Part II | Vascular risk factors for depression and apathy 145 8 stroke, with the estimated absolute risk difference associated with depression being 106 cases for total stroke per 100,000 individuals per year 1. In 2008, we offered several explanations for the depression-stroke association, which are still relevant today. We proposed that depression could aggravate atherosclerosis, which was supported by the dose-response effect that we found. Diminished heart-rate variability during stress 2, altered platelet responses related to serotonin 3 and more heart-rhythm irregularities in depressed patients 4 were mentioned as pathophysiological pathways. Since then, HPA-axis dysfunction, metabolic disease and inflammation have been acknowledged as other possible depression-to-atherosclerosis mechanisms 5. Additionally, it has been suggested that depression could also lead to stroke as a result of a less healthy lifestyle and diminished adherence to vascular treatment 5. Today, in 2022, we can add another explanation, since heritability of (ischaemic) stroke is 37.9% 6 and depression and stroke share genetic pathways, where genetic polymorphisms of four genes, methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein E (ApoE) have been shown to be associated with an increased risk of both depression and stroke, while there is also some - although not conclusive - evidence for associations between polymorphisms in angiotensin converting enzyme (ACE) and serum paraoxonase (PON1) with depression 7. These genetic polymorphisms are related to an immune-inflammatory imbalance, increased oxidative and nitrative stress, dysregulation of lipoprotein and lipid metabolism and changes of cerebrovascular morphology and function 7. Also in the LASA study, we suggested that a synergistic reciprocal relationship between depression and vascular disease might account for the findings that the association between depression and stroke was observed in individuals with a prior history of cardiac disease only. Cardiac disease and cardiac procedures are now known to be associated with silent cerebral infarcts 8, infarcts that have been related to depression and stroke 89, offering a more concrete explanation. Furthermore, depressive symptoms could also be an indicator of a poor prognosis in cardiac patients because the number of depressive symptoms scored on the CES-D (partly) correlated with the severity of underlying cardiovascular disease 10, while the use of antidepressants could also play a role 5. Summing up, although in our LASA study the depression-stroke association was mediated by existing cardiac disease, the formerly mentioned meta-analysis reported a pooled association between depression and stroke in cardiac as well as noncardiac patients 1. These findings illustrate that the likelihood of finding a specific association can be enhanced or diminished by the way study population are defined, since associations are often synergistic or interact with other factors, that are not randomly distributed and may be impossible to fully control for.
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