1. Mini Lecture 2 Module: Effects of Tobacco on the Cardiovascular System
SMOKING AND CARDIOVASCULAR DISEASES: THE MECHANISMS
Mini Lecture 2
Module: Effects of Tobacco on the
Cardiovascular System
Key References:
Burns DM. Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Dis. 2003; 46(1):11-29.
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):
Law MR, Wald NJ. Environmental tobacco smoke and ischemic heart disease. Prog Cardiovasc Dis. 2003; 46(1):31-8.

2. Objectives of the Mini Lecture
GOAL OF MINI-LECTURE: Provide students with knowledge about the risks of cardiovascular disease among tobacco users.
LEARNING OBJECTIVES
Students will be able to:
Discuss how smoking can cause cardiovascular diseases.
Understandthe mechanisms underlying the hazardous effects of smoking on cardiovascular diseases.
Describe the impacts of secondhand smoking on cardiovascular diseases.
Module Description:
This module is intended to provide students with knowledge on the causal link between smoking and tobacco use and cardiovascular diseases. A detailed discussion of the mechanisms underlying the hazardous effects of smoking on cardiovascular diseases will be presented.

3. Contents Core Slides: Optional Slides: Smoking and CVD: Causation
Pathophysiology of Cigarette Smoking and CVD (1)
Pathophysiology of Cigarette Smoking and CVD (2)
Secondhand Smoke and CVD: the Underlying Mechanism
Pathophysiology of Cigarette Smoking and CVD: Hemodynamic Effects
Pathophysiology of Cigarette Smoking and CVD: Endothelial Injury and/or Dysfunction
Pathophysiology of Cigarette Smoking and CVD: Thrombosis
Pathophysiology of Cigarette Smoking and CVD: Inflammation
Gene–Environment Interaction in the Causation of CHD

4. CORE SLIDES Smoking and Cardiovascular Diseases: The Mechanisms
Mini Lecture 2
Module: Effects of Tobacco on the
Cardiovascular System
The core slides include five slides:
Smoking and CVD: Causation
Pathophysiology of Cigarette Smoking and Cardiovascular Disease (1)
Pathophysiology of Cigarette Smoking and Cardiovascular Disease (2)
Secondhand Smoke and CVD: the Underlying Mechanism

5. Smoking and CVD: Causation
Cigarette smoking is a cause of peripheral vascular disease (PVD), aortic aneurysm, coronary heart disease (CHD), and cerebrovascular disease (stroke).
Smoking contributes to the development and progression of atherosclerosis plaque, which leads to an increased risk of thrombosis of the narrowed vessels.
Smoking induces a localized inflammatory response in the lungs.
Smoking induces a systemic inflammatory response  elevations in inflammatory markers, which is a risk marker (and potentially a risk factor) of CVD
USDHHS 2004; Burns 2003
Notes:
Studies have shown the consistent association between smoking and cardiovascular diseases. Smoking has detrimental effects on endothelium morphology and function. Dysfunctional endothelium secretes growth factors, which can draw in inflammatory cells and cytokines, and later stimulate atherosclerosis. The cytokines can stimulate smooth muscle cell proliferation, monocyte/lymphocyte adhesion, and subendothelial migration. These cascades lead to loss of the endothelium’s normal antithrombic function, and the atherosclerosis process can begin.
Smoking is a causative factor for many cardiovascular diseases, including coronary heart diseases (myocardial infarction, ischemic heart disease, and angina pectoris), cerebrovascular diseases, and abdominal aortic aneurysm. Therefore asking patients about smoking and advising them to quit is an essential part of both prevention and treatment of CVD.
References:
Burns DM. Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Dis. 2003; 46(1):11–29.
US Department of Health and Health Services and Centers for Disease Control. Health consequences of tobacco use: a report of the Surgeon General. Washington, D.C.: United States Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; Chapter 3: Cardiovascular diseases; p. 361–419.

