unidades de Cuidados Coronarios , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome de Dificultad Respiratoria/prevención & control , Valsartán/uso terapéutico , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , COVID-19 , Infecciones por Coronavirus/mortalidad , Método Doble Ciego , Esquema de Medicación , Humanos , Pacientes Internos , Estudios Multicéntricos como Asunto , Países Bajos , Pandemias , Placebos/uso terapéutico , Neumonía Viral/mortalidad , Respiración Artificial , Síndrome de Dificultad Respiratoria/mortalidad , SARS-CoV-2 , Factores de Tiempo , Valsartán/administración & dosificación
4.
Hum Mol Genet ; 25(10): 2093-2103, 2016 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-26962151

RESUMEN

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.


Asunto(s)
Arritmias Cardíacas/genética , Síndrome de Brugada/genética , Electrocardiografía , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas Adaptadoras Transductoras de Señales/genética , Arritmias Cardíacas/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Síndrome de Brugada/fisiopatología , Trastorno del Sistema de Conducción Cardíaco , Muerte Súbita Cardíaca/patología , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Masculino , Canal de Sodio Activado por Voltaje NAV1.5/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genética , Canales de Potasio Shab/genética , Canales de Potasio Shal/genética
5.
Bioessays ; 38 Suppl 1: S136-45, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27417117

RESUMEN

Depletion of mitochondrial endo/exonuclease G-like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G-like-depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G-like depletion. Interestingly, PE-induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease G-like-depleted cells, suggesting a reverse signaling function of endo/exonuclease G-like. Endo/exonuclease G-like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G-like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G-like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G-like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death.


Asunto(s)
Muerte Celular , Endonucleasas/fisiología , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Animales , ADN Mitocondrial/metabolismo , Transporte de Electrón , Endonucleasas/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo , Consumo de Oxígeno , Ratas
6.
Am Heart J ; 185: 140-149, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28267467

RESUMEN

BACKGROUND: Patients with atrial fibrillation (AF) are prone to cardiovascular events and anticoagulation-related bleeding complications. We hypothesized that patients with anemia are at increased risk for these outcomes. METHODS: We performed a post hoc analysis of the ARISTOTLE trial, which included >18,000 patients with AF randomized to warfarin (target international normalized ratio, 2.0-3.0) or apixaban 5 mg twice daily. Multivariable Cox regression analysis was used to determine if anemia (defined as hemoglobin <13.0 in men and <12.0 g/dL in women) was associated with future stroke, major bleeding, or mortality. RESULTS: Anemia was present at baseline in 12.6% of the ARISTOTLE population. Patients with anemia were older, had higher mean CHADS2 and HAS-BLED scores, and were more likely to have experienced previous bleeding events. Anemia was associated with major bleeding (adjusted hazard ratio [HR], 1.92; 95% CI, 1.62-2.28; P<.0001) and all-cause mortality (adjusted HR, 1.68; 95% CI, 1.46-1.93; P<.0001) but not stroke or systemic embolism (adjusted HR, 0.92; 95% CI, 0.70-1.21). The benefits of apixaban compared with warfarin on the rates of stroke, mortality, and bleeding events were consistent in patients with and without anemia. CONCLUSIONS: Chronic anemia is associated with a higher incidence of bleeding complications and mortality, but not of stroke, in anticoagulated patients with AF. Apixaban is an attractive anticoagulant for stroke prevention in patients with AF with or without anemia.


Asunto(s)
Anemia/epidemiología , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Hemorragia/inducido químicamente , Mortalidad , Accidente Cerebrovascular/prevención & control , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Embolia/epidemiología , Embolia/etiología , Embolia/prevención & control , Inhibidores del Factor Xa/uso terapéutico , Femenino , Hemorragia/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Tromboembolia/epidemiología , Tromboembolia/etiología , Tromboembolia/prevención & control , Warfarina/uso terapéutico
7.
J Mol Cell Cardiol ; 97: 70-81, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27094714

