1 1 1 1 2, 3 4 1 5, 6 1 1 1,6 1 2 3 4 5 6 Abstract J Geriatr Cardiol 2018; 15: 451?459. doi:10./ 1 Introduction Chronic heart failure (CHF) is a syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. [1] [2] [3] 2 Epidemiology CHF is highly prevalent in the elderly population with an incidence of > 4%, one-year mortality of > 20% and a prevalence of > 20% in individuals 3 [4,5] [6] [7] [8–18] [8] [18] [12] [9–11,13,14,16,17,19] [11] [13,15] 3 Pathophysiology The causal relationship between depression and CHF is not clearly understood. Several mechanisms are involved in the physiopathology of CHF and depression which may represent the common ground for their interaction. We have analysed them to hypothesize possible interplays between the two conditions that involve them all (Figure 1). 3.1 Behavioural factors Depressive symptoms, such as increased fatigue, lack of motivation and inability to concentrate compromise patients’ adherence to therapy and healthy lifestyle, with reduced physical activity and increased tobacco and alcohol consumption. This behaviour leads to obesity, atherosclerosis and coronary artery disease, which is the main cause of CHF. [20] [21] [6] [22] 3.2 Neurohormonal activation Stress factors play a key role in CVDs and depression. In both these conditions, the stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, also known to be more active in the elderly, and by the sympathetic branch of the autonomous nervous system (ANS). [23] [24] [25] [26] 3.3 Inflammatory mediators It is well established that the aging process promotes a proinflammatory state in the depression is associated with elevated levels of inflammatory biomarkers and acute-phase proteins, such as interleukine-1 (IL-1), interleukine-6 (IL-6), C Reactive Protein (CRP) and fibrinogen. This pro-inflammatory state is present even when depression is not associated with other medical conditions. [27] [28] [21] [29] [30] [31] 3.4 Hypercoagulability CHF, depression and the aging process independently contribute to a hypercoagulable state. Patients with CHF have higher levels of von Willebrand factor (vWf) and fi-brinogen and increased plasma viscosity and platelet activ-ity. [32] [33] [34] [35] 3.5 Vascular damage In contrast to depressive disorders in younger adults, depression in the elderly, also called late-life depression, is directly associated with ischemic brain lesions. These latter are characterised by white matter hyper-intensities on structural magnetic resonance imagingand frontal and temporal, especially hyppocampal, grey matter changes or atrophy. [36] [37] 3.6 Depression and CHF relationship: an intriguing hypothesis Both depression and CHF are able to negatively affect one-other. These two conditions could possibly interact at several different pathophysiological levels, as previously described. More specifically, starting from a more comprehensive and systemic level, depression and CHF mutually affect themselves through the common pathways related to the induction of a proinflammatory and hypercoagulability state. In this setting, also the neurohormonal dysfunction is involved in both diseases onset and progression. In fact, acting through both hypercortisolism and ANS imbalance, neurohormonal dysfunction not only worsens CHF and other CVDs, but also depression, as hypothesized in the Polyvagal theory. The proinflammatory and hypercoagulability state along with the neurohormonal dysfunction lead to the next level of interaction between depression and CHF, represented by the vascular involvement. This condition is responsible for the onset and worsening of depressive state through ischemic brain lesions but also for the progression of CVDs associated with CHF. Finally, the behavioural component of the interaction between depression and CHF acts when one or both conditions are present contributing either to the rise of the other one or to their mutual worsening (Figure 1), through social issues related to CHF and poor compliance associated to depression. Nevertheless, in order to argue which condition came first, we suggest that would be necessary a type of study that, starting from healthy subjects, follows them in time to detect the development of depression or CHF and consequently treat the condition raised and verify the effect on the development of the other one. Unfortunately, at the present time, this type of study is not available. 4 Clinical findings Depression may be unrecognized in cardiac patients for many reasons, the more important being represented by the similarities between the symptoms of depression and CHF (e.g., low energy, fatigue, sleep disturbance, weight loss or gain, decreased attention and concentration, memory impairment). [38] [39] These symptoms, worsen quality of life (QoL), are independent risk factors for adverse clinical outcomes among CHF patients and are associated with an increased risk of adverse cardiac events thus making their recognition and treatment crucial and time sensitive issues. [30,40] [41] 5 Diagnosis In a meta-analysis of 27 studies, the mean prevalence rate of clinically significant depression among CHF patients was 21.5%, even if this result is influenced by the use of either screening tools or diagnostic interview (33.6% and 19.3%, respectively) and by NYHA class (11% in class I, 42% in class IV). [41] [14] [3] [42] Similarly, the European Society of Cardiology (ESC), in the recently released CHF guidelines, defined as good practice the routine screening for depression in these patients using validated questionnaires. [1] [43] [44] [45] It is important to underline that screening questionnaires facilitate the assessment of depression but cannot stand for a diagnostic interview by mental health professionals and that the diagnosis of major depression is clinical and based on DSM-V criteria. [2] 6 Prognosis In Table 2 [4,16,38,46–51] [4,16,48,49] [52] [38,46] [46] [46,51] [50] [46] [47] [53] 7 Therapy Therapeutic approach in elderly patients with CHF and depression is complex. Of course, CHF therapy should be optimized according to the more recent guidelines. [1] th [4] 7.1 Antidepressants Several studies have been conducted on the use of antidepressants in elderly CHF patients and the results have been conflicting. Fosbol, et al [54] [55] [56] [57,58] [59] b [53] [54,60,61] [60–64] [65,66] b [53] a [67] [68] 7.2 Non-pharmacological interventions Psychotherapy is the application of clinical methods and interpersonal stances derived from established psychological principles with the aim to take care of individual’s mental health problems. This can be reached through several methods, among these the most useful for treating depression is cognitive behavioral therapy (CBT). [20] [69] Several studies show how exercise training is an effective non-pharmacologic therapeutic choice able to reduce depressive symptoms among CHF patients. [69] [39] [70] [1] ECT is considered the “gold standard” in the treatment of geriatric patients with major depression resistant to pharmacotherapy and psychotherapy and who require a rapid response because of the severity of their psychiatric or medical condition. [71] per se [72] [73] 8 Conclusions CHF and depressive disorders have a high prevalence and incidence in the elderly. Depression tends to exacerbate CHF and this latter worsens QoL and leads to the develop-ment of depressive symptoms. Depression is a well-estab-lished independent negative prognostic factor in elderly patients with CHF but is often unrecognized in cardiac pa-tients. 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