The Heart-Mind Connection: Evaluating the Association Between Ceramides and Cognitive Decline in Coronary Artery Disease

Many studies have shown that those with coronary artery disease (CAD) have a more rapid decline in memory than expected and that they are at an increased risk of developing dementia. It is not understood how memory decline is linked to CAD; however, it has recently been discovered that certain byproducts of fat breakdown involved in the development of CAD, called ceramides, can harm brain cells. In the present study the investigators will recruit 129 CAD patients from a cardiac rehabilitation facility and measure memory performance and blood ceramide concentrations at baseline, 3 months and 6 months. The investigators will also measure important blood messengers of inflammation and assess whether they are associated with ceramide production. In addition, relationships between ceramides and other aspects of brain function, such as thinking speed and the ability to plan and sort information will be explored.

Coronary artery disease (CAD) affects about 19.8% of Canadians over the age of 65 and significantly affects quality of life. Of particular importance, cognitive impairment, ranging from cognitive complaints to vascular dementia, is frequently part of the clinical presentation of CAD. Our own prospective pilot data suggest that 22.5% of CAD patients attending cardiac rehabilitation (CR) have evidence of cognitive impairment with lower verbal memory performance, a marker of hippocampal function, predicting poorer CR outcomes. The pathophysiological mechanisms that may contribute to cognitive decline in those with CAD have not been fully elucidated.

Ceramides are metabolites of sphingomyelin, lipid species enriched in the outer leaflet of the plasma membrane and cell organelles of all tissues. Higher peripheral blood concentrations of ceramides have been associated with the development and progression of CAD. We propose to use a specific and sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) assay to measure concentrations of ceramide species from human plasma and elucidate the relationship between ceramides and the change in verbal memory performance over 6 months in 129 subjects with CAD undergoing CR.

We hypothesize that higher plasma concentrations of the long chain ceramide species C22:0 and C24:0 will be associated with decline in verbal memory performance and overall cognitive performance as assessed by a standardized battery of cognitive tests recommended for the investigation of vascular cognitive impairment. We also hypothesize that changes in the plasma concentration of TNF-α (tumor necrosis factor-alpha) will be associated with changes in plasma concentrations of C22:0 and C24:0 over 6 months.

This study aims to clarify the significance of a novel mechanism involving ceramides and the propagation of inflammatory signals from the periphery to the brain in mediating neurodegeneration associated with CAD.

Eligibility Criteria:
Inclusion Criteria:

* 50-75 years of age
* speak and understand English
* evidence of CAD based on at least 1 of the following:
* previous hospitalization for myocardial infarction
* angiographic evidence of ≥ 50% blockage in ≥ 1 major coronary artery
* a prior revascularization procedure
* no recent (last 4 weeks) hospitalization for cardiac events such as acute myocardial infarction, unstable angina, congestive heart failure, ventricular arrhythmias, coronary revascularization, or Canadian Cardiovascular Society Class 4 angina

Exclusion Criteria:

* Type I diabetes
* hypothyroidism, Parkinson's disease, any diagnosis of dementia including Alzheimer's disease, inflammatory disease (irritable bowel syndrome, Crohn's, arthritis, etc.), Huntington's chorea, brain tumour, other conditions that may affect cognitive performance such as history of epilepsy, subdural hematoma, traumatic brain injury, and clinical stroke, progressive supranuclear paralysis, Killip Class III or IV states, multiple sclerosis, severely disrupted liver/ kidney/ lung function
* use of hypnotics, antipsychotics, antidepressants, and anticholinergic medication
* premorbid psychiatric diagnosis of schizophrenia or bipolar disorder
* significant cognitive impairment (MMSE ≤ 24)
* diagnosis of any current Axis I disorder other than depression, phobias or nicotine abuse/dependence