Nicotine exposure alone leads to pulmonary hypertension — first study

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A study conducted by a team of researchers at Louisiana State University Health New Orleans has shown for the first time that chronic exposure to inhaled nicotine alone increases blood pressure (hypertension), in both the body’s general circulation and in the lungs that can lead to pulmonary hypertension. The study also found that nicotine-induced pulmonary hypertension is accompanied by changes in the size, shape and function (remodelling) of the blood vessels in the lung and the right lower chamber of the heart.

Although cigarette smoking is the single most important risk factor for developing cardiovascular and lung diseases, the role of nicotine in the development of disease has not been well understood. The researchers used a novel nicotine inhalation model in mice that closely mimics human smokers/e-cigarette users to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac re-modelling.

The researchers documented that nicotine inhalation increased systemic systolic and diastolic blood pressure as early as the first week of exposure. “The increase was transient, but was sufficiently long to pose potential health risks in individuals with pre-existing cardiopulmonary conditions,” notes Dr Eric Lazartigues, professor of pharmacology at LSU Health New Orleans School of Medicine.

Pulmonary hypertension is also often associated with re-modelling of the blood vessels of the lung. The study findings suggest that chronic nicotine inhalation leads to muscularisation of previously non-muscular pulmonary arterioles (small branches of arteries leading to capillaries) consistent with increased right ventricular systolic pressure and pulmonary vascular resistance.

Right ventricle failure is a major cause of death in pulmonary hypertension. The researchers found an eight-week exposure to nicotine resulted in significantly higher right ventricular systolic pressure, as well as thickening of the walls and enlargement of the right ventricle.

“Interestingly, the adverse effects of inhaled nicotine are largely isolated to the right heart, as we found no significant changes in left heart re-modelling or protein expression,” adds Dr Xinping Yue, assistant professor of physiology at LSU Health New Orleans School of Medicine.

According to the US Centres for Disease Control and Prevention, tobacco use is the leading cause of preventable disease, disability, and death in the US. Based on 2018 data, about 34m US adults smoke cigarettes. Every day, about 2,000 young people under age 18 years smoke their first cigarette, and more than 300 begin smoking cigarettes daily.

Over 16m people live with at least one disease caused by smoking, and 58m non-smoking Americans are exposed to second-hand smoke. In 2017, 25.2% of Louisiana high school youth reported currently using any tobacco product, including e-cigarettes. Among Louisiana high school youth, 12.3% reported currently smoking cigarettes.

“There is a frightening trend of increasing usage of e-cig and vape products in youths and young adults,” says Dr Jason Gardner, associate professor of physiology at LSU Health New Orleans School of Medicine. “Recent high-profile cases of hospitalization and death following e-cig usage necessitate a greater understanding regarding the health impact of inhaled nicotine delivery systems. The current study clearly demonstrates the adverse effects of nicotine on both systemic and pulmonary blood pressure and cardiac re-modelling. This study should help raise the awareness of the adverse effects of nicotine inhalation on the cardiopulmonary system and help formulate public health policies on e-cigarettes.”

This study was supported in part by research grants from the National Institute of Health and the Department of Veterans Affairs.

Abstract
Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.

Authors
Joshua M Oakes, Jiaxi Xu, Tamara M Morris, Nicholas D Fried, Charlotte S Pearson, Thomas D Lobell, Nicholas W Gilpin, Eric Lazartigues, Jason D Gardner, Xinping Yue

Louisiana State University Health Sciences Center material

Hypertension abstract

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