Nicotine May Accelerate Atherosclerosis, May Be As Dangerous As Tar

By comparing reduced-nicotine cigarettes like Quest 3 and Eclipse with regular cigarettes, researchers discovered that the extent of cigarette-smoke induced atherosclerosis in mice correlated with the levels of nicotine—the higher the nicotine, the more disease.

"Right now, the general consensus is that the problem with cigarettes is tar and that nicotine is safe. That's why you can buy nicotine gum or patches to help you stop smoking. Our study presents new evidence that nicotine may not be safe at all, especially for your heart," says Dr. Daniel F. Catanzaro, principal investigator of the study, recently published in the journal Cardiovascular Toxicology. Dr. Catanzaro is associate research professor of physiology and biophysics in the Departments of Medicine and Cardiothoracic Surgery at Weill Cornell Medical College.

Previous studies have suggested that nicotine in cigarettes can hurt the heart by activating the sympathetic nervous system and increasing the heart rate—potentially leading to fatal arrhythmias. (Nicotine also affects most organ systems—including the gastrointestinal tract, the skin and the central nervous system.)

The new Weill Cornell study looked at two so-called "potentially reduced exposure products" (PREPs)—Eclipse and Quest. Eclipse cigarettes work by heating inhaled air to activate its contents without burning the tobacco. Quest cigarettes are made with tobacco that is genetically-modified to have lower nicotine. Eclipse and Quest 3 have nicotine yields of 0.2 and 0.05 mg per cigarette, respectively.

This compares to the two regular cigarettes studied—2R4F and Quest 1, with nicotine yields of 1 and 0.6 mg per cigarette, respectively. Eclipse and Quest cigarettes are marketed with the implication that they may be less harmful or addictive than conventional cigarettes. Quest cigarettes purportedly provide smokers the opportunity to taper their nicotine consumption by progressively moving to lower nicotine cigarettes. 2R4F is a research cigarette supplied by the University of Kentucky.

The study found that mice exposed to smoke from low-nicotine cigarettes had significantly smaller atherosclerotic lesions, compared to those exposed to regular cigarettes but still larger than lesions in control mice not exposed to cigarette smoke, which showed the least evidence of atherosclerosis. The accelerating effects of smoking on lesions was seen early, within weeks of smoke exposure.

"While our study seems to suggest that low-nicotine cigarettes are safer, we also know that smokers adjust their smoking habits to maintain their level of nicotine. In other words, if you switch to a low-nicotine product, you will probably increase the number of cigarettes you smoke, or change the way you smoke to get more nicotine out of each cigarette. The best thing to do is quit," says Dr. Catanzaro.

Although Quest 1, Quest 3 and 2R4F cigarettes all have the same tar yield (10 mg/cigarette), mice exposed to smoke from the high-nicotine 2R4F and Quest 1 cigarettes developed larger lesions than did mice exposed to smoke from Quest 3, which has the lowest nicotine content of all the products tested. According to the Weill Cornell investigators, this finding points to the special role of nicotine in promoting arteriosclerosis.

Researchers also found that iPF2alphaV, a marker for oxidative stress that has been linked with atherosclerosis in humans, increased proportionately with the level of nicotine. This finding may indicate that nicotine promotes atherosclerosis, in part, by blocking production of nitric oxide, a chemical that mediates the protective functions of the lining of blood vessels.

"These findings are preliminary. Going forward we will want to look at whether doping cigarettes with extra nicotine increases their atherogenic potential; whether blockers of nicotine reduce atherosclerosis; and if oral administration of nicotine has the same effects," says Dr. Catanzaro.

About 20 percent of Americans smoke. Cigarette smoke is linked to risk for cancer, chronic lung disease (emphysema and chronic bronchitis), cardiovascular disease (atherosclerosis, thrombosis and vascular dysfunction), stroke and cataracts as well as poor wound healing.

Co-authors include Weill Cornell's Drs. Andrew J. Dannenberg, Babette B. Weksler, Ying Zhou, Rong Chen, Fangmin Yu, Sarah E. Catanzaro, Mariana S. De Lorenzo, Kotha Subbaramaiah and Xi Kathy Zhou, and University of Pennsylvania's Dr. Domenico Pratico.

Atherosclerosis

Atherosclerosis is the process by which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery. This buildup is called plaque. It usually affects large and medium-sized arteries. Plaques can grow large enough to significantly reduce the blood's flow, but most of the damage occurs when they become fragile and rupture.

Plaques that rupture cause blood clots to form that can block blood flow or break off and travel to another part of the body. If either happens and blocks a blood vessel that feeds the heart, it causes a heart attack. If it blocks a blood vessel that feeds the brain, it causes a stroke. And if blood supply to the arms or legs is reduced, it can cause difficulty walking and eventually lead to gangrene.