RESUMEN

Cardiac hypertrophy is associated with growth and functional changes of cardiomyocytes, including mitochondrial alterations, but the latter are still poorly understood. Here we investigated mitochondrial function and dynamic localization in neonatal rat ventricular cardiomyocytes (NRVCs) stimulated with insulin like growth factor 1 (IGF1) or phenylephrine (PE), mimicking physiological and pathological hypertrophic responses, respectively. A decreased activity of the mitochondrial electron transport chain (ETC) (state 3) was observed in permeabilized NRVCs stimulated with PE, whereas this was improved in IGF1 stimulated NRVCs. In contrast, in intact NRVCs, mitochondrial oxygen consumption rate (OCR) was increased in PE stimulated NRVCs, but remained constant in IGF1 stimulated NRVCs. After stimulation with PE, mitochondria were localized to the periphery of the cell. To study the differences in more detail, we performed gene array studies. IGF1 and PE stimulated NRVCs did not reveal major differences in gene expression of mitochondrial encoding proteins, but we identified a gene encoding a motor protein implicated in mitochondrial localization, kinesin family member 5b (Kif5b), which was clearly elevated in PE stimulated NRVCs but not in IGF1 stimulated NRVCs. We confirmed that Kif5b gene and protein expression were elevated in animal models with pathological cardiac hypertrophy. Silencing of Kif5b reverted the peripheral mitochondrial localization in PE stimulated NRVCs and diminished PE induced increases in mitochondrial OCR, indicating that KIF5B dependent localization affects cellular responses to PE stimulated NRVCs. These results indicate that KIF5B contributes to mitochondrial localization and function in cardiomyocytes and may play a role in pathological hypertrophic responses in vivo.


Asunto(s)
Cardiomegalia/genética , Cardiomegalia/metabolismo , Cinesinas/genética , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Animales Recién Nacidos , Respiración de la Célula , Células Cultivadas , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cinesinas/metabolismo , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Biogénesis de Organelos , Fenilefrina/farmacología , Ratas
8.
Diabetologia ; 59(3): 634-43, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26684450

RESUMEN

AIMS/HYPOTHESIS: Diabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown. METHODS: We cloned murine Lxrα (also known as Nr1h3) behind the α-myosin heavy chain (αMhc; also known as Myh6) promoter to create transgenic (Lxrα-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks. RESULTS: HFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxrα-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxrα-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxrα-Tg hearts, in part through 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in LXRα-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac LXRα overexpression. CONCLUSIONS/INTERPRETATION: Cardiac-specific LXRα overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes.


Asunto(s)
Cardiomegalia/metabolismo , Cardiomegalia/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Receptores X del Hígado/fisiología , Obesidad/complicaciones , Animales , Inmunoprecipitación de Cromatina , Diabetes Mellitus Tipo 2/etiología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Receptores X del Hígado/genética , Ratones , Ratones Transgénicos , Miocardio/metabolismo
9.
Basic Res Cardiol ; 111(1): 3, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26611207

RESUMEN

Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.


Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Corazón/fisiopatología , Miocitos Cardíacos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Animales , Insuficiencia Cardíaca/metabolismo , Humanos , Receptores X del Hígado
10.
J Am Soc Nephrol ; 26(9): 2213-21, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25568176

RESUMEN

Galectin-3 has been linked to incident renal disease, experimental renal fibrosis, and nephropathy. However, the association among galectin-3, renal function, and adverse outcomes has not been described. We studied this association in two large cohorts of patients over a broad range of renal function. We measured galectin-3 concentrations in baseline samples from the German Diabetes mellitus Dialysis (4D) study (1168 dialysis patients with type 2 diabetes mellitus) and the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2579 patients with coronary angiograms). Patients were stratified into three groups: eGFR of ≥90 ml/min per 1.73 m(2), 60-89 ml/min per 1.73 m(2), and <60 ml/min per 1.73 m(2). We correlated galectin-3 concentrations with demographic, clinical, and biochemical parameters. The association of galectin-3 with clinical end points was assessed by Cox proportional hazards regression within 10 years (LURIC) or 4 years (4D) of follow-up. Mean±SD galectin-3 concentrations were 12.8±4.0 ng/ml (eGFR≥90 ml/min per 1.73 m(2)), 15.6±5.4 ng/ml (eGFR 60-89 ml/min per 1.73 m(2)), 23.1±9.9 ng/ml (eGFR<60 ml/min per 1.73 m(2)), and 54.1±19.6 ng/ml (dialysis patients of the 4D study). Galectin-3 concentration was significantly associated with clinical end points in participants with impaired kidney function, but not in participants with normal kidney function. Per SD increase in log-transformed galectin-3 concentration, the risks of all-cause mortality, cardiovascular mortality, and fatal infection increased significantly. In dialysis patients, galectin-3 was associated with the combined end point of cardiovascular events. In conclusion, galectin-3 concentrations increased with progressive renal impairment and independently associated with cardiovascular end points, infections, and all-cause death in patients with impaired renal function.


Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Nefropatías Diabéticas/sangre , Galectina 3/sangre , Tasa de Filtración Glomerular , Infecciones/mortalidad , Insuficiencia Renal Crónica/sangre , Anciano , Proteínas Sanguíneas , Causas de Muerte , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/terapia , Femenino , Estudios de Seguimiento , Galectinas , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/terapia , Índice de Severidad de la Enfermedad
11.
J Am Soc Nephrol ; 26(12): 3151-60, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25918036

RESUMEN

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 × 10(-5)) and diastolic BP (P = 7.61 × 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 × 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.


Asunto(s)
Presión Sanguínea/genética , Factor 1 de Crecimiento de Fibroblastos/genética , Hipertensión/genética , Riñón/química , Adolescente , Adulto , Anciano , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Neprilisina/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/análisis , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Renina/genética , Transducción de Señal/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Proteína Quinasa Deficiente en Lisina WNK 1 , Adulto Joven
12.
Am J Physiol Cell Physiol ; 308(2): C155-63, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25377088

RESUMEN

Recently, a locus at the mitochondrial exo/endonuclease EXOG gene, which has been implicated in mitochondrial DNA repair, was associated with cardiac function. The function of EXOG in cardiomyocytes is still elusive. Here we investigated the role of EXOG in mitochondrial function and hypertrophy in cardiomyocytes. Depletion of EXOG in primary neonatal rat ventricular cardiomyocytes (NRVCs) induced a marked increase in cardiomyocyte hypertrophy. Depletion of EXOG, however, did not result in loss of mitochondrial DNA integrity. Although EXOG depletion did not induce fetal gene expression and common hypertrophy pathways were not activated, a clear increase in ribosomal S6 phosphorylation was observed, which readily explains increased protein synthesis. With the use of a Seahorse flux analyzer, it was shown that the mitochondrial oxidative consumption rate (OCR) was increased 2.4-fold in EXOG-depleted NRVCs. Moreover, ATP-linked OCR was 5.2-fold higher. This increase was not explained by mitochondrial biogenesis or alterations in mitochondrial membrane potential. Western blotting confirmed normal levels of the oxidative phosphorylation (OXPHOS) complexes. The increased OCR was accompanied by a 5.4-fold increase in mitochondrial ROS levels. These increased ROS levels could be normalized with specific mitochondrial ROS scavengers (MitoTEMPO, mnSOD). Remarkably, scavenging of excess ROS strongly attenuated the hypertrophic response. In conclusion, loss of EXOG affects normal mitochondrial function resulting in increased mitochondrial respiration, excess ROS production, and cardiomyocyte hypertrophy.


Asunto(s)
Respiración de la Célula/fisiología , Endonucleasas/metabolismo , Exonucleasas/metabolismo , Hipertrofia/metabolismo , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Respiración de la Célula/genética , ADN Mitocondrial/genética , Endonucleasas/genética , Exonucleasas/genética , Expresión Génica/genética , Hipertrofia/genética , Potencial de la Membrana Mitocondrial/genética , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/genética , Mitocondrias/fisiología , Miocitos Cardíacos/fisiología , Oxidación-Reducción , Fosforilación Oxidativa , Fosforilación/genética , Fosforilación/efectos de la radiación , Ratas , Transducción de Señal/genética , Transducción de Señal/fisiología
13.
Am Heart J ; 169(5): 693-701.e3, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25965717

RESUMEN

AIMS: We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. METHODS AND RESULTS: Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007). CONCLUSIONS: Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction.