6. Pathophysiology of Cigarette Smoking and CVD (1)
Mechanisms by which smoking causes acute cardiovascular disease:
Thrombosis
Endothelial dysfunction
Inflammation
Hemodynamic changes
Smoking-mediated thrombosis appears to be a major factor in the pathogenesis of acute cardiovascular events.
Notes:
There are several pathways and mechanisms through which smoking can cause acute cardiovascular diseases. Smoking can lead to thrombosis, endothelial dysfunction, inflammation, and hemodynamic changes. Detailed explanations of how each of the mechanisms can lead to acute CVD are provided in the optional slides.
Since some of these are very acute, dynamic mechanisms, when a smoker quits, their risk for AMI quickly begins to decrease (benefits of quitting that can be conveyed to patients).
Reference:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):91–111.
Benowitz 2003

7. Pathophysiology of Cigarette Smoking and CVD (2)
Notes:
Reference:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):91–111.
Overview of mechanisms by which cigarette smoking causes acute cardiovascular event.
1. Benowitz 2003

8. Secondhand Smoke and CVD: the Underlying Mechanism
Secondhand smoke increases platelet aggregation that leads to thrombosis, endothelial dysfunction, and inflammation.1
Exposure of non-smoker to secondhand smoke increases white blood cells, C-reactive protein, homocysteine, fibrinogen, and oxidized low density lipoprotein cholesterol – value similar to active smokers.2
In animal experiments, there was evidence of a cause- effect vascular toxicity.1
Notes:
Secondhand smoke does not significantly increase plasma fibrinogen, reduce high-density lipoprotein cholesterol, and increase carboxyhemoglobin. The three risk factors that increase the risk for ischemic heart disease are influenced by active smoking. Secondhand smoke increases platelet concentration and aggregation. Secondhand smoke has similar effects with active smoking on white blood cells, C-reactive protein, homocysteine, fibrinogen, and oxidized low density lipoprotein cholesterol.
Treatment with aspirin for patients with ischemic heart disease can therefore reduce platelet aggregation and the risk of recurrent ischemic heart diseases.
References:
Law MR, Wald NJ. Environmental tobacco smoke and ischemic heart disease. Prog Cardiovasc Dis. 2003; 46(1):31–8.
Pechacek TF, Babb S. How acute and reversible are the cardiovascular risks of secondhand smoke? BMJ. 2004; 328(7446):980–3.
1. Law and Wald 2003; 2. Pechacek and Babb 2004

9. OPTIONAL SLIDES Smoking and Cardiovascular Diseases: The Mechanisms
Mini Lecture 2
Module: Effects of Tobacco on the
Cardiovascular System
The optional supplementary slides include five slides:
Pathophysiology of Cigarette Smoking and CVD: Hemodynamic Effects
Pathophysiology of Cigarette Smoking and CVD: Endothelial Injury and/or Dysfunction
Pathophysiology of Cigarette Smoking and CVD: Thrombosis (Hypercoagulable State)
Pathophysiology of Cigarette Smoking and CVD: Inflammation
Gene–Environment Interaction in the Causation of CVD

10. Pathophysiology of Cigarette Smoking and CVD: Hemodynamic Effects
Mainly mediated by nicotine.
Related to coronary ischemia due to imbalance of myocardial oxygen demand and blood supply.
The mechanisms are:
Stimulation of sympathetic nervous system  increases myocardial oxygen demand.
Constriction of coronary artery  decreases coronary blood flow.
Notes:
The hemodynamic effects of smoking are primarily mediated by nicotine. Nicotine affects the balance between myocardial oxygen demand and myocardial blood supply, and subsequently produces coronary ischemia.
There are two mechanisms through which nicotine can lead to myocardial oxygen demand and blood supply:
Nicotine stimulates the sympathetic nervous system, and this stimulation leads to increase in heart rate and myocardial contractility. These actions result in increased myocardial oxygen demand.
Nicotine constricts coronary arteries and this leads to decreased coronary blood flow .
References:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):
Ford CL, Zlabek JA. Nicotine replacement therapy and cardiovascular disease. Mayo Clin Proc. 2005; 80(5):
1. Benowitz 2003; 2. Ford and Zlabek 2005

