Transcript PPT - The Citadel

Chapter 05
Coronary Heart Disease
• Coronary Heart Disease Mortality
o History and Magnitude of the Problem
• Heart Disease has been the #1 cause of death in the US since 1920.
• CHD remains the number-one cause of death in the United States,
costing an estimated $177 billion in 2010, more than one-third of the
costs of all cardiovascular diseases.
• Mortality Rates have decreased since 1950
o Smoking has decreased
o Better hypertension medications
o Increased public awareness on dietary intervention
o Better medical treatment for heart attacks
• Coronary Heart Disease
o Magnitude of the Problem
• Currently (2010), an estimated 17.6 million persons aged 20 years and
older in the United States have CHD.
• It is estimated that approximately every 25 seconds, an American will
suffer a coronary event and that approximately every minute, one
American will die from such an event.
• About half of American men and a third of American women will
develop CHD. The average age at first MI for men is about 65 years;
for women, it’s 70 years.
• Coronary Heart Disease Risk Factors
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Genetic Susceptibility (Family History)
Sex (Male)
Age
Hypercholesterolemia
Low HDL-cholesterol
Cigarette Smoking
Uncontrolled Hypertension
Obesity
Diabetes
Physical Inactivity
• Major Modifiable Risk Factors for CHD
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Hypercholesterolemia
Hypertension
Hyperlipidemia
Physical Inactivity
Smoking
Diabetes
Obesity
Stress
Alcohol abuse
• CHD – Etiology (Study of causation) Video
o CHD is caused by Atherosclerosis
o Atherosclerosis (plaque
formation ) is a form of
Arteriosclerosis (hardening of the artery) is
characterized by fatty deposits called atheromas.
Atherosclerosis is a disease affecting arterial blood
vessels. It is a chronic inflammatory response in
the walls of arteries, in large part to the
deposition of lipoproteins (plasma proteins that
carry cholesterol and triglycerides). It is
commonly referred to as a "hardening" or "furring"
of the arteries. It is caused by the formation of
multiple plaques within the arteries.
• Pathologically, the atheromatous plaque is divided
into three distinct components:
• The atheroma ("lump of porridge", from Athera,
porridge in Greek,) is the nodular accumulation of a
soft, flaky, yellowish material at the center of large
plaques, composed of macrophages nearest the
lumen of the artery.
• Underlying areas of cholesterol crystals.
• Calcification at the outer base of older/more
advanced lesions.
• The atheromatous plaques, eventually lead
to plaque ruptures and stenosis (narrowing)
of the artery and, therefore, an insufficient
blood supply (ischemia) to the organ it
feeds.
• An ischemic event in the myocardium can
cause a heart attack
• Tearing of the plaque can cause a
thrombus formation also causing a heart
attack
• A second problem occurs if the
compensating artery enlargement process is
excessive, a net aneurysm results.
• The atherosclerotic process begins in childhood. (see
Progression of Atherosclerosis – next slide)
• Severity is related to an increase in LDLcholesterol, and conversely (retards atheroma growth)
to HDL-cholesterol. HDL is believed to transport
cholesterol from atheromas back to the liver.
• Cigarette smoking, high blood pressure, and
dietary intake of saturated fat and cholesterol
also contribute to atherosclerosis.
• LDL-cholesterol readily enters the artery wall by
crossing the endothelial membrane. Once in
the arterial wall, if LDL accumulates, it is subject
to modification. The modification of LDLcholesterol accelerates the genesis of
atheromas.
Progression of
Atherosclerosis
•Stages
•Initial Lesion
•Fatty Streak
Formation
•Intermediate Lesion
•Atheroma
•Fibroatheroma
•Complicated Lesion
• Atherogenesis
o Begins with lesions of the artery intima (inner
lining) The intima includes the surface endothelial
cells and the underlying connective tissue.
o Lesions occur from elevated lipoprotein levels
(cholesterol), toxic effects of chemicals in
cigarettes, and elevated homocysteine levels.
o Atherogenesis is a staged process that begin
with the circulating blood platelets and the in
endothelium
o Staged process of atherosclerosis (atherogenesis)
follows..
• Staged Process of Atherogenesis
1) Platelets adhere to the connective tissue beneath the damaged
endothelial cells
2) Platelet adhesion activates fibrinogen
3) Fibrinogen enhances platelet aggregation
(positive feedback)
4) Fibrinogen releases a growth factor that stimulates
smooth proliferation (chemotactic) and fibroblasts (Fibroblasts
provide a structural framework for many tissues, and play a
critical role in wound healing. They are the most common cells of
connective tissue )
5) Smooth muscle cells and fibroblasts migrate into the
intima and cause fibrosis (hardening) by the production of
collagen, elastin (both connective tissue)
** LDL-cholesterol continues to collect in
the damaged area.