Asunto(s)
Amidas/uso terapéutico , Fumaratos/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Circulación Renal/efectos de los fármacos , Renina/antagonistas & inhibidores , Anciano , Amidas/farmacología , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Femenino , Fumaratos/farmacología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Renina/sangre , Sistema Renina-Angiotensina/efectos de los fármacos , Volumen Sistólico
14.
Am Heart J ; 169(1): 94-101.e2, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25497253

RESUMEN

BACKGROUND: In established cardiovascular disease and heart failure (HF), low hemoglobin levels are associated with unfavorable outcome. Whether hemoglobin levels are associated with the development of new-onset HF in the population is unclear. This study sought to investigate the relationship between hemoglobin levels and development of new-onset HF in the community. METHODS: In 6,744 patients from PREVEND, a prospective, community-based, cohort study, we analyzed the relationship between hemoglobin levels and the risk of new-onset HF. RESULTS: Mean age (±SD) was 53 ± 12 years, 49.8% was male, and mean hemoglobin level was 13.7 ± 1.2 g/dL. During a median follow-up of 8.3 years (interquartile range 7.8-8.9), 217 subjects (3.2%) were newly diagnosed with HF. The association between hemoglobin levels and the risk for new-onset HF was U shaped (P< .001), remaining significant after full adjustment in a multivariable model with established cardiovascular risk factors (P= .015). Furthermore, a increased annual HF incidence was already observed in subjects with high-normal hemoglobin levels (men >16 g/dL or women >15 g/dL; P= .041), whereas on the other side of the distribution, only severe anemia (men <11 g/dL or women <10 g/dL; P= .018) was associated with a higher annual incidence. CONCLUSIONS: The impact of hemoglobin level on the risk of new-onset HF in the community is best described as U shaped. Interestingly, higher hemoglobin levels, already within the high-reference range, are associated with an increased incidence. This in contrast to anemia, where a higher annual HF incidence was only observed for severe anemia.


Asunto(s)
Insuficiencia Cardíaca/sangre , Hemoglobinas/análisis , Adulto , Anciano , Estudios de Cohortes , Femenino , Insuficiencia Cardíaca/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo
15.
Cardiovasc Drugs Ther ; 29(3): 277-85, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26071975

RESUMEN

PURPOSE: To evaluate whether ß-blockers were associated with a reduction in cardiovascular events or angina after Coronary Artery Bypass Graft (CABG) surgery, in otherwise stable low-risk patients during a mid-term follow-up. METHODS: We performed a post-hoc analysis of the IMAGINE (Ischemia Management with Accupril post-bypass Graft via Inhibition of angiotensin coNverting Enzyme) trial, which tested the effect of Quinapril in 2553 hemodynamically stable patients with left ventricular ejection fraction (LVEF) >40 %, after scheduled CABG. The association between ß-blocker therapy and the incidence of cardiovascular events (death, cardiac arrest, myocardial infarction, revascularizations, angina requiring hospitalization, stroke or hospitalization for heart failure) or angina that was documented to be due to underlying ischemia was tested with Cox regression and propensity adjusted analyses. RESULTS: In total, 1709 patients (76.5 %) were using a ß-blocker. Patients had excellent control of risk factors; with mean systolic blood pressure being 121 ± 14 mmHg, mean LDL cholesterol of 2.8 mmol/l, 59% of patients received statins and 92% of patients received antiplatelet therapy. During a median follow-up of 33 months, ß-blocker therapy was not associated with a reduction in cardiovascular events (hazard ratio 0.97; 95 % confidence interval 0.74-1.27), documented angina (hazard ratio 0.85; 95 % confidence interval 0.61-1.19) or any of the individual components of the combined endpoint. There were no relevant interactions for demographics, comorbidities or surgical characteristics. Propensity matched and time-dependent analyses revealed similar results. CONCLUSIONS: ß-blocker therapy after CABG is not associated with reductions in angina or cardiovascular events in low-risk patients with preserved LVEF, and may not be systematically indicated in such patients.


Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Angina de Pecho/fisiopatología , Puente de Arteria Coronaria , Paro Cardíaco/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/fisiopatología , Accidente Cerebrovascular/fisiopatología , Anciano , Angina de Pecho/terapia , Puente de Arteria Coronaria/mortalidad , Método Doble Ciego , Femenino , Paro Cardíaco/terapia , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Quinapril , Factores de Riesgo , Accidente Cerebrovascular/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico
16.
BMC Med Genet ; 15: 140, 2014 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-25528061

RESUMEN

BACKGROUND: Recent genome-wide association studies have identified multiple loci that are associated with an increased risk of developing coronary artery disease (CAD). The impact of these loci on the disease severity and prognosis of ischemic heart failure due to CAD is currently unknown. METHODS: We undertook association analysis of 7 single nucleotide polymorphism (rs599839, rs17465637, rs2972147, rs6922269, rs1333049, rs501120, and rs17228212) at 7 well established CAD risk loci (1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21, and 15q22.33, respectively) in 3,320 subjects diagnosed with systolic heart failure of ischemic aetiology and participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) trial. The primary outcome was the composite of time to first event of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, secondary outcomes included mortality and hospitalization due to worsening heart failure. RESULTS: None of the 7 loci were significantly associated with the primary composite endpoint of the CORONA trial (death from cardiovascular cases, nonfatal myocardial infarction, and nonfatal stroke). However, the 1p13.3 locus (rs599839) showed evidence for association with all-cause mortality (after adjustment for covariates; HR 0.74, 95%CI [0.61 to 0.90]; P = 0.0025) and we confirmed the 1p13.3 locus (rs599839) to be associated with lipid parameters (total cholesterol (P = 1.1x10(-4)), low-density lipoprotein levels (P = 3.5 × 10(-7)) and apolipoprotein B (P = 2.2 × 10(-10))). CONCLUSION: Genetic variants strongly associated with CAD risk are not associated with the severity and outcome of ischemic heart failure. The observed association of the 1p13.3 locus with all-cause mortality requires confirmation in further studies.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Insuficiencia Cardíaca Sistólica/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico
17.
Eur Heart J ; 34(19): 1424-31, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23470495

RESUMEN

AIMS: Differences in clinical characteristics and outcome of patients with established heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are well established. Data on epidemiology and prediction of new onset HFpEF, compared with HFrEF, have not been described. METHODS AND RESULTS: In 8592 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND), a community-based, middle-aged cohort study, we performed cause-specific hazard analyses to study the predictive value of risk factors and established cardiovascular biomarkers on new onset HFrEF vs. HFpEF (left ventricular ejection fraction ≤ 40 and ≥ 50%, respectively). A P-value for competing risk (Pcr) <0.10 between HFrEF and HFpEF was considered statistically significant. All potential new onset heart failure cases were reviewed and adjudicated to HFrEF or HFpEF by an independent committee. During a median follow-up of 11.5 years, 374 (4.4%) subjects were diagnosed with heart failure, of which 125 (34%) with HFpEF and 241 (66%) with HFrEF. The average time to diagnosis of new onset HFrEF was 6.6 ± 3.6 years; it was 8.3 ± 3.3 years for HFpEF (P < 0.001). Male gender was associated with new onset HFrEF, whereas female gender with new onset HFpEF (Pcr < 0.001). Higher age and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased the risk for both HFpEF and HFrEF, although for age this was stronger for HFpEF (Pcr = 0.018), whereas NT-proBNP was stronger associated with risk for HFrEF (Pcr = 0.083). Current smokers, increased highly sensitive troponin T, and previous myocardial infarction conferred a significantly increased risk for HFrEF, but not for HFpEF (Pcr = 0.093, 0.091, and 0.061, respectively). Conversely, a history of atrial fibrillation, increased urinary albumin excretion (UAE), and cystatin C were significantly more associated with the risk for HFpEF, but not for HFrEF (Pcr < 0.001, 0.061, and 0.033, respectively). The presence of obesity at baseline was associated with comparable prognostic information for both HFpEF and HFrEF. CONCLUSION: Higher age, UAE, cystatin C, and history of atrial fibrillation are strong risk factors for new onset HFpEF. This underscores differential pathophysiological mechanisms for both subtypes of heart failure.


