RESUMEN
OBJECTIVE: Morphological and functional right ventricular (RV) changes during normal pregnancy remain poorly characterized. Similar to left ventricle, RV load and function are expected to change, and establishing reference values for RV during a healthy pregnancy is critical for the evaluation of pregnancy-related heart disease. The aim of the study was to describe RV adaptation in a prospective cohort. METHODS: Serial echocardiographic examinations were performed in second trimester (24 ± 2 weeks), third (32 ± 2 week) trimester, and postpartum (>3 months after delivery). Nulliparous women were evaluated as control group. RV linear dimensions, areas, and function were assessed and compared. RESULTS: Forty-three pregnant women were evaluated and compared with nineteen nulliparous women as control. Function parameters decreased along gestation. RV fractional area fell from second to third trimester (52.01 ± 0.92 vs 48.73 ± 0.97, P < .05), as well as tricuspid annular plane systolic excursion (2.62 ± 0.05 vs 2.41 ± 0.05, P < .05); however, RV longitudinal strain (L) decreased earlier, showing main changes from second trimester (26.17 ± 0.86 vs 22.71 ± 0.57, P < .003, control vs second trimester). S'-wave velocity followed a different pattern without changes during pregnancy. RV diameters significantly increased during pregnancy: basal (3.65 ± 0.06 vs 3.90 ± 0.06, P < .05), mid- (2.70 ± 0.06 vs 3.00 ± 0.07, P < .05), longitudinal (6.90 ± 0.09 vs 7.32 ± 0.11, P < .05), and right ventricle outflow tract proximal diameter (3.20 ± 0.06 vs 3.44 ± 0.06, P < .05). RV areas also suffered early variation during pregnancy. In postpartum evaluation, all these changes were reversed. CONCLUSION: During pregnancy, RV experiments important variations. RV size increases, and its function decreases. Changes in LS were earlier compared with other function measures.
Asunto(s)
Ventrículos Cardíacos , Función Ventricular Derecha , Ecocardiografía , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Embarazo , Estudios Prospectivos , Valores de ReferenciaRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/- mouse model of HGPS. Challenge of Zmpste24-/- mice with the ß-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Trastorno del Sistema de Conducción Cardíaco/fisiopatología , Progeria/fisiopatología , Adolescente , Adulto , Animales , Arritmias Cardíacas/metabolismo , Calcio/fisiología , Trastorno del Sistema de Conducción Cardíaco/metabolismo , Niño , Preescolar , Conexina 43/metabolismo , Conexina 43/fisiología , Femenino , Corazón/fisiología , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Metaloendopeptidasas/genética , Metaloendopeptidasas/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Lámina Nuclear/fisiología , Progeria/metabolismo , Retículo Sarcoplasmático/fisiología , Adulto JovenRESUMEN
Cardiovascular disease (CVD) is the leading cause of death worldwide affecting both sexes equally. However, in comparison to men, in women, it often is underrecognized and undertreated in both primary and secondary prevention settings. It is clear, that in the healthy population, there are profound differences both anatomically and biochemically between women and men, and this may impact how both groups present when they become ill. Moreover, some diseases affect more frequently women than men such as myocardial ischemia or infarction without obstructive coronary disease, Takotsubo syndrome, some atrial arrhythmias, or heart failure with preserved ejection fraction. Therefore, diagnostic and therapeutic strategies that have been established largely on the basis of clinical studies with a predominantly male population must be adapted before being applied to women. There is a paucity of data regarding cardiovascular disease in women. It is inadequate to only perform a subgroup analysis evaluating a specific treatment or invasive technique when women constitute fifty percent of the population. In this regard, this may affect the time of clinical diagnosis and severity assessments of some valvulopathies. In this review, we will focus on the differences in the diagnosis, management, and outcomes for women with the most frequent cardiovascular pathologies including coronary artery disease, arrhythmia, heart failure, and valvopathies. In addition, we will describe diseases that exclusively affect women that are related to pregnancy, and some of them are life-threatening. Although the lack of research on women plays a role in the poorer outcomes in women, especially in ischemic heart disease, some techniques such as transcatheter aortic valve implantation and transcatheter edge-to-edge therapy seem to have better outcomes in women.
Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Insuficiencia Cardíaca , Isquemia Miocárdica , Humanos , Masculino , Femenino , Factores de RiesgoRESUMEN
AIMS: To assess the progression of the disease and evolution of the main echocardiographic variables for quantifying AS in patients with severe low-flow low-gradient (LFLG) AS compared to other severe AS subtypes. METHODS AND RESULTS: Longitudinal, observational, multicenter study including consecutive asymptomatic patients with severe AS (aortic valve area, AVA < 1.0 cm²) and normal left ventricle ejection fraction (LVEF ≥ 50%). Patients were classified according to baseline echocardiography into: HG (high gradient; mean gradient ≥ 40 mmHg), NFLG (normal-flow low-gradient; mean gradient < 40 mmHg, indexed systolic volume (SVi) > 35mL/m2), or LFLG (mean gradient < 40 mmHg, SVi ≤ 35 mL/m²). AS progression was analyzed by comparing patients' baseline measurements and their last follow-up measurements or those taken prior to aortic valve replacement (AVR). Of the 903 included patients, 401 (44.4%) were HG, 405 (44.9%) NFLG, and 97 (10.7%) LFLG. Progression of the mean gradient in a linear mixed regression model was greater in low-gradient groups: LFLG vs. HG (regression coefficient 0.124, P = 0.005) and NFLG vs. HG (regression coefficient 0.068, P = 0.018). No differences were observed between the LFLG and NFLG groups (regression coefficient 0.056, P = 0.195). However, AVA reduction was slower in the LFLG group compared to the NFLG (P < 0.001). During follow-up, in conservatively-managed patients, 19.1% (n = 9) of LFLG patients evolved to having NFLG AS and 44.7% (n = 21) to having HG AS. In patients undergoing AVR, 58.0% (n = 29) of LFLG baseline patients received AVR with a HG AS. CONCLUSION: LFLG AS shows an intermediate AVA and gradient progression compared to NFLG and HG AS. The majority of patients initially classified as having LFLG AS changed over time to having other severe forms of AS, and most of them received AVR with a HG AS.
Asunto(s)
Estenosis de la Válvula Aórtica , Humanos , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Ecocardiografía , Válvula Aórtica/diagnóstico por imagen , Función Ventricular Izquierda , Volumen Sistólico , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Systemic lupus erythematosus (SLE) patients display an increased risk of cardiovascular disease (CVD). With the improved clinical management of other classical severe manifestation of the disease, CVD is becoming one of the most relevant complications of SLE, and it is an important factor causing morbidity and mortality. Several immune constituents have been shown to be involved in the pathogenesis of atherosclerosis and endothelial damage in SLE patients, including specific circulating cell populations, autoantibodies, and inflammatory mediators. In this review, we summarize the presentation of CVD in SLE and the role of the autoimmune responses present in SLE patients in the induction of atherogenesis, endothelial impairment and cardiac disease. Additionally, we discuss the utility of these immune mediators as early CVD biomarkers and targets for clinical intervention in SLE patients.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Cardiopatías , Lupus Eritematoso Sistémico , Humanos , Enfermedades Cardiovasculares/etiología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Biomarcadores , Aterosclerosis/etiologíaRESUMEN
Chagas disease is an emerging infectious disease in Europe and other non-endemic areas, mainly owing to migration from endemic areas. We aimed at investigating the value of advanced echocardiography (ECHO) and cardiac magnetic resonance (CMR) in patients newly diagnosed with Chagas disease to compare findings with those of electrocardiogram (ECG) and conventional ECHO and thus detecting cardiac abnormalities. We included consecutive patients with newly diagnosed Chagas disease and registered cardiac test results (ECG, ECHO, and CMR). We divided ECHO parameters into three tiers: 1) left ventricular ejection fraction, regional wall motion abnormality, and left ventricular diastolic dimension (ECHO-1); 2) other common ECHO parameters (ECHO-2); and 3) global longitudinal strain (GLS) (ECHO-3). Cardiac magnetic resonance included global and segmental biventricular function, the presence of myocardial fibrosis, and edema. The study comprised 100 patients from South America. The mean age was 43.9 ± 0.9 years, and 66% were women. Mean time living in Spain was 9.7 ± 0.5 years. The ECG revealed ≥ 2 abnormal findings in 47% of patients. ECHO-1 was abnormal in 22% of patients, ECHO-2 in 52%, and GLS in 16%. Cardiac magnetic resonance was abnormal in 50% of cases, and in 3% of these, ECHO was normal. When ECG and conventional ECHO were taken together, abnormalities were detected in 83% of patients. This value increased to 86% and 92% for GLS and CMR, respectively. These findings suggest that ECG and conventional ECHO should be used routinely as standard cardiac tests for newly diagnosed cases of Chagas disease. The value of advanced ECHO techniques and CMR is low.