• LDL and Atherogenesis
o Oxidized LDL occurs via combining with a free radical of
oxygen created from cellular respiration ( A free radical is an
atom or group of atoms that transiently exists in an unstable state by
carrying an unpaired electron until an electron can be stolen from
another atom.)
o Oxidized LDL secretions attract macrophages which
become foam cells (Oxidized LDL stimulates secretion of
monocyte chemo-attractant protein-1 (MCP-1), which results in a
fatal attraction for immune cells known as macrophages, already
drawn to the arterial lesion to ingest the debris of injured
endothelial cells)
o Oxidized leads to further injury of the endothelial cells
(cytotoxic).
• Inflammation and Atherogenesis
o The atherosclerotic disease involves an inflammatory process.
o Major risk factors for CVD including hyperlipidemia, hypertension,
diabetes, and obesity all have pro-inflammatory features as do viral and
bacterial infections
o Inflammatory responses can be measured via C-reactive protein.
Associated with the presence of C-reactive protein includes the uptake of
LDL by marcophages, and attraction of the monocytes to the
endothelium, and the production of MCP-1.
o In healthy men and women with normal LDL cholesterol levels but
elevated C-reactive protein a drug (rosuvastatin) that lowered both LDL
cholesterol (by 50%) and C-reactive protein levels (by 37%), resulted in a
44% reduction in the occurrence of a first cardiovascular event
o Other inflammatory markers include elevated white blood cell counts and
elevated levels of circulating fibrinogen
o The anti-inflammatory effect of physical activity may be mediated
through beneficial changes in body weight.
• Hemostasis
o Hemostatic (blood clotting) factors are risk
factors for CVD.
o Coagulation or clotting of blood involves platelet
aggregation and fibrinogenesis.
Blood Coagulation
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Blood coagulation is the most effective
means of hemostasis.
2.
Blood coagulation is very complex and
uses clotting factors.
3.
Damaged tissues release a chemical
called tissue thromboplastin, which
activates the first in a series of factors
leading to the production of prothrombin
activator.
4. Prothrombin activator converts prothrombin in
the plasma into thrombin. This in turn, catalyzes
a reaction that converts fibrinogen into fibrin.
5. The major event in blood clot formation is the
conversion of soluble fibrinogen into net like
insoluble fibrin (fibrinogenesis)causing the blood
cells to catch.
6. The amount of prothrombin activator formed is
proportional to the amount of tissue damage.
7. Once a blood clot forms, it promotes still more
clotting through a positive feedback system.
8. After a clot forms, fibroblasts invade the
area and produce fibers throughout the
clots.
9. A clot that forms abnormally in a vessel is a
thrombus; if it dislodges, it is an embolus.
• Process of Hemostasis
o Thus, the concentration of fibrinogen in the blood also is a
risk factor for MI and stroke due to hemostasis. A high level
of fibrinogen in blood plasma doubles the risk of
developing CVD, and increases recurrent MI and ischemic
stroke by 8%, independently of overall CVD risk status,
smoking, and age
o Fibrinogen levels increase with age, smoking, waist to hip
ratios, and LDL cholesterol levels.
o Plasmin is formed in the blood from plasminogen by tissuetype plasminogen activator (tPA), which is released from
endothelial cells in blood vessels or by drugs such as
streptokinase and trypsin.
o A major contributor to impaired fibrinolysis is a high blood
level of plasminogen activator inhibitor-1 (PAI-1), which
also is released by blood vessel endothelial cells and
inhibits tPA. High PAI-1 is a risk factor for first heart attack or
stroke, a recurrent heart attack among heart attack
survivors, and cardiac death among people reporting
angina.
• Homocysteine
o A natural intermediate amino acid formed during the metabolism
of methionine (essential amino acid)
o Elevated levels of homocysteine in the blood are associated with
a higher risk of developing CVD, although whether this link is
causal is unclear. Recent research diminishes the association with
homocysteine and CVD (2008).
o The homocysteine hypothesis of CVD is credited to physician
Kilmer McCully (1969), who observed that children with the
genetic condition homocystinuria (which leads to abnormally
high levels of homocysteine because of deficiencies in metabolic
enzymes) usually died from arteriosclerosis at an early age.
o It is hypothesized that homocysteine damages the endothelial
cells which results in platelet aggregation and blood clotting
o Increasing dietary levels of B6 and B12 and Folic Acid (B9)
deters homocysteine formation.
