Rationale: Depressive and cognitive symptoms are highly prevalent and often persist in patients with coronary artery disease (CAD) undertaking cardiac rehabilitation. These symptoms may interfere with risk factor management strategies by influencing activity levels, lifestyle choices, and compliance with medications. Therefore, the mechanisms contributing to increased depressive and cognitive symptoms are of importance. Elevated levels of proinflammatory cytokines have been observed in CAD and correlated with vascular injury and central nervous system changes. Proinflammatory cytokines are known to activate the indolamine-2,3-dioxygenase enzyme (IDO), which catabolizes tryptophan, producing kynurenine (KYN). Elevated ratios of plasma KYN to tryptophan concentrations (K/T ratio) have been observed in CAD, reflecting peripheral IDO activation. Endogenous KYN metabolites can exacerbate excitotoxic injury to the hippocampus, which is important for acquisition and recall of verbal information. Reduced hippocampal volume is also a marker of depression.
Objective: Our goal is to assess the mood and cognitive correlates of elevated K/T and cytokine levels in persons with CAD. We hypothesize that reduced plasma tryptophan will be associated with depressive symptoms, while increased K/T will be associated with deficits in verbal memory.
Methods: Longitudinal observation of CAD patients (target n = 100) as they progress through a 1-year cardiac rehabilitation program. Depressive symptoms (Centre for Epidemiological Studies Depression scale; CES-D), verbal acquisition and recall (California Verbal Learning Test, 2nd ed; CVLT-II), and executive function (Trail Making Test B; TMT-B and Stroop test) will be assessed at baseline, 6 months, and 12 months. Blood samples will be taken at each interview for analysis of proinflammatory cytokines and K(T ratios. Persistent elevation in K/T and plasma cytokine levels will be assessed for correlations with the persistence of depressive and cognitive symptoms over 1 year to implicate pathophysiological links.
Results: To date, we have collected cross-sectional pilot data on 93 patients entering rehabilitation, finding depressive symptoms (CES-D <= 16 in 22.8%) or cognitive deficits (CVLT-II std. scores <= 1.5 or TMT-B or Stroop scaled scores < 5 in 17.7%) in 35.5% of patients. In 19 patients, we analyzed plasma cytokines and K/T ratios. We observed trends toward correlations between K/T ratios and acquisition (r = -.338, P = .218) and short (r = -.500, P = .058) and long (r = -.388, P = .153) delayed verbal recall using the CVLT-II, and a correlation between the inflammatory marker C-reactive protein and depressive symptoms (r = 0.510, P = .036). Relevance to rehabilitation outcomes was suggested by baseline correlations between higher K/T ratios and higher BMI (r = 0.660, P = .010) and reduced VO2 Max (r = -.452, P = .105) and between higher BMI and reduced short (r = -520, P = .027) and long (r = -.428, P = .076) delayed verbal recall.
Conclusions: These pathophysiological markers seem to be clinically important and continuation of recruitment for further baseline and longitudinal assessment is warranted. This study may help explain why depressive and cognitive symptoms persist in a subset of patients, providing a rationale to test the efficacy of neuroprotective pharmacotherapies in the treatment of these symptoms in a cardiac rehabilitation setting.