Asunto(s)
Cardiomiopatía Chagásica/diagnóstico , Enfermedad de Chagas/patología , Corazón/fisiopatología , Enfermedades Transmisibles Emergentes , Ecocardiografía/métodos , Electrocardiografía/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , América del Sur , España , Función Ventricular IzquierdaRESUMEN
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCS Tie2Cre+/tg and LmnaLCS/LCS SM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCS SM22αCre+/tg , but not in those from LmnaLCS/LCS Tie2Cre+/tg mice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin-induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.
Asunto(s)
Modelos Animales de Enfermedad , Músculo Liso Vascular/efectos de los fármacos , Progeria/tratamiento farmacológico , Progeria/genética , Nitrito de Sodio/farmacología , Nitrito de Sodio/uso terapéutico , Rigidez Vascular/efectos de los fármacos , Animales , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Progeria/patología , Nitrito de Sodio/administración & dosificaciónRESUMEN
During heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from preexisting ones. It is unclear whether the heart is composed of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identify a subset of preexistent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded after cryoinjury. Genetic ablation of sox10+ cardiomyocytes impairs cardiac regeneration, revealing that these cells play a role in heart regeneration.
Asunto(s)
Miocitos Cardíacos/metabolismo , Regeneración , Factores de Transcripción SOXE/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Corazón/fisiología , Miocitos Cardíacos/fisiología , Factores de Transcripción SOXE/genética , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
INTRODUCTION AND OBJECTIVES: Current therapeutic options for severe aortic stenosis (AS) include transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Our aim was to describe the prognosis of patients with severe AS after the decision to perform an intervention, to study the variables influencing their prognosis, and to describe the determinants of waiting time > 2 months. METHODS: Subanalysis of the IDEAS (Influence of the Severe Aortic Stenosis Diagnosis) registry in patients indicated for TAVI or SAVR. RESULTS: Of 726 patients with severe AS diagnosed in January 2014, the decision to perform an intervention was made in 300, who were included in the present study. The mean age was 74.0 ± 9.7 years. A total of 258 (86.0%) underwent an intervention: 59 TAVI and 199 SAVR. At the end of the year, 42 patients (14.0%) with an indication for an intervention did not receive it, either because they remained on the waiting list (34 patients) or died while waiting for the procedure (8 patients). Of the patients who died while on the waiting list, half did so in the first 100 days. The mean waiting time was 2.9 ± 1.6 for TAVI and 3.5 ± 0.2 months for SAVR (P = .03). The independent predictors of mortality were male sex (HR, 2.6; 95%CI, 1.1-6.0), moderate-severe mitral regurgitation (HR, 2.6; 95%CI, 1.5-4.5), reduced mobility (HR, 4.6; 95%CI, 1.7-12.6), and nonintervention (HR, 2.3; 95%CI, 1.02-5.03). CONCLUSIONS: Patients with severe aortic stenosis awaiting therapeutic procedures have a high mortality risk. Some clinical indicators predict a worse prognosis and suggest the need for early intervention.
Asunto(s)
Estenosis de la Válvula Aórtica/cirugía , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Anciano , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/mortalidad , Toma de Decisiones Clínicas , Femenino , Prótesis Valvulares Cardíacas , Humanos , Masculino , Insuficiencia de la Válvula Mitral/complicaciones , Insuficiencia de la Válvula Mitral/mortalidad , Pronóstico , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Factores Sexuales , España/epidemiología , Análisis de Supervivencia , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Listas de EsperaRESUMEN
During development, mesodermal progenitors from the first heart field (FHF) form a primitive cardiac tube, to which progenitors from the second heart field (SHF) are added. The contribution of FHF and SHF progenitors to the adult zebrafish heart has not been studied to date. Here we find, using genetic tbx5a lineage tracing tools, that the ventricular myocardium in the adult zebrafish is mainly derived from tbx5a+ cells, with a small contribution from tbx5a- SHF progenitors. Notably, ablation of ventricular tbx5a+-derived cardiomyocytes in the embryo is compensated by expansion of SHF-derived cells. In the adult, tbx5a expression is restricted to the trabeculae and excluded from the outer cortical layer. tbx5a-lineage tracing revealed that trabecular cardiomyocytes can switch their fate and differentiate into cortical myocardium during adult heart regeneration. We conclude that a high degree of cardiomyocyte cell fate plasticity contributes to efficient regeneration.
