Association between depressive symptoms and fibrosis markers: The Cardiovascular Health Study

Abstract

Objective-Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above.Methods-Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9 ±5.9, 49% women) using a case-control design based on heart failure status (307 HF patients and 563 age-and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D ≥ 8). Covariates included: demographic and clinical variables.Results-Depression was associated with higher levels of PIP (median=411.0, inter quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, vs. 4.53,.22 μg/L, p=0.024), but not PIIIINP (4.07, IQR = 2.75-5.54 μg/mL vs. 3.58, IQR=2.71-5.01 μg/mL, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers.Conclusions-Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.Corresponding Author: Willem J. Kop, University of Maryland Baltimore, 22 South Greene Street, Ste. 3B08, Baltimore, MD 21201, Phone: 410-328-2063, FAX: 410-328-4382, wkop@medicine.umaryland.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Fibrosis contributes to cardiovascular disease progression in general and heart failure in particular. Myocardial fibrosis and subsequent cardiac remodelling occurs in heart failure because of increased collagen production and collagen deposition as a result of pressure overload, myocardial ischemia, as well as neurohormonal activation (including the reninagiotensin-aldosterone axis and sympathetic nervous system activation) (Gonzalez et al., 200...

Acute and chronic psychological stress as risk factors for cardiovascular disease: Insights gained from epidemiological, clinical and experimental studies

“…depression was proven to be predictive for cardiovascular mortality, which was at least partly explained by the contribution of inflammation (i.e. CRP and IL-6 levels) (Kop et al, 2010;Vaccarino et al, 2007).…”

“…, CRP, fibrinogen, IL-10 VonKänel et al (2008),Toker et al (2005),Mommersteeg et al (2006),Kop et al (2010),Vaccarino et al (2007) Affective disorders Depression CRP, IL-6 (after additional stress exposure)Rice et al (2009), Fagundes et al (2013) Anxiety disorders CRP, IL-6, TNFa, Duivis et al (2013) Post Traumatic Stress Disorder CRP, TNFa, IL-4 Plantinga et al (2013), Spitzer et al (2010), Von Känel et al (2007), Turner et al (2013) Low socioeconomic status CRP, IL-6 (after additional stress exposure), sICAM, ET-1 Nazmi and Victora (2007), Brydon et al (2004), Hong et al (2006) Caregiver stress IL-6, CRP, D-dimer Nazmi and Victora (2007), Kiecolt-Glaser et al (2003), Von Känel et al (2006), Miller et al (2008) Loneliness/social isolation IL-6, CRP, sICAM-1 Ford et al (2006), Loucks et al (2006), Heffner et al (2011) Early life stress/childhood maltreatment CRP, fibrinogen Danese et al (2007), Rooks et al IL-6, IL-1RA, sE-selectin Schultze-Florey et al (2012), Cohen et al (2015) Anger outburst CPR, IL-6 Suarez (2004), Coccaro et al (2014) Acute laboratory stressors IL-1b, TNFa, IL-2, IL-4, IL-10, CRP Slavish et al (2015)…”

Depression and Cardiac Disease

“…51 Depression has also been linked to increased levels of cytokines (specifically CRP, IL-1, and IL-6), both in patients with and without a history of cardiac disease. 20,[52][53][54] Two studies provide evidence that inflammation associated with depression predicts the development of cardiac disease and CV mortality. In a population cohort study of 908 patients without known CVD, Kop et al 24 found that depression predicted cardiovascular mortality; controlling for inflammatory markers reduced the association by 12.7%, suggesting that inflammation modestly contributed to the effects of depression on CV mortality.…”

Circulating levels of a biomarker of collagen metabolism are associated with health-related quality of life in patients with chronic heart failure

“…Furthermore, Patients with left ventricular ejection fraction C55% à Calculated using Cockcroft-Gault formula neuro-hormonal mediators apart from being implicated in triggering the transcriptional mechanisms responsible for the deregulation of collagen metabolism at the same time are associated with behavioral abnormalities [33]. In a recent study, Kop et al [33] reported that depression is associated with higher CITP levels although this association was not observed in a subgroup analysis regarding CHF patients. However, in the same study, the interaction effect between depression and group status (CHF vs. controls) was not significant and the authors suggested that further investigation is required in the specific CHF subgroup.…”

“…These endocrine and autocrine pathways in turn result in altered cardiac extracellular metabolism [30], myocyte contractile dysfunction [30], and also in peripheral vascular [30,31] and muscular dysfunction [30,32]. Furthermore, Patients with left ventricular ejection fraction C55% à Calculated using Cockcroft-Gault formula neuro-hormonal mediators apart from being implicated in triggering the transcriptional mechanisms responsible for the deregulation of collagen metabolism at the same time are associated with behavioral abnormalities [33]. In a recent study, Kop et al [33] reported that depression is associated with higher CITP levels although this association was not observed in a subgroup analysis regarding CHF patients.…”