11. Pathophysiology of Cigarette Smoking and CVD: Endothelial Injury and/or Dysfunction
Mainly related to oxidant chemicals.
Oxidant chemicals lead to constriction of blood vessels and inhibition of platelet aggregation.
Changes in the structure and function of vascular smooth muscle and endothelial cells  vascular thickening.
Releases of basic fibroblast growth factor lead to DNA synthesis, mitogenic activity, and endothelial proliferation.
Notes:
The endothelial injury and dysfunction due to cigarette smoking are mainly related to the effects of oxidant chemicals. Oxidant chemicals in cigarettes degrade nitric oxide and reduce nitric oxide release, therefore antagonizing the actions of nitric oxide to dilate blood vessels and inhibiting platelet aggregation.
Nicotine alters the structural and functional characteristics of vascular smooth muscle and endothelial cells, and leads to vascular myointimal thickening in experimental animal studies.
Nicotine also enhances the release of basic fibroblast growth factor and increases DNA synthesis, mitogenic activity, and endothelial proliferation.
Reference:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):
Benowitz 2003

12. Pathophysiology of Cigarette Smoking and CVD: Thrombosis
Mainly related to increased platelet aggregation.
Several mechanisms:
Lack of inhibition of platelet activation by nitric oxide
Impaired fibrinolysis (low tPA and high PAI-1)
Higher levels of tissue factor
Increased blood viscocity related to compensation for relative hypoxemia
Notes:
Smoking is associated with thrombus formation due to increased platelet aggregation. Several mechanisms are responsible for this phenomenon.
Smoking-related endothelial dysfunction results in:
Reduced release of nitric oxide, which normally inhibits platelet activation.
Reduced secretion of tPA and increased secretion of PAI-1, which result in impaired fibrinolysis.
Cigarette smoking results in higher levels of tissue factor (a thrombogenic factor that contributes to thrombosis after atherosclerotic plaque disruption).
Carbon monoxide results in relative hypoxemia, which leads to increase in red cell mass (compensation mechanism), which increases blood viscosity.
References:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):91–111.
Ford CL, Zlabek JA. Nicotine replacement theraphy and cardiovascular disease. Mayo Clin Proc. 2005; 80(5):652–6.
1. Benowitz 2003; 2. Ford and Zlabek 2005

13. Pathophysiology of Cigarette Smoking and CVD: Inflammation
The inflammation mechanisms are unclear.
Oxidant stress appears to play a major role.
Nicotine as a chemotactic agent for neutrophil migration.
Nicotine acts on human monocyte-derived dendritic cells.
Inflammation is believed to contribute to atherogenesis.
Notes:
Cigarette smoking results in a chronic inflammatory state. The mechanisms are unclear.
Oxidant stress appears to play a major role (oxidized LDL and lipid peroxidation products are pro-inflammatory stimuli). Nicotine may contribute to inflammation by acting as a chemotactic agent for neutrophil migration and by acting on human monocyte-derived dendritic cells to stimulate an inflammatory response. Inflammation is believed to contribute to atherogenesis.
Since smoking causes inflammation in other parts of body—lungs, gingival—this increases the total inflammatory burden affecting CVD risk.
Reference:
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46(1):91–111.
Benowitz 2003

14. Gene–Environment Interaction in the Causation of Chronic Heart Disease (CHD)
A prospective study in Great Britain found:
Smokers have 1.94 times higher risk (95% CI = 1.25– 3.01) for CHD compared to non-smokers.
Smoking interacts with genetic factors (carrier of allele ApoE 4) and increases risk by 197% (OR 2.97; 95% CI = 1.59–4.91).1
Possible mechanisms:
ApoE 4 is more suspectible to LDL oxidation.
A high level of ApoE inhibits migration of invitro vascular smooth cells – patients with ApoE 4 have higher risk of lesion development on vascular bed.2
Notes:
CHD is a multifactorial disease, caused by both genetic and environmental factors. Gene-environmental theory posits that genetic risk factor are more likely to lead to negative health outcomes in environments of high risk as compared to those in environments of low risk.
Apolipoprotein E (ApoE) polymorphism has been identified as a risk factor for coronary heart disease and Alzheimer’s.
ApoE exerts its inhibitory effects on cell proliferation via activation of inducible nitric oxide synthase (iNOS). However, ApoE inhibition of cell migration is mediated by a mechanism independent of iNOS activation.
References:
Talmud PJ. How to identify gene-environment interactions in a multifactorial disease: CHD as an example. Proc Nutr Soc. 2004; 63(1):5–10.
Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, Miller GJ. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet. 2001; 358(9276):115–9.
1. Talmud 2004; 2. Humphries et al. 2001

15. The most important health message a doctor can give to patients is to quit smoking.