Asunto(s)
Ventrículos Cardíacos/citología , Miocardio/citología , Miocitos Cardíacos/citología , Regeneración/genética , Proteínas de Dominio T Box/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Diferenciación Celular , Linaje de la Célula/genética , Rastreo Celular , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ventrículos Cardíacos/crecimiento & desarrollo , Ventrículos Cardíacos/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Organogénesis/genética , Células Madre/citología , Células Madre/metabolismo , Proteínas de Dominio T Box/deficiencia , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismo , Proteína Fluorescente RojaRESUMEN
INTRODUCTION AND OBJECTIVES: Calculation of the effective regurgitant orifice (ERO) is regarded as the most accurate way of assessing the severity of mitral regurgitation (MR), but the technique's complexity limits its use. Our objective was to modify and validate a previously published semiquantitative method of assessment based on measurement of the proximal isovelocity surface area (PISA) in order to adapt it to recent recommendations from American and European cardiology societies. METHODS: In the PISA method, maximum regurgitant flow (MRF) is a function of the radius and aliasing velocity (AV). Using this relationship, it is possible to construct a nomogram formed by lines of different MRF value, which can be easily derived by looking for radius values on the graph and observing where they cross with AV values. The MR severity limits on the nomogram were set to reflect the different severity grades and limits recommended for use with ERO measurements by American and European cardiology societies. RESULTS: We studied 76 patients with MR using Doppler echocardiography. There was an excellent correlation between MRF and ERO (r=0.98, P< .001). Estimates of MR severity made using the new nomogram were in good agreement with those derived from the ERO: for a scale with three severity grades, kappa was 0.951 and the standard error was 0.11; for four grades, kappa was 0.969 and the standard error, 0.11. CONCLUSIONS: Estimates of MR severity derived semiquantitatively from MRF using the nomogram proposed here were in excellent agreement with quantitative estimates obtained using the ERO, and the method was faster and easier to use.
Asunto(s)
Ecocardiografía Doppler , Insuficiencia de la Válvula Mitral/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Velocidad del Flujo Sanguíneo , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/fisiopatología , Modelos Cardiovasculares , Índice de Severidad de la EnfermedadRESUMEN
The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 ± 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies.
Asunto(s)
Estenosis de la Válvula Aórtica/terapia , Tratamiento Conservador , Sistema de Registros , Tasa de Supervivencia , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/epidemiología , Estenosis de la Válvula Aórtica/fisiopatología , Enfermedades Asintomáticas , Toma de Decisiones Clínicas , Comorbilidad , Ecocardiografía , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Oportunidad Relativa , Pronóstico , Índice de Severidad de la Enfermedad , España , Volumen Sistólico , Centros de Atención Terciaria , Resultado del TratamientoRESUMEN
OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of γ-secretase, and to test preclinically the therapeutic efficacy of γ-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the γ-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the γ-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of γ-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic γ-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Cardiomegalia/prevención & control , Dibenzazepinas/uso terapéutico , Hipertensión/prevención & control , Hipertrofia Ventricular Izquierda/prevención & control , Angiotensina II , Animales , Presión Sanguínea/efectos de los fármacos , Células Cultivadas , Dibenzazepinas/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hipertensión/inducido químicamente , Masculino , Ratones , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
After myocardial infarction in humans, lost cardiomyocytes are replaced by an irreversible fibrotic scar. In contrast, zebrafish hearts efficiently regenerate after injury. Complete regeneration of the zebrafish heart is driven by the strong proliferation response of its cardiomyocytes to injury. Here we show that, after cardiac injury in zebrafish, telomerase becomes hyperactivated, and telomeres elongate transiently, preceding a peak of cardiomyocyte proliferation and full organ recovery. Using a telomerase-mutant zebrafish model, we found that telomerase loss drastically decreases cardiomyocyte proliferation and fibrotic tissue regression after cryoinjury and that cardiac function does not recover. The impaired cardiomyocyte proliferation response is accompanied by the absence of cardiomyocytes with long telomeres and an increased proportion of cardiomyocytes showing DNA damage and senescence characteristics. These findings demonstrate the importance of telomerase function in heart regeneration and highlight the potential of telomerase therapy as a means of stimulating cell proliferation upon myocardial infarction.