Asunto(s)
Insuficiencia Cardíaca/epidemiología , Adulto , Factores de Edad , Anciano , Biomarcadores/metabolismo , Métodos Epidemiológicos , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/mortalidad , Factores Sexuales , Volumen Sistólico/fisiología , Tiempo de Tratamiento
18.
J Cell Mol Med ; 17(6): 743-53, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23617620

RESUMEN

Atrial fibrillation (AF) often occurs in the presence of an underlying disease. These underlying diseases cause atrial remodelling, which make the atria more susceptible to AF. Stretch is an important mediator in the remodelling process. The aim of this study was to develop an atrial cell culture model mimicking remodelling due to atrial pressure overload. Neonatal rat atrial cardiomyocytes (NRAM) were cultured and subjected to cyclical stretch on elastic membranes. Stretching with 1 Hz and 15% elongation for 30 min. resulted in increased expression of immediate early genes and phosphorylation of Erk and p38. A 24-hr stretch period resulted in hypertrophy-related changes including increased cell diameter, reinduction of the foetal gene program and cell death. No evidence of apoptosis was observed. Expression of atrial natriuretic peptide, brain natriuretic peptide and growth differentiation factor-15 was increased, and calcineurin signalling was activated. Expression of several potassium channels was decreased, suggesting electrical remodelling. Atrial stretch-induced change in skeletal α-actin expression was inhibited by pravastatin, but not by eplerenone or losartan. Stretch of NRAM results in elevation of stress markers, changes related to hypertrophy and dedifferentiation, electrical remodelling and cell death. This model can contribute to investigating the mechanisms involved in the remodelling process caused by stretch and to the testing of pharmaceutical agents.


Asunto(s)
Remodelación Atrial , Atrios Cardíacos/patología , Miocitos Cardíacos/patología , Actinas/genética , Actinas/metabolismo , Animales , Animales Recién Nacidos , Anticolesterolemiantes/farmacología , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Factor Natriurético Atrial/agonistas , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Calcineurina/genética , Calcineurina/metabolismo , Muerte Celular , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factor 15 de Diferenciación de Crecimiento/agonistas , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/agonistas , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Canales de Potasio/genética , Canales de Potasio/metabolismo , Pravastatina/farmacología , Presión , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estrés Mecánico , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
19.
Am Heart J ; 166(2): 357-364.e2, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23895820

RESUMEN

BACKGROUND: Many chronic heart failure (CHF) patients have low vitamin D (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients. METHODS AND RESULTS: We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriuretic peptide natriuretic peptide and fibrosis markers. CONCLUSIONS: Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration.


Asunto(s)
Colecalciferol/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Renina/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Vitaminas/uso terapéutico , Anciano , Enfermedad Crónica , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Deficiencia de Vitamina D/etiología
20.
Cardiovasc Drugs Ther ; 27(5): 433-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23784615

RESUMEN

PURPOSE: The HEBE III trial showed that epoetin alfa administration in patients with a first ST-elevation myocardial infarction (STEMI) did not improve left ventricular function at 6 weeks after primary percutaneous coronary intervention (PCI). The long term effects of erythropoiesis- stimulating agents on cardiovascular morbidity and mortality are unknown, therefore we evaluated clinical events at 1 year after PCI. METHODS: A total of 529 patients with a first STEMI and successful primary PCI were randomized to standard optimal medical treatment (N = 266) or an additional bolus of 60,000 IU epoetin alfa administered intravenously (N = 263) within 3 h after PCI. Analyses were performed by intention to treat. RESULTS: At 1 year after STEMI, 485 patients had complete follow-up. The rate of the composite end point of all-cause mortality, re-infarction, target vessel revascularization, stroke and/or heart failure was 6.4 % (N = 15) in the epoetin alfa group and 9.6 % (N = 24) in the control group (p = 0.18). Thromboembolic events were present in 1.3 % (N = 3) of patients in the epoetin alfa group and 2.4 % (N = 6) in the control group. There was no evidence of benefit from epoetin alfa administration in subgroups of patients. CONCLUSIONS: Administration of a single bolus of epoetin alfa in patients with STEMI does not result in a reduction of cardiovascular events at 1 year after primary PCI. There was a comparable incidence of thromboembolic complications in both treatment groups, suggesting that epoetin alfa administration is safe at long term.


Asunto(s)
Eritropoyetina/administración & dosificación , Hematínicos/administración & dosificación , Infarto del Miocardio/terapia , Anciano , Epoetina alfa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Intervención Coronaria Percutánea , Proteínas Recombinantes/administración & dosificación , Tromboembolia/etiología
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