Heart failure in young adults

Heart failure (HF) is a major health concern affecting 15 million people in Europe and around 900 000 people in the U.K. HF predominantly affects the elderly, with the mean age of patients with a diagnosis of HF between 70 and 80 years. Most previous HF studies have accordingly focused on older patients. Although HF is less common in younger adults (<65 years), 15% to 20% of patients hospitalised with HF are younger than 60 years of age. Very few studies have described the characteristics of younger adults with HF and its outcome. The aims of this thesis are to describe the clinical characteristics of younger adults with HF, explore the epidemiology of HF in younger adults and determine their short- and long-term outcomes. This was made possible by access multiple databases consisting of large patient cohorts with HF. The first chapter is a systematic literature review of younger adults with HF. Gaps in the current literature were identified and the thesis focused on some of these. The CHARM study allows detail characterisations of younger adults with HF. It recorded characteristics of patients with HF, including symptoms and signs of HF, electrocardiographic changes, chest radiographic findings, and also left ventricular ejection fraction. HF hospitalisations and its precipitating factors were also recorded systematically. Younger adults were more likely to have a third heart sound and hepatomegaly, but less likely to have pulmonary crackles and peripheral oedema. Similarly, radiological findings in younger adults were less likely to show interstitial pulmonary oedema or pleural effusion. Interestingly, younger adults aged <40 years not only have similar HF hospitalisation rate to older patients, however during their presentation with decompensated HF, they were less likely to have clinical pulmonary oedema and radiological signs of HF. Physicians managing younger adults with HF need to be aware of this. Younger adults were also less compliant with medications and lifestyle restriction resulting in hospitalisation with decompensated HF. Fortunately, despite these challenges, mortality rates in younger adults with HF were lower compared to older patients. To further substantiate the findings from the CHARM study, the MAGGIC study, a meta-analysis consists of over 40 000 patients with HF from large observational studies and randomised controlled trials, was examined. In both databases, the commonest aetiology of HF in younger adults was dilated cardiomyopathy. The ejection fraction was the lowest in younger adults. Similar to the CHARM study, mortality rates in younger adults were lower compared to older patients. However, in the MAGGIC study, by stratifying mortality into patients with preserved ejection fraction and with reduced ejection fraction, younger patients with preserved ejection fraction have a much lower mortality rate compared to patients with reduced ejection fraction. Findings from clinical trials are not always reflective of the real life clinical practice. The U.K. Clinical Practice Research Datalink (CPRD), a large and well-validated primary care database with 654 practices contributing information into the database representing approximated 8% of the U.K. population, is a rich dataset offering a unique opportunity to examine the characteristics, treatments, and outcomes of younger adults with HF in the community. In contrast to the CHARM and MAGGIC studies, younger adults aged <40 years were stratified into 20-29 and 30-39 years in the CPRD analysis. This is possible due to the larger number of younger adults with HF. Further stratifying the younger age groups demonstrated heterogeneity among younger adults with HF. In contrast to previous data showing younger adults have lower co-morbidities, the proportions of depression, chronic kidney disease, asthma, and any connective tissue disease were high among patients aged 20-29 years in the analysis from the CPRD. Surprisingly, the treatment rates for angiotensin converting enzyme (ACE) inhibitor, and aldosterone antagonist were the lowest in patients aged 20-29 years. With the exception of patients aged ≥80 years, treatment rate with beta-blocker was also the lowest in patients aged 20-29 years. With over two decades of follow up, long-term mortality rates in younger adults with HF can be determined. The mortality rates continued to decline from 1988 to 2011. Physicians managing younger adults with HF can now use this contemporary data to provide prognostic information to patients and their family. A hospital administrative database is the logical next platform to explore younger adults with HF. The Alberta Ministry of Health database links an outpatient database to a hospitalisation database providing ample data to examine the relationship between outpatient clinic visits and hospital admissions in younger adults with HF. Following a diagnosis of HF in the outpatient setting, younger adults were admitted to the hospital with decompensated HF much sooner than older patients. Younger adults also presented to emergency department more frequently following their first hospitalisation for HF. In conclusion, this thesis presented the characteristics and outcomes of younger adults with HF, and helped to extend our current understanding on this important topic. I hope the data presented here will benefit not only physicians looking after younger adults with HF, but also patients and their family.

Mapping and modulating spatial attention asymmetries in young and older adults

Healthy young adults demonstrate a group-level, systematic preference for stimuli presented in the left side of space relative to the right (‘pseudoneglect’) (Bowers & Heilman, 1980). This results in an overestimation of features such as size, brightness, numerosity and spatial frequency in the left hemispace, probably as a result of right cerebral hemisphere dominance for visuospatial attention. This spatial attention asymmetry is reduced in the healthy older population, and can be shifted entirely into right hemispace under certain conditions. Although this rightward shift has been consistently documented in behavioural experiments, there is very little neuroimaging evidence to explain this effect at a neuroanatomical level. In this thesis, I used behavioural methodology and electroencephalography (EEG) to map spatial attention asymmetries in young and older adults. I then use transcranial direct current stimulation (tDCS) to modulate these spatial biases, with the aim of assessing age-related differences in response to tDCS. In the first of three experiments presented in this thesis, I report in Chapter Two that five different spatial attention tasks provide consistent intra-task measures of spatial bias in young adults across two testing days. There were, however, no inter-task correlations between the five tasks, indicating that pseudoneglect is at least partially driven by task-dependent patterns of neural activity. In Chapter Three, anodal tDCS was applied separately to the left (P5) and right (P6) posterior parietal cortex (PPC) in young and older adults, with an aim to improve the detection of stimuli appearing in the contralateral visual field. There were no age differences in response to tDCS, but there were significant differences depending on baseline performance. Relative to a sham tDCS protocol, tDCS applied to the right PPC resulted in maintained visual detection across both visual fields in adults who were good at the task at baseline. In contrast, left PPC tDCS resulted in reduced detection sensitivity across both visual fields in poor performers. Finally, in Chapter Four, I report a right-hemisphere lateralisation of EEG activity in young adults that was present for long (but not short) landmark task lines. In contrast, older adults demonstrated no lateralised activity for either line length, thus providing novel evidence of an age-related reduction of hemispheric asymmetry in older adults. The results of this thesis provide evidence of a highly complex set of factors that underlie spatial attention asymmetries in healthy young and older adults.