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Effects of nicotine on postinfarction cardiac remodeling

Institution: University of California, San Diego
Investigator(s): Francisco Villarreal, M.D., Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0109H Award: $459,799
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking is a potent risk factor for heart disease. Smokers have a 70% excess death rate from blood vessel-related heart diseases. Many factors are likely responsible for this excess death rate including increased incidence of atherosclerosis and thrombosis. However, clinical studies indicate that in patients who smoke, a significant impairment of wounds healing occurs in tissues such as skin, bone, and stomach. Studies performed in our laboratory indicate that exposure of infarcted rats to nicotine results in enlarged hearts with thin infarcted walls (i.e. worsened or aggravated heart remodeling). Aggravated heart remodeling is known to correlate closely with inadequate healing of an infarcted wall. A worsened prognosis for the development of heart failure and death is likely in patients who smoke if aggravated heart remodeling follows a heart attack. The hypothesis to be tested in this proposal is that exposure to nicotine, prior to and up to the time of a heart attack, adversely affects the healing and growth (remodeling) of the heart. We will address the above stated hypothesis in 3 subprojects. We will pursue studies in cell culture (subproject.1), in an animal model exposed to nicotine during a heart attack (2) and in patients that suffer a heart attack and reach UCSD Medical Services and the San Diego VA Hospital (3). The study focuses on several of the undesirable effects of smoking (including second hand smoke and nicotine) as they affect the evolution of patients who have suffered a heart attack. These effects have not been described before and to the extent that they occur in humans they will result in significant additional financial costs and (potentially preventable) loss of life.

In specific terms, the outcome of the proposed studies should give us insight as to how cigarette smoking (and in particular nicotine) modifies the process of healing and remodeling of the infarcted heart and how it impacts patient recovery and prospects for survival. Aggravated heart remodeling in humans frequently results in the development of heart failure. In the USA, approximately 5 million patients are affected by heart failure, which is the leading cause of hospitalization in Medicare patients and whose annual cost is estimated at 50 billion dollars. Benefits to be gained by the public include the development of alternative treatment strategies to reduce the adverse effects of smoking on the infarcted healing heart. The corroboration of our hypothesis may also be relevant to patients who participate in smoking cessation programs that rely on the use of nicotine. The benefits of understanding the mechanisms by which nicotine affects wound healing and how it may be prevented may also extend and apply to other tissues such as bone, stomach and skin.

Final Report
Cigarette smoking is a risk factor for heart disease and is associated with an excessive death rate. Factors responsible for this excess death rate include diseases such as atherosclerosis and thrombosis. Patients who smoke also suffer from the impairment of wound healing. We propose that improper healing of heart tissue affects the outcome of patients who smoke up to the time of their heart attack or beyond. We have modeled in our laboratory how animals with a heart attack who are exposed to nicotine suffer from adverse healing and growth of the heart. With the purpose of understanding the mechanism by which nicotine induces these alterations we have explored for nicotine modified function of the cells responsible for healing heart tissue. Our data indicates that these cells can respond to nicotine and that nicotine can modestly alter their functions. However, recent data indicates that nicotine may affect healing after a heart attack by impairing the function of the immune system. In this regard results from experiments indicate that nicotine can impair the release of factors which stimulate the function of the cells responsible for the healing of tissues. We have embarked in new studies in rats subjected to a heart attack in order to assess for possible drugs which may prevent the undesirable effects of nicotine with very good results. Briefly the short term use of doxycycline after a heart attack reduces the amount of tissue damage. As part of our ongoing studies we continue to examine in humans who suffer a heart attack for altered cardiac growth and function using echocardiography. Results derived from studies of about 30 patients indicates that smokers who suffer a heart attack do not show signs of improvement in heart function of over the course of 6 months. This is in contrast to nonsmoking patients who show improvement in heart function. Our data also suggests the undesirable enlargement of hearts of patients who smoke and had a heart attack. Thus, a worsened prognosis may be expected in patients who smoke if inadequate healing occurs in wounded heart tissue. This is because it is essential that heart wounds heal properly in order to avoid developing a severely enlarged and deformed heart. Unfortunately, this type of a worsened outcome is associated with the development of heart failure and even death. A significant impact on TRDRP priority issues is expected out of the ongoing studies. In the USA, ~ 5 million patients suffer heart failure which is the leading cause of hospitalization in medicare patients and whose annual cost is estimated at 50 billion dollars. The current study focuses on the undesirable effects of smoking as they affect the evolution of patients after a heart attack. These effects have only begun to been described in animal models of nicotine exposure and to the extent that they are further verified to occur in humans they will result in significant additional financial costs and (potentially preventable) loss of life. Aggravated heart remodeling in humans frequently results in the development of heart failure.
Publications

