The things they carried: The biological residue of childhood misfortune

There is a well-established relationship between childhood misfortune and adult health, but how these early-life experiences “get under the skin” to later manifest as poor health is less clear. To elucidate this process, this dissertation investigates (1) how childhood conditions influence immune functioning and (2) whether these physiological consequences of early misfortune lead to poor health, indicated by ischemic heart disease (IHD) onset. Guided by cumulative inequality theory and biological embedding, this dissertation also examines adult health lifestyles and socioeconomic status (SES) as possible mechanisms linking childhood misfortune to inflammation and IHD in later life. Data come from six waves of the Health and Retirement Study between 2004 and 2014, comprising a sample of over 8,000 adults aged 51 and older. The empirical investigation is presented in two main articles. The first article presented in Chapter 2 investigates the relationship between childhood misfortune and chronic inflammation, and examines mediators of adult health lifestyles and SES. Building on the findings in Chapter 2, the second article presented in Chapter 3 investigates the relationship between childhood misfortune and IHD risk, and examines mediators of adult health lifestyles, SES, and inflammation. In both articles, alternative specifications of childhood misfortune are tested. Findings from this dissertation reveal that childhood misfortune predicts higher levels of inflammation and IHD risk in later-life. For inflammation, additive childhood misfortune and lower childhood SES led to elevated levels of inflammation via adult health lifestyles and SES. For IHD risk, lower childhood SES raised IHD risk by directly impacting adult health lifestyles and SES, which subsequently led to higher levels of inflammation, resulting in onset of IHD. These findings clarify how childhood misfortune impacts health among older adults. Using multiple mediating domains to assess the long-term effects of early-life conditions can enhance health policy in an effort to reduce the associated disease burden of childhood misfortune

Metabolomics contributions to targeted and untargeted clinical analysis by chromatography and mass spectrometry

La investigación desarrollada en esta Tesis Doctoral se centró en realizar contribuciones en el ámbito del análisis clínico a través de estrategias metabolómicas tanto orientadas como globales en diferentes tipos de muestras biológicas mediante cromatografía de líquidos (LC) y espectrometría de masas (MS). Para ello primeramente se revisó exhaustiva y críticamente la bibliografía para conocer el estado del tratamiento de la orina como muestra y de los métodos de análisis de aire exhalado condensado, dos de los biofluidos utilizados en el desarrollo de esta Tesis. Además, se optimizaron métodos de análisis orientado para mejorar la cuantificación tanto de compuestos con potencial biomarcador como de fármacos y sus metabolitos para su aplicación en el diagnóstico y seguimiento de enfermedades o tratamientos. También se analizaron de forma global biofluidos para, (a) estudiar y optimizar el tratamiento de una muestra escasamente utilizada en el área clínica (el aire exhalado condensado –EBC), (b) identificar metabolitos con potencial predictivo para ayudar en el diagnóstico del cáncer de próstata utilizando la orina como muestra, y (c) mejorar y acelerar el tratamiento de datos a través de herramientas quimiométricas desarrolladas para combinar en una única matriz los datos obtenidos mediante ionización positiva y negativa en espectrometría de masas

Arterial stiffness, cardiovascular risk and physical functioning in the Whitehall II study

BACKGROUND: Arterial stiffness measured by carotid-femoral Pulse Wave Velocity (cf-PWV) is a predictor of cardiovascular events, incident hypertension and a cross-sectional marker of low physical functioning. This thesis aims to expand the knowledge on the bidirectional relationship between cf-PWV and incident hypertension, investigate the predictive value of a second cf-PWV measurement and study its prospective effects on physical function. METHODS: Data from 5236 participants of the Whitehall II study from 2008 to 2019 were used to examine the relationship between incident hypertension and baseline arterial stiffness, as well as arterial stiffness progression among different blood pressure status subgroups. Linear mixed models were used to assess the progression in cf-PWV between subgroups and logistic regression models were used to estimate the odds of incident hypertension. The risk of clinical events was validated through hospital health records and analysed using survival models with a mean follow-up of 11.2 years. The prospective relationship between arterial stiffness and change in standardised measures of physical functioning 8 years later was assessed using linear mixed models. RESULTS: A bidirectional relationship between arterial stiffness and hypertension was observed. Participants in the highest tertile of cf-PWV at baseline had three times higher odds of incident hypertension than participants in the first tertile. Participants with uncontrolled blood pressure at baseline had the highest increase in cf-PWV compared to normotensives. Change between two measurements of a-PWV did not improve the C-statistic but adding a single measurement to the 10-year atherosclerotic cardiovascular disease score improved both the C-statistic and the net reclassification index. Baseline and prospective change of cf-PWV were associated to decline in the scores of the physical component of the SF-36 questionnaire and the instrumental activities of daily living. CONCLUSIONS: The bidirectional relationship between arterial stiffness and hypertension shown in some studies was replicated in the Whitehall II cohort. The sample size allowed for subgroup comparisons that were previously unpowered in previous studies. A second compared to a single measurement of cf-PWV did not seem to improve the predictive ability of cardiovascular risk models. Higher C-statistic and net reclassification index for prediction models using the components of the 10-year atherosclerotic cardiovascular disease score were seen after including cf-PWV. Finally, cf-PWV is a prospective marker of decrease in standardised measures of physical functioning