• Physical Activity and CHD: The Evidence
• Occupational Activity and CHD Risk
o London Bus Conductors (Morris)
• Conductors at lower risk than drivers
• If conductors developed CHD, it was less severe
• BP was lower in conductors, if BP was the same between
conductors and drivers, the conductors had fewer heart
related problems than the drivers
• Bus drivers rate of coronary death was higher independent of
body mass
Occupational Activity and CHD Risk
o San Francisco Longshoremen (Dock Workers)
• Active group had death rates 50% of the inactive group
• Active group had sudden death rates 66% lower than the
inactive group
o Other early studies of Occupational Activity
• Most studies report active workers have 33 to 75% fewer fatal
CHD events than least active workers
• Many studies did not control for confounding factors such as
smoking and dietary habits, between workers with different
occupational activity levels.
Leisure-Time Physical Activity and CHD Risk
o Retrospective Cohort and Case-Control Studies
• The Netherlands
o A significant inverse relationship between heart attack
and walking, cycling, and gardening, if performed more
than eight months per year.
• King County Washington
o Risk of cardiac death was 55-65% lower in men and
women in higher intensity physical activity compared to
those who did not engage in any higher intensity physical
activity.
Leisure-Time Physical Activity and CHD Risk
o Retrospective Cohort and Case-Control Studies
• Health Insurance Plan of New York
o Incidence of MI in heavy and moderate activity
groups was about 50% of the light activity group
o Least active men had mortality rate 4.5x greater
than the most active men following an MI.
• Prospective Studies
o 26 Study Meta-analysis = The relative risk of CHD
associated with a moderate, compared with a low, level of
leisure-time physical activity was 0.88 (95% CI: 0.83-0.93) (Sofi
et al. 2008). For high compared with low level of leisure-time
physical activity, the relative risk was 0.73 (0.66-0.80)
o Additional Meta-analysis findings that 150 min/week had
14% reduction in RR; whereas 300 min/week = 20%
reduction in RR.
o British Civil Servants Study
• CHD death rate twice as high in the non-vigorous vs.
vigorous group
• Higher rates of CHD found in those who stopped activity
• Vigorous sport activities protective for younger, lower
intensity exercise protective for older men. Thus, the
dose-response effect of exercise may vary with age.
• Prospective Studies
o Harvard Alumni Study
• Men who expended < 2000 kcal/wk were at 64% higher
risk of CHD – There is a consistent dose-response
relationship for optimal reductions in CHD morbidity and
mortality at/around 2000 kcal expenditure/wk
• Athletes did not have any risk reduction in later years if
they discontinued exercise
o Framingham
• Relative Risk for CHD in least active men 1.3x that of the
most active men.
• Prospective Studies
o Seven Countries Study
• Three of seven countries showed inverse relationship
between physical inactivity and CHD. Note relatively few of
the men in the study were classified as sedentary
o Finnish Cohorts
• CHD was clearly associated with sedentary habits
o Puerto Rico Heart Health Program
• Inverse association between the incidence of CHD and
physical activity
• Physical inactivity independently contributes to the risk
of CHD
• Prospective Studies
o Multiple Risk Intervention Trials (MRFIT)
• CHD mortality in the most active 67% of the least active
• Daily caloric threshold between 75-200kcal has a
protective effect
• Greater than 220, up top 640 kcal/day further
decreases mortality rates.
• A modest amount (20 min/day) of exercise decreases
risk of CHD in middle-aged and older men.
• Prospective Studies
o Nurses Health Study
• Strong, Graded, and Inverse relationship between CHD
risk and physical activity
• Those women who exercised vigorously 1.5 hours per
week had the greatest protective effect of exercise
(adjusting for other risk factors)
o Women’s Health Initiative Observational Study
• Postmenopausal women
• Women in the top three quintiles (most active) had
significantly lower risk (equivalent of 2.5h of brisk
walking/week)
• Prospective Studies
o Health Professionals Follow-up Study
• Total physical activity, running, weight training, and
rowing were each inversely and linearly related to risk of
CHD
o Running for an hour or more per week was
associated with a 42% risk reduction
o Weight training for 30 min or more per week was
associated with a 23% risk reduction
o Rowing for 1 h or more per week was associated
with an 18% risk reduction
o A half hour per day or more of brisk walking was
associated with an 18% risk reduction
• Physical Fitness and Coronary Heart Disease
Risk
** The true size of the protective effect of physical
activity against CHD is probably underestimated.