Nicotine modified postinfarction scarring and left ventricular remodeling
Periodical: American Journal of Physiology Index Medicus:
Authors: Villarreal FJ, Hong D, Omens J ART
Yr: 1999 Vol: 276 Nbr: Abs: Pg: H1103-H1106

The effects of adenosine on rat cardiac fibroblast function
Periodical: FASEB Journal Index Medicus:
Authors: Makhsudova L, Zimmermann S, Buser G, Phan M, Ito B, Villarreal FJ ABS
Yr: 2000 Vol: 14 Nbr: A420 Abs: Pg:

TNF-alpha upregulates the alpha-1 procollagen gene promoter following coronary occlusion
Periodical: FASEB Journal Index Medicus:
Authors: Zimmerman S, Breindl M, Powell J, Agurkis D, Villarreal FJ, Covell J ABS
Yr: 2000 Vol: 14 Nbr: A424 Abs: Pg:

Expression of functional nicotinic receptors on cultured rat cardiac fibroblasts
Periodical: Molecular Biology of the Cell Index Medicus:
Authors: Villarreal FJ, Pascual G ABS
Yr: 1998 Vol: 9 Nbr: Abs: 480a Pg:

Effects of smoking on left ventricular remodeling following myocardial infarction
Periodical: Circulation Index Medicus:
Authors: Blanchard D, Strachan M, Reynolds S, et al ART
Yr: 2000 Vol: 102 Nbr: Abs: Pg: 11-716

Myocardial infaarction induced degradation of cardiac collagens
Periodical: Circulation Index Medicus:
Authors: Villarreal F, Covell J, Zimmerman S, Sabbadini R, Klepper R ABS
Yr: 2001 Vol: 20 Nbr: Abs: A464 Pg:

Inhibition of adenosine kinase alters MI scar formation
Periodical: Circulation Index Medicus:
Authors: Zimmerman S, Villarreal F, Covell J ABS
Yr: 2001 Vol: 20 Nbr: Abs: A461 Pg:

Effects of short term collagenase inhibition with doxycycline on post-infarction left ventricular structure and function.
Periodical: Circulation Index Medicus:
Authors: Villarreal I, Omens FJ, Dillmann J, and Covell J ART
Yr: 0 Vol: Nbr: Abs: Pg:

Serum evidence of early collagenase activation and collagen degradation after myocardial infarction and inhibition by doxycycline.
Periodical: Circulation Index Medicus:
Authors: Villarreal FJ, Omens J, Dillmann W, and covell J ART
Yr: 0 Vol: Nbr: Abs: Pg:

Effects of smoking on left ventricular remodeling following myocardial infarction.
Periodical: Journal of American College Cardiology Index Medicus:
Authors: Blanchard D, Strachan M, Reynolds S, Sawhney N, Sadeghi M, Hope J, DeMaria A et al ART
Yr: 0 Vol: Nbr: Abs: Pg:

Modulation of post-infarction remodeling and cardiac fibroblast function by adenosine A2b receptors.
Periodical: Circulation Research Index Medicus:
Authors: Zimmermann S, Makhsudova L, Epperson S, and Villarreal FJ ART
Yr: 0 Vol: Nbr: Abs: Pg:

The effects of nicotine on cardiac fibroblast collagen synthesis and degradation.
Periodical: American Journal of Physiology Index Medicus:
Authors: Makhsudova L, Pascual G, Manso AM, Villarreal FJ ART
Yr: 0 Vol: Nbr: Abs: Pg:

Short term inhibition of MMP with doxycycline and post-myocardial infarction remodeling.
Periodical: Journal of Molecular and Cellular Cardiology Index Medicus:
Authors: Villarreal F, Omens J, Dillmann W, and Covell J ABS
Yr: 2001 Vol: 33 Nbr: Abs: Pg: A125

Adenosine kinase inhibitor AKI modulation of post-myocardial infarction fibrosis.
Periodical: Journal of Molecular and Cellular Cardiology Index Medicus:
Authors: Villarreal F, Makhsudova L, Epperson L, Omens J, and Ito B ABS
Yr: 2001 Vol: 33 Nbr: Abs: Pg: A126

Serum evidence of early collagenase activation and collagen degradation after infarction and inhibition by doxycycline.
Periodical: Circulation Index Medicus:
Authors: Villarreal FJ, Omens J, Dillmann W, and Covell J ABS
Yr: 2001 Vol: 104 Nbr: Abs: Pg: 11 - 305

Post-infarction remodeling following short term inhibition of collagenases.
Periodical: Circulation Index Medicus:
Authors: Villarreal FJ, Omens J, Dillmann W, and Covell J ABS
Yr: 2001 Vol: 104 Nbr: Abs: Pg: 11 - 167