RESUMEN
BACKGROUND: Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. Progression to heart failure is usually preceded by ventricular dysfunction, linked to matrix metalloproteinase (MMP) mediated extracellular matrix changes. We hypothesise that the minor allele of genetic variant rs3918242 in the promoter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progression of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure. METHODS: We genotyped 498 diabetes patients participating in the St Vincent's Screening TO Prevent Heart Failure (STOP-HF) follow-up programme for the rs3918242 single nucleotide polymorphism and investigated associations with the co-primary endpoints hypertension and/or myocardial infarction using a dominant model. We also evaluated resulting cardiometabolic phenotype and progression of ventricular dysfunction and cardiac structural abnormalities over a median follow-up period of 3.5 years. RESULTS: The CT/TT genotype comprised 28.1% of the cohort and was associated with a twofold higher risk of myocardial infarction (17.9% vs 8.4%), a reduction in ejection fraction and greater left ventricular systolic dysfunction progression [adjusted OR = 2.56 (1.09, 6.01), p = 0.026] over a median follow-up of 3.5 years [IQR 2.6, 4.9 years]. Conversely, rs3918242 was not associated with hypertension, blood pressure, pulse pressure or left ventricular mass index at baseline or over follow up. CONCLUSIONS: Diabetes patients with the minor T allele of rs3918242 in the STOP-HF follow up programme have greater risk of myocardial infarction, lower ejection fraction and greater progression of left ventricular systolic abnormalities, a precursor to heart failure. These data may support further work on MMP-9 as a biomarker of ventricular dysfunction and the investigation of MMP-9 inhibitors for heart failure prevention in diabetes, particularly in the post-infarction setting. ClinicalTrials.gov Identifier: NCT00921960.
Asunto(s)
Hipertensión/genética , Metaloproteinasa 9 de la Matriz/genética , Infarto del Miocardio/etiología , Polimorfismo de Nucleótido Simple , Disfunción Ventricular Izquierda/genética , Población Blanca/genética , Anciano , Presión Sanguínea , Diabetes Mellitus/etnología , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/diagnóstico , Hipertensión/etnología , Hipertensión/fisiopatología , Irlanda/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/etnología , Infarto del Miocardio/fisiopatología , Fenotipo , Prevalencia , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etnología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
There is currently a lack of knowledge about the feasibility of performing procedures for fertility preservation after chemotherapy treatment has been initiated. In this experimental controlled study using adolescent mice, we aimed to investigate if the chance of rescuing and growing in vitro secondary follicles (SeF) would be affected three days after a single injection of cyclophosphamide (CPA). The main outcomes included were: 1) The number of SeF with good morphologic quality obtained per ovary 3 days after CPA injection, 2) SeF development in culture, 3) small follicle density (SFD) on histology, and 4) apoptosis markers, including terminal deoxynucleotidyl transferase dUTP nick end-labelling (TUNEL), mRNA expression, and distribution of p 53 upregulated modulator of apoptosis (Puma) and phosphatase and tensin homolog (Pten). We found a 60% reduction of SeF obtained per ovary in all CPA-treated groups vs. controls. However, in vitro survival rates at culture day 12 and antrum formation were similar among all groups. On histology, SFD was only significantly reduced in the high CPA dose group. Apoptotic cells were mainly found in large growing follicles of CPA groups. Our study indicates the feasibility of SeF isolation and in vitro follicle culture 3 days following CPA treatment and a still preserved SFD, particularly following a low-dose CPA treatment.
Asunto(s)
Ciclofosfamida/farmacología , Preservación de la Fertilidad , Técnicas de Maduración In Vitro de los Oocitos/métodos , Oocitos/citología , Folículo Ovárico/citología , Envejecimiento , Animales , Antineoplásicos Alquilantes/farmacología , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Femenino , Ratones , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Since the first reported birth following in vitro fertilization in 1978, further developments in assisted reproductive technology (ART) treatments have produced at least 8 million babies worldwide. Cryopreservation techniques have been central to this treatment revolution, increasing cycle efficacy by allowing the banking of supernumerary embryos for later use, as well as affording the prospective patient more time in cases of anticipated fertility decline. Additionally, these techniques have demonstrated promise in increasing the safety of ART treatments, by reducing complications such as ovarian hyperstimulation, leading to increased support for the introduction of a 'total freeze' policy involving deferred embryo transfers. Importantly, the effective cryopreservation of both spermatozoa and oocytes has permitted long-term gamete storage without degradation of quality, facilitating gamete banking for personal use or fertility treatment. Here, we will summarise the indications for applying cryopreservation methods in clinical reproductive medicine, highlighting recent technical advances and examining the evidence base that supports the continued use of cryopreservation in ART.