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Researchers identify how binge drinking may drive heart disease

As the holidays arrive, a group of researchers has identified the precise mechanisms by which binge drinking contributes to clogs in arteries that lead to heart attack and stroke, according to a study published today in the journal Atherosclerosis. The works adds to a growing body of evidence that drinking patterns matter as much, if not more, to risk for cardiovascular disease than the total amount consumed.

According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), going on a 'binge' means having five or more drinks for men, and four or more drinks for women, in two hours. Many studies suggest that an irregular pattern of heavy drinking brings about a two-fold increase in risk for a fatal heart attack, even as moderate drinking has been shown to reduce risk (the red wine effect). About 65 percent of Americans drink alcohol, with 15 percent reporting binge patterns in a national survey of problem drinkers.

Alcoholic beverages contain ethanol, which is mostly converted into acetaldehyde once in the human system at 'binge' levels, with the levels of acetaldehyde remaining high for many hours after the binge has ended. The current study clarified for the first time that binge levels of acetaldehyde cause an important type of immune cell, the monocyte, to become better able to stick to blood vessel walls, an important step in initiating atherosclerotic disease. Clarifying these mechanisms promises to empower the design of new treatments to counter the effects when combined with lifestyle change, researchers said.

In the past, experts believed that atherosclerosis developed when too much cholesterol clogged arteries with fatty deposits called plaques. When blood vessels became completely blocked, heart attacks occurred. Now most believe that the reaction of the body's immune system, more than the build-up itself, creates heart attack risk. Vessel walls mistake fatty deposits for intruders, akin to bacteria, and call for help from the immune system. Among other cell types, monocytes arrive with the goal of preventing infection, but end up causing inflammation that drives blood vessel blockage.

"Factors like binge-drinking have been linked to increased risk for heart disease, and the newer inflammatory model is beginning to explain how," said John Cullen, Ph.D., assistant professor in the Department of Surgery at the University of Rochester Medical Center. "One of our experiments found that acetaldehyde, at levels found in the blood after binge drinking, increased the number of monocytes that can adhere to cells lining blood vessels by 700 percent," said Cullen, who led the study.

Health psychologists argue that motivating people to stop binging depends upon their belief that it is harming them. Thus, the authors of the current study hope the results empower public health campaigns that discourage binge drinking.

Study Details

In between infections and injuries, dormant monocytes ride along with the bloodstream until they "realize" they are passing by part of a blood vessel wall close to the site of an injury or infection, or in the case of atherosclerosis, the site of cholesterol buildup. At this point, adhesion molecules on the monocyte surfaces unfold and grab onto key proteins on the surface of blood vessel wall cells, resisting the surrounding blood flow.

Whey they arrive on the scene, monocytes send out tethers, like anchors that snag the vessel wall. Once the monocyte swings close to the wall on its tether, it can then roll along the wall, getting stickier and sticker until it sticks in place permanently. Without this step, a major part of the immune component of atherosclerosis could not get underway.

In the current study, the team examined the effects of acetaldehyde on the ability of monocytes to home in on, tether to and roll along cells lining blood vessel walls. Researchers made cultures of the cells lining blood vessels (e.g. human umbilical venous endothelial cells (HUVEC)), and of two types of monocytes that stick to those vessel-lining cells when activated (e.g. primary blood monocytes (PBM) and THP-1 monocytes). The team then treated all cell cultures with acetaldehyde at varying doses (0.1󈞅 M) known to correlate with binge drinking for six hours.

Specifically, the current study found that acetaldehyde stimulated monocyte adhesion through its effect on three important proteins, CCR2, P-selectin, and tumor necrosis factor alpha (TNFα).

Several studies provide compelling evidence for a direct role of the monocyte chemoattractant protein-1 (MCP-1) receptor called chemokine (C-C motif) receptor 2 (CCR2) in the rush of monocytes to blood vessel walls as part of atherosclerosis. CCR2 is a receptor, a protein that occurs on the surfaces of monocytes that links up with MCP-1 as part of the signal that brings monocytes homing in on diseased blood vessel walls. The current study found that the addition of acetaldehyde to monocytes increased by more that twofold the number of cells with CCR2 expressed on their surfaces.

P-selectin is a cell adhesion molecule (CAM) that, upon receiving the right signal, quickly rises to the surface of the cells lining blood vessels (endothelial cells) to help monocytes grab them. The team found a 40 percent increase in endothelial cells showing P-selectin on their surfaces when exposed to acetaldehyde, and a 50 percent increase in the density of P-selectins expressed on the surface of each cell.

The study also found that the genetic expression of TNFα, an important driver of several aspects of inflammation in blood vessels, in endothelial cells increased by about 2.5 fold in the presence of acetaldehyde (10M). Given the above results, it is not surprising that the addition of acetaldehyde increased the overall adhesion of primary blood monocyte to endothelial cells by approximately 250 percent for 0.1 M acetaldehyde, and 700 percent for 25M acetaldehyde, when compared to controls.

When endothelial cells were subjected to a technique that shut down the genes that code for both P-selectin and TNFα prior to the addition of acetaldehyde, the ability of acetaldehyde to cause increased monocyte adhesion was reduced by 90 percent. These results argue strongly that acetaldehyde has its effects on monocytes primarily through these proteins.

Along with Cullen, the work was led in Rochester by Eileen Redmond, David Morrow, Sreenath Kundimi and Carol Miller-Graziano within in the Department of Surgery at the Medical Center. The work was supported in part by grants from the American Heart Association and the National Institutes of Health.

"Our study demonstrates for the first time that physiologically relevant concentrations of acetaldehyde can initiate several key steps involved in the monocyte recruitment cascade, specifically through P-selectin, CCR2 and TNFα," Cullen said. "We hypothesize that, following alcohol consumption, there is a delicate equilibrium between the effects of alcohol and its metabolite, acetaldehyde, on blood vessel walls. Further studies are underway to confirm that these actions of acetaldehyde underlie, in part, the detrimental effects of binge drinking on cardiovascular disease. "


Contact: Greg Williams
University of Rochester Medical Center

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