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Exposure to adverse childhood experiences (ACEs) has lasting repercussions throughout an individual’s lifetime. An adult with a history of childhood trauma is at increased risk for excessive stress reactivity, which exacerbates the development of chronic disease. It is important to investigate how this information can be used for adult trauma survivors. This study assessed the psychophysiological impacts of providing “ACE insight”. Participants completed questionnaires and were given false feedback that their childhood experiences put them at increased risk for excessive stress reactivity and the development of disease. Following ACE insight, participants underwent a speech stressor task during which cardiovascular reactivity was monitored and psychological reactions were assessed. Results indicated that participants with more adverse childhoods reported feeling more worried and less happy about feedback. Further, ACE insight caused a significant increase in cardiac output for participants with a history of childhood trauma. Implications and future directions are discussed.

PhD Thesis / Background: The home care population is a cohort of medically complex older adults at risk for cardiac arrest and poor post-cardiac arrest health outcomes. Research Question: What is the prognosis of cardiac arrest among patients receiving home care, and what pre-arrest features and geriatric syndromes (e.g., frailty) are prognostic of survival and post-cardiac arrest health? Methods: Following a systematic review and meta-analysis that evaluated the prognostic association between frailty and post-cardiac arrest outcomes, a population-based retrospective cohort was created of adults (≥18 years) who received cardiac arrest care at a hospital in Ontario, Canada, between 2006 and 2018. Patients receiving home care and nursing home residents were identified using the Home Care Dataset and the Continuing Care Reporting System. Arrests were analyzed overall and within distinct sub-groups of in-hospital (IHCA) and out-of-hospital cardiac arrests (OHCA). The primary outcome for this thesis was 30-day survival post-cardiac arrest. Frailty was measured using the Clinical Frailty Scale and a valid frailty index. The odds of survival from cardiac arrest were estimated using multivariable logistic regression. Prognostic models were internally validated using bootstrap resampling (n= 2000). Results: We found high certainty evidence for an association between the Clinical Frailty Scale and death prior to hospital discharge after IHCA (OR = 2.93; 95% CI = 2.43 – 3.53) after adjusting for age as a minimum confounder. Our retrospective cohort contained 86,836 unique adult cardiac arrests, of which 39,610 were OHCA and 47,226 were IHCA. Patients receiving home care represented 10.7% of the cohort and were less likely to survive to hospital discharge (RD = -6.4; 95%CI = -7.4– -5.2) and one-year (RD = -12.8; 95%CI = -14.6 – -10.9) post-cardiac arrest compared to community-dwelling individuals receiving no support in the community. Frail patients receiving home care had worse odds of 30-day survival when measured with the CFS (OR=0.78; 95%CI = 0.61-0.98) and a frailty index (OR=0.89; 95%CI = 0.85-0.95), after adjusting for age, sex, and arrest setting. My prognostic model out-performed the two valid frailty measures and demonstrated fair discriminative accuracy (AUROC = 0.66; 95%CI=0.65-0.65) and good calibration (Slope = 0.95) for group-level prognostication when internally validated among patients receiving home care. Conclusion:Patients receiving home care have a worse absolute risk of death when compared to community-dwelling individuals receiving no community-based support services. Frailty is associated with survival and post-cardiac arrest declines in cognition and function when evaluated in patients receiving home care. The prognostic model developed within my thesis outperformed the ability of frailty to predict 30-day survival and is suitable for group-level prognostication. / Dissertation / Doctor of Philosophy (PhD) / The proportion of older adults receiving home care is growing. The home care population is frail and medically complex, with a greater risk for cardiac arrest. This thesis aims to evaluate the prognosis and prognostic factors influencing survival and other health outcomes, to develop a statistical model that can predict 30-day survival post-cardiac arrest. Findings from my research demonstrate that patients receiving home care have worse survival outcomes post-cardiac arrest compared to well-being older adults living in the community. In my research, frailty was associated with survival and declines in post-cardiac arrest functional independence and cognitive performance among patients receiving home care. Our statistical model performed better than valid frailty measures and had respectable accuracy for group-level prognostication. The home care population is ideally positioned for proactive and shared decision-making about end-of-life care preferences, bearing in mind their receipt of detailed and routine health assessments.

