Publicação
Pathophysiology of mood disorders and common pathways with heart failure : implications for an outpatient-setting program
| datacite.subject.fos | Ciências Médicas::Medicina Clínica | pt_PT |
| dc.contributor.advisor | Filipe, Maria Luísa Caruana Canessa Figueira da Cruz | |
| dc.contributor.advisor | Andreazza, Ana Cristina | |
| dc.contributor.advisor | Costa-Vitali, Atílio Eugenio | |
| dc.contributor.author | Luís, Pedro Miguel Zuzarte | |
| dc.date.accessioned | 2021-06-09T17:10:45Z | |
| dc.date.available | 2021-06-09T17:10:45Z | |
| dc.date.issued | 2019-10 | |
| dc.date.submitted | 2019-04 | |
| dc.description.abstract | Introduction: Cardiovascular disease (CVD) and mood disorders (MD) are two of the world’s leading health problems. Both conditions are chronic, debilitating, and extremely prevalent among the general population, often occurring together in the same individual. Epidemiological evidence has been growing suggesting that there is a two-way relationship between them. In fact, a significant proportion of people with no prior record of MD develop depression after a cardiovascular event. As well, physically healthy individuals who are diagnosed with depression are at increased risk of developing CVD compared to the general population. This link is particularly evident between depression and heart failure (HF). The HF population with depression is particularly known to have an increased risk of hospitalizations, emergency visits and re-admissions with higher mortality rates and worse health-related outcomes. The burden of these diseases is overwhelming when they occur individually and even greater when they occur in comorbidity, yet there is still no consensus or any particular guidelines for the best method to treat patients with comorbid MD and CVD. This may be partially due to the fact that MD remains poorly understood. To better clarify the pathophysiology behind this spectrum of disorders we should not be confined to certain conceptual boundaries. First, although there are clear clinical distinctions between depression and Bipolar Disorder (BD), experts still debate the possibility of some degree of continuum between these diseases. Second, the biological mechanisms behind MD are not yet fully understood; namely what separates them and what mechanisms they have in common. This is also true if we aim to identify common biological changes between CVD and MD, particularly between HF and depression. HF is one of the most common causes of hospitalization, mortality, and economic burden worldwide. It is crucial to develop new and improved models of care for this condition. A new program design at Health Sciences North (HSN) called the Heart Failure Disease Management Program (HFDMP) utilizes various outpatient strategies that aim to avoid emergency department (ED) visits, to decrease HF hospitalizations, to improve outcomes, and to decrease mortality and health care costs. The success of this outpatient program model needs to be evaluated. Furthermore, since the association of depression with HF seems to be extremely relevant the prevalence and impact of depression in an original program like the HFDMP needs to be clarified. The general aims of this work were: 1. To investigate pathophysiological mechanisms in mood disorders; 2. To investigate common pathophysiological mechanisms between mood disorders and cardiovascular disease, particularly depression and heart failure; 3. To further investigate the relationship between depression and heart failure from a clinical perspective. The following specific aims were established to address the general goals of this work: 1 To investigate pathophysiological changes in mood disorders, namely the role of mechanisms known to be relevant to the pathophysiology of cardiovascular disease. 1.1 To investigate oxidative stress changes across the life span of patients with MD, Specifically, to analyse the levels of oxidative damage in plasma from 185 subjects, consisting of 110 euthymic older BD patients (BD-I and BD-II with 35 years of evolution of disease) compared to 75 healthy controls; 1.2 To investigate oxidative changes in different mood episodes and mood polarities (depression, hypomania and euthymia) and their relationship with hippocampus changes in patients with MD; specifically, to analyse peripheral levels of oxidative stress markers and decreased hippocampal subvolume dentate gyrus–cornu ammonis (CA4) in correlation to depressive, hypomanic and euthymic episodes in 62 subjects consisting of 29 patients with BD-II and 33 healthy controls. 2 To investigate common pathophysiological mechanisms between mood disorders and cardiovascular disease, particularly between depression and heart failure: 2.1 To review the role of inflammation as a pathophysiological mechanism shared between depression and CVD; specifically, to discuss the evidence of the benefit ofanti-inflammatory drugs in both conditions in support of the hypothesis of a shared pathophysiology between these diseases through inflammation. 2.2 To investigate further common biological pathways between MD and CVD, in HF patients with depression; specifically, to investigate whether NT-proBNP mediated reduced ejection fraction (EF) and depressive symptoms in 124 subjects with HF and depression compared to HF patients without depression. 3 To evaluate an original outpatient program for heart failure management and the relationship of depression with patients as well as the program’s outcomes: 3.1 To investigate the safety and effectiveness of the program HFDMP in managing HF in an outpatient setting; specifically, to investigate the ability of the program to reduce emergency department visits, to decrease HF admissions and readmissions, to improve HF outcome, and to decrease mortality in 138 patients enrolled and followed in the program over a period of 12 months; 3.2 To investigate the relationship between depression, quality of life (QoL) and HF outcomes in the HFDMP; specifically, to investigate the prevalence of depression in the HFDMP and the impact of depression in the QoL and clinical symptoms and outcomes of 124 patients enrolled and followed in the program over a period of 12-months. Results and discussion: The pathophysiological mechanisms responsible for MD are complex and multifaceted. The