• Los Angeles Public Safety Workers
o Below average fitness = 2.2 RR (relative risk) of MI ;
increasing to 6.6 with two additional risk factors
(hypercholesterolemia, systolic hypertension, cigarette smoking)
• Lipid Research Clinics Prevalence Study
o CHD mortality RR in least fit was 6.5x for CVD death
o See figure 5.8, p.108, and next slide for dose response
• Physical Fitness and Coronary Heart Disease
Risk
• Lipid Research Clinics Prevalence Study
Cumulative rates of death from cardiovascular diseases
in healthy men according to quartiles of exercise test
heart rate. Men who were most active (first quartile) had
the lowest CVD death rate. Divergence of mortality
curves over follow-up indicates that the effect on
cardiovascular mortality is unlikely to be due to bias.
• Physical Fitness and Coronary Heart Disease Risk
o Aerobics Center Longitudinal Study
• Mortality rate for highly fit 50% of the moderately fit, and the
rate of the least fit 3x that of the moderately fit men
• In women, mortality rate 3.6x in the moderately fit compared
to the highly fit, and the low fit mortality rate was 2.5x that of
the moderately fit
o St James Women Take Heart Project
• The relative risks for cardiac death among high-, medium-,
and low-fit women were 1.00 (referent), 2.02 (95% CI: 0.468.82), and 4.27 (1.0317.6), respectively
*** A review of the physical fitness studies show a
causal relationship between regular physical
activity and a reduced risk of CHD.
Population Attributable Risk (PAR) for Physical
Inactivity
o PAR = a estimate of the reduction in mortality rate that
might occur if all individuals with a particular risk factor
(inactivity) were to eliminate that risk factor.
o Estimate Reports
• PAR U.S. Sedentary Lifestyle = 16% CHD Mortality
• PAR Sedentary Lifestyle = 13% All Cause Mortality (similar to
cigarette smoking, hypertension, and overweight)
• Longitudinal Studies PAR for sedentary behavior show that low
fitness had a PAR Mortality that was similar to , if not larger
than the other risk factors.
• Summary – Sedentary behavior substantially contributes to the
public health burden, and eliminating this behavior would
have as great, or greater, impact on reducing excess
mortality as eliminating other major CHD risk factors.
• Strength of the Association between
Physical Activity in All Cause and CHD
Mortality
o Strength of the Evidence
• Temporal Sequence
o Prospective Cohort designs in physical activity measure
the independent variables before the outcome occurs,
thus demonstrating the appropriate temporal sequence.
• Strength of the Association
o Review of literature on CHD and Mortality show that the
RR of mortality is almost 2x as great for sedentary when
compared to active persons
• Strength of the Association between Physical
Activity in All Cause and CHD Mortality
o Strength of the Evidence
• Consistency of Results
o Results are consistent about the association of physical
activity with all-cause CHD mortality in both men and women
• Biological Plausibility
o Exercise decreases coronary atherosclerosis, and thus,
increase myocardial oxygen demand
o Exercise decreases the risk of coronary thrombosis reducing
the risk for clotting in the coronary vessels
o Acute bouts of exercise promotes fibrinolysis (decrease in
blood clotting activity)
o Chronic exercise decreases plasma fibrinogen and increases
tissue plasminogen when compared to sedentary
counterparts.
• Strength of the Association between Physical
Activity in All Cause and CHD Mortality
o Strength of the Evidence
• Biological Plausibility (cont.)
o Exercise decreases myocardial irritability, reducing
the rate of ventricular fibrillation
• Dose Response
o Review of 31 studies show that physical activity has
a causal, dose-response relationship with reduced
CHD morbidity and mortality.
o There is a threshold where the RR of CHD Mortality
tends to plateau, possibly around 2-3,000 kcal/wk,
with a tendencey to see reduction in risk around
500kcal/week
o The accumulation of caloric expenditure is more
closely associated with the overall risk reduction in
CVD.
Summary of Findings
• Activity for CHD risk reduction should ideally require
150 min/week of moderate-intensity aerobic
activity, or 75 min/week of vigorous-intensity
physical activity, or the equivalent energy
expenditure in a combination of moderate and
vigorous activities. Physical activity can be
accumulated in bouts of at least 10 min in duration
to count toward the total.
• For persons willing to do more, additional amounts
of physical activity beyond that confer additional
risk reductions.
END OF PRESENTATION