Endothelial factors. The endothelium is the lining of blood vessel walls. It's where cholesterol accumulates in plaques, the hallmark of atherosclerosis. Plaque, in turn, impedes the smooth flow of blood and attracts blood platelets. Most heart attacks are caused by the rapid gathering at such sites of blood platelets that form a clot, blocking the flow of blood and the delivery of oxygen to the heart muscle.
Depression seems to compromise the endothelium and abet atherosclerosis. The increase in sympathetic nervous activity influences injury to the arterial wall and the buildup of plaque.
Inflammation. It's no understatement to say that the circulating immune factors that make the body red-hot are themselves the red-hot subjects of scrutiny for their role in heart disease. The reason: Inflammation of the cells lining the blood vessels is associated with plaque buildup and the attraction of white blood cells to plaque, setting the stage for a heart attack. Perhaps the best known of the inflammatory markers linked to heart disease is C-reactive protein, but there are others, and they strut and fret through the bloodstream, playing significant but subtle roles linking depression and heart disease.
Montreal's Frasure-Smith has identified an inflammatory factor in depression known as ICAM. It affects the way molecules in the bloodstream move against the endothelium. It causes cells to snag on artery walls, tripping off the cascade to heart attack.
British Columbia's Miller is studying the extent to which symptoms of depression foster inflammatory processes involved in heart disease. Chronic stress, he says, "takes the brakes off" the immune system so that it doesn't shut itself down properly. There is indeed increased expression of inflammatory markers among depressed individuals.
But he suspects the inflammation is part of a larger, more elaborate sequence of events and it's set in motion as much by behavior as by biology—specifically, by the weight gain that follows the inactivity of depression. The increased inflammatory markers, he suggests, spur a variety of pathogenic processes: insulin resistance, growth of atherosclerotic plaque, rupture of existing plaque and formation of occlusive blood clots. Depression, he contends, may not be influencing heart disease directly but through a gain in weight.
"Depressed patients have a risk," says Francois Lespérance, M.D., associate professor of psychiatry at University of Montreal. "Whether depression carries a risk is not yet proven. Rather, the risk is in patients."
The problem is, it isn't clear that treating depression rids the risk of heart disease. Only one controlled trial so far has tested whether depression treatment improves cardiac outcome. Called the ENRICHD study, it was a bust. The treatment it tested, cognitive-behavioral therapy, failed to reduce mortality. A separate trial of antidepressant treatment fared little better. Called the SADHEART study, it did show that the SSRI sertraline is safe for cardiac patients. But it has no significant impact on cardiac outcome.
It may be that the studies failed because existing treatments are fundamentally inadequate. "Depression is a cardiac risk factor in search of a successful intervention," says Lespérance. "There are no really effective treatments for depression." Sixty percent of depressed patients improve 50 percent on antidepressant drugs—but so do 40 percent of those given a placebo. Almost everyone agrees that a 50 percent cut in depressive symptoms isn't good enough. It may not impact cardiac risk.
There's some evidence that the highly popular drugs known as statins may be of specific help—not just to lower cholesterol. Studies show they also reduce markers of inflammation. And one study indicates they even make a dent in depression. Whatever else it takes, almost everybody believes that omega-3 fatty acids are going to be part of the solution. "They can augment the effectiveness of antidepressant treatment. And they have cardiovascular benefits," says Carney. "They're worth taking." Adds Lespérance: "Depression is a multi-system condition. There are many links to heart disease. Treatment must target them all."
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