Background Frailty is an aging-associated vulnerability to poor health comes when challenged by physiologic stressors. Frailty is a common problem amongst the elderly and is associated with increased mortality and health care resource utilization. Frailty is common in recipients of cardiac devices. What is not known is whether interventions will improve frailty and if this changes patient outcomes. Methods There are four chapters in this thesis. In chapter 1, a review of the current state of frailty research, methods of measurement, biomarkers, imaging modalities and interventions are presented. In chapter 2, a pilot randomized controlled trial is proposed to determine if a supervised exercise program and nutritional supplement improves physical frailty in cardiac device patients. Chapter 3 presents the results of the pilot study to date. In chapter 4, we discuss the challenges faced during the COVID-19 pandemic with respect to recruitment and conducting the trial and changes to the protocol that could have improved the study and adapted to the current state of research. Results There are two conceptual models of frailty which include the frailty phenotype and frailty index. Frailty instruments are abundant and there is no gold standard measurement. Frailty biomarkers, imaging techniques in their current state are complementary measures and are not yet ready for clinical practice. The DEFINIT P trial is single centre RCT involving 24 cardiac device patients randomized to 12 month supervised exercise program and nutritional supplement. Recruitment was halted due to COVID-19 pandemic. Conclusions Frailty is common in cardiac device recipients. A gold standard frailty instrument is not yet established though efforts are currently underway. The DEFINIT P study is feasible with respect to recruitment and consent targets but whether the adherence target to the exercise intervention and nutritional supplement is achieved remains unknown due to stopping the pilot trial as a result of the COVID 19 pandemic. / Thesis / Master of Science (MSc) / Frailty is a state of vulnerability in elderly that makes them susceptible to large declines in health from minor illnesses. Frail elderly are more likely to be admitted to the hospital, nursing homes and have higher chance of dying. Old age and frailty are not the same. Frailty is common in patients with a pacemakers and defibrillators. The purpose of this study is to test whether a supervised exercise program and a nutritional supplement will help improve frailty. We planned to recruit 24 patients into the randomized control trial and 100 patients in the registry and follow them for a period of one year. We aimed to understand how common is frailty in elderly with pacemakers and defibrillators and what factors contribute to developing frailty.

Myocardial infarction is one of the most severe acute pathologies of the cardiovascular system. The adult mammalian heart is indeed unable to regenerate most of the lost cardiomyocytes (CMs) after cardiac injury. The loss of cardiomyocytes and the myocardial scarring after myocardial infarction eventually compromise contractility of the remaining myocardium, leading to heart failure. Therefore, promoting heart regeneration is one of the most crucial therapeutic targets in cardiovascular medicine. The lack of regenerative response is due to the loss of proliferative capacity of adult CMs which in mice occurs seven days after birth. One of the events which occur at birth in neonatal hearts is a sudden increase in mechanical loading that may contribute to switching mammal CMs phenotype from neonatal proliferative to adult postmitotic. Therefore, understanding the role of mechanotransduction in regulating the balance between CM proliferation and maturation may bring us to the identification of unknown mediators and new potential strategies to induce cardiac regeneration. Regulation of mechanical load in bi-dimensional cultures of CMs can be achieved in different ways, however, the poor degree of CM maturation that can be reached in a culture dish together with the lack of a tridimensional structure represent a major limitation to performing mechanotransduction studies. In our work we developed a novel system to study mechanotransduction of CMs based on 3D culture of cardiac cells, called engineered heart tissues (EHTs), that allow us to reduce or increase mechanical loading easily. We show that the three-dimensional setting of the culture leads to an improvement of CM maturation that may be reversed by mechanical unloading inducing cell proliferation. On the other hand, a persisting overload stimulus eventually induces CM switch to a more mature phenotype with a low degree of proliferation. Also, we have focused our work on developing an EHT-based model able to recapitulate the adult infarct injury in order to investigate the biology of cardiac regeneration in this setting. Specifically, we set up a cryoinjury protocol that is relatively easy and reproducible. Cryoinjury produces a localized injury without compromising EHT’s structural integrity. Indeed, all the EHTs subjected to cryoinjury preserved their contractile activity and did not show any significant change in shape. Considering that EHTs are unpurified cardiac culture rich in fibroblast and endothelial cells, we observed that cryoinjury induce fibroblast proliferation and activation together with a lack of proliferative response of the cardiomyocytes which is, on the other hand, present in the early phase of EHT’s development, similarly to what has been shown in mice and rats after myocardial infarction, highlighting the robustness of our cryoinjury approach as a model to investigate cardiac regeneration.

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