multiple studies conducted in this work and its respective findings support the idea of that complexity. The hypothesis of a central role for oxidative stress in MD is supported and highlighted by the findings (*1.1) of increased levels of an early component of the peroxidation chain, the lipid hydroperoxide (LPH), in euthymic patients with BD-I and BD-II into late life. This suggests a persistent effect of reactive species of oxygen throughout a BD patient’s life. Further proof for this hypothesis can be gleaned from the findings (*1.2) of increased peripheral levels of two lipid peroxidation markers, the 4-hydroxy-2-nonenal (4-HNE) and LPH, which is significantly correlated with depressive episodes and with decreased dentate gyrus–CA4 volume. It was shown that a larger number of depressive episodes predict a greater volume loss in patient’s hippocampus. Furthermore, it was shown that 4-HNE is negatively associated with left and right dentate gyrus–CA4 volumes. Altogether, these results are consistent in proving the by oxidative stress in the pathophysiology of MD. Furthermore, they suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume loss in these patients. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations and may one day represent a biomarker for these disorders. Oxidative stress is a mechanism well established in CVD and in our findings it appears to also play a central role in MD pathophysiology. Therefore, oxidative stress is an extremely likely biological interface between mood and heart problems. Oxidative stress and inflammation are closely related pathophysiological mechanisms. One can be easily induced by the other, therefore both processes are simultaneously found in many pathological conditions. Similar to oxidative stress, inflammation also seems to be implicated in the pathophysiology of both depression and CVD. Inflammation also seems to have a central role in MD and to be a central candidate mediating the link between depression and CVD, as suggested by the results of our review (*2.1). Taking this hypothesis further, we have found original and seemingly important biological pathways shared between depression and HF, highlighted by the findings in our study (*2.2) that suggest that NT-proBNP is a potential mediator between reduced EF and depression in patients with HF. This indicates that NT-proBNP may be a potential biomarker for HF patients with reduced EF and depression who are at higher risk in terms of disease prognosis and mortality. In this work we have also investigated the original approach established at HSN for HF management named HFDMP. This program was shown (*3.1) to be a safe and effective way to manage HF and avoid ED visits and decrease HF hospitalizations and mortality, all while improving clinical symptoms and decreasing health care expenditures. Finally, we have shown that depression is extremely prevalent in this program’s HF population (*3.2) and is associated with worse QoL levels in patients and worse outcomes in the program. On the other hand, this program was shown to be highly effective in improving patients’ QoL over time, both physically and emotionally. Altogether, these studies provide further evidence of the strong association between HF and depression, from molecular to clinical perspectives. Conclusion: Altogether this work leads to several conclusions. Firstly, oxidative stress and inflammation appear to have a central role in the pathophysiology of MD. Oxidative stress and a decreased volume in hippocampus seem to be directly implicated in the pathophysiology of depressive episodes in MD. Furthermore, oxidative stress and inflammation are central candidates for proving a shared pathophysiology between MD and CVD. Clinical and biological pathways were found between HF and depression in patients enrolled in the HFDMP. This original program for HF management – demonstrated also in this work to be an efficient and safe way to manage HF in an outpatient setting – was shown to have a population where depression is extremely prevalent and where depression influences HF patients’ QoL and outcomes. Finally, in this work we have found an important indicator for the existence of a shared pathophysiology between depression and HF: depressive symptoms and reduced ejection fraction in HF seem to be mediated by NT-proBNP, a gold-standard indicator of the clinical status, diagnosis and severity of HF. We have found that this biological marker, extremely well established in HF, reacts differently with the existence of depressive symptoms in HF patients. This finding provides a strong hint at the common pathways between these diseases. Altogether, this work contributed to clarifications on the pathophysiology of MD as well as the biological connections between MD and CVD. Furthermore, this work has shown important indicators of common pathways between depression and HF, two highly impactful comorbid diseases. It is expected that these findings may in the future contribute to the development of better therapeutic approaches and biomarkers that will help in the diagnosis of disease progression and the evaluation of treatment response in patients with this comorbidity. | pt_PT |
| dc.identifier.tid | 101454066 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/48452 | |
| dc.language.iso | eng | pt_PT |
| dc.subject | Mood disorders | pt_PT |
| dc.subject | Cardiovascular disease | pt_PT |
| dc.subject | Depression | pt_PT |
| dc.subject | Heart failure | pt_PT |
| dc.subject | Bipolar disorder | pt_PT |
| dc.subject | Pathophysiology | pt_PT |
| dc.subject | Oxidative stress | pt_PT |
| dc.subject | Inflammation | pt_PT |
| dc.subject | NT-proBNP | pt_PT |
| dc.subject | Quality of life | pt_PT |
| dc.subject | Outpatient management programs | pt_PT |
| dc.subject | Teses de doutoramento - 2019 | pt_PT |
| dc.title | Pathophysiology of mood disorders and common pathways with heart failure : implications for an outpatient-setting program | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| rcaap.rights | restrictedAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| thesis.degree.name | Tese de doutoramento, Medicina (Psiquiatria e Saúde Mental), Universidade de Lisboa, Faculdade de Medicina, 2019 | pt_PT |
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