Asunto(s)
Corazón/fisiología , Regeneración , Telomerasa/fisiología , Proteínas de Pez Cebra/fisiología , Animales , Proliferación Celular , Expresión Génica , Técnicas de Inactivación de Genes , Miocardio/enzimología , Miocitos Cardíacos/fisiología , Técnicas de Cultivo de Tejidos , Pez CebraRESUMEN
AIMS: While zebrafish embryos are amenable to in vivo imaging, allowing the study of morphogenetic processes during development, intravital imaging of adults is hampered by their small size and loss of transparency. The use of adult zebrafish as a vertebrate model of cardiac disease and regeneration is increasing at high speed. It is therefore of great importance to establish appropriate and robust methods to measure cardiac function parameters. METHODS AND RESULTS: Here we describe the use of 2D-echocardiography to study the fractional volume shortening and segmental wall motion of the ventricle. Our data show that 2D-echocardiography can be used to evaluate cardiac injury and also to study recovery of cardiac function. Interestingly, our results show that while global systolic function recovered following cardiac cryoinjury, ventricular wall motion was only partially restored. CONCLUSION: Cryoinjury leads to long-lasting impairment of cardiac contraction, partially mimicking the consequences of myocardial infarction in humans. Functional assessment of heart regeneration by echocardiography allows a deeper understanding of the mechanisms of cardiac regeneration and has the advantage of being easily transferable to other cardiovascular zebrafish disease models.
Asunto(s)
Frío/efectos adversos , Ecocardiografía/métodos , Ventrículos Cardíacos/fisiopatología , Infarto del Miocardio/prevención & control , Regeneración/fisiología , Disfunción Ventricular/diagnóstico , Disfunción Ventricular/prevención & control , Animales , Infarto del Miocardio/etiología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Disfunción Ventricular/etiología , Pez Cebra/crecimiento & desarrolloRESUMEN
Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.
Asunto(s)
Ciclina A2/fisiología , Citocinesis , Infarto del Miocardio/terapia , Miocitos Cardíacos/citología , Regeneración , Animales , Infarto del Miocardio/fisiopatología , PorcinosRESUMEN
BACKGROUND: Little information exists regarding the prognostic role of biomarkers of inflammation in Mediterranean patients. High C-reactive protein and neopterin levels - a marker of macrophage activation - predict cardiovascular events in stable angina patients and patients with acute coronary syndromes (ACS). We sought to assess whether plasma neopterin levels predict adverse clinical outcomes in Mediterranean patients with non-ST elevation (NSTE) ACS, i.e. unstable angina (UA) and NSTE myocardial infarction (MI). METHODS: We prospectively assessed 397 patients (74% men) admitted with NSTEACS, 147 (37%) had unstable angina and 250 (63%) NSTEMI. Blood samples for neopterin and CRP assessment were obtained at admission. The study endpoint was the composite of cardiac death, acute myocardial infarction and unstable angina at 180 days. RESULTS: Baseline neopterin concentrations (nmol/L) were similar in unstable angina and NSTEMI patients (8.3 [6.6-10.7] vs. 7.9 [6.2-10.9]; p=0.4). Fifty-nine patients (14.9%) had events during follow-up. Twenty-nine (21.5%) patients with neopterin levels in the highest third experienced the combined endpoint, compared to 30 (11.5%) patients with neopterin levels in the second and the lowest thirds (log-rank 7.435, p=0.024). On multivariable hazard Cox regression, neopterin (highest vs. 1st and 2nd thirds, HR 1.762, 95% CI [1.023-3.036]) was independently associated with the combined endpoint. CONCLUSION: Increased neopterin levels are an independent predictor of 180-day adverse cardiac events in Mediterranean patients with NSTEACS.