cad

2.  Oxidative stress is a condition in which reactive oxygen species
(ROS) or free radicals, namely O2 –, H2O2 , and •OH, are
generated extra- or intracellularly and exert toxic effects on cells.
Heart is one of the major organs affected by ROS.
 Chronic and acute overproduction of reactive oxygen species
(ROS) under pathophysiologic conditions is integral in the
development of Coronary Artery Disease.
 Oxidative stress is the unifying mechanism for many Coronary
Artery Disease risk factors, which additionally supports its central
role in CAD.
 ROS mediate various signaling pathways that underlie vascular
inflammation in atherogenesis: from the initiation of fatty streak
development through lesion progress to ultimate plaque rupture.

3.  Oxidative stress is caused by an imbalance
between the oxidant and antioxidant systems of
the body in favor of the oxidants.

4.  Are the molecules that contain one or more
unpaired electrons in their outer orbit, which makes
them highly reactive.
 Are generated constantly in vivo and may cause
oxidative damage to nucleic acids, lipids, and
proteins and affect cell membrane properties. Their
accumulation may lead to the oxidative destruction
of cells.
 Some of the most important free radicals in
biological systems are derivatives of oxygen
(reactive oxygen species [ROS]) such as
superoxide anion radical, hydroxyl radical,
hydrogen peroxide, and triplet or singlet O2.

5.  ROS are produced in low amounts during cellular
metabolism under normal conditions:
 by proton leakage during oxidative phosphorylation in
mitochondria
 by various enzymes such as NADH/NADPH oxidase in
endothelial cells, vascular smooth muscle cells and
neutrophils
 xanthine oxidase in endothelium
 cytochrome P450
 lipoxygenase/cyclooxygenase pathways
 and the auto-oxidation of various substances, particularly
catecholamines

6. Exogenous Sources of Oxidants
 Cigarette Smoke
 Ozone Exposure
 Air pollution
 UV rays
 Chemicals, pesticides
 Ionizing radiation
 Food and food additives
 Heavy metal ions, such as iron, copper, cadmium, mercury, nickel, lead,
and arsenic, can induce generation of reactive radicals and cause
cellular damage via depletion of enzyme activities through lipid
peroxidation and reaction with nuclear proteins and DNA.

7.  Antioxidant enzymes
 Non-enzymatic antioxidants
 Trace elements

8.  Antioxidant enzymes
 Superoxide dismutase (SOD)
 Catalase (CAT)
 Glutathione peroxidase (GPx)

10.  Non-enzymatic antioxidants
 Alpha tocopherol (vitamin E)
 Ascorbic acid (vitamin C)
 Beta carotene
 Trace elements
 selenium

11.  Reactive oxygen species can be produced by normal
cellular metabolism and react with biomolecules like
protein, lipid, and DNA to cause cellular damage and
responsible for degenerative changes.
 At low concentration free radicals play a vital role in the
physiological regulation and cellular signaling processes
but the high level can cause deleterious changes in the
cell.
 Contrary to these antioxidants lowers the oxidants by
donating its own electron to stabilize free radical and make
it not reactive compound so as to minimize the harmful
effects generated by these radicals in the cell.

12.  The biological effects of ROS-mediated reactions are due to their direct
interaction with cellular lipids, proteins, and DNA (e.g. nicking, base-pair
mutations, rearrangements, deletions, insertions, and sequence amplifi
cation), causing cell damage and death.
 ROS also causes lipid peroxidation, which results in damage to the cell
membrane and the membranes of cellular organelles.
 ROS and RNS can also damage mitochondrial DNA, and such damage
has been suggested to be important in several human diseases and in the
aging process. These alterations in DNA may significantly affect gene
expression.
 The modification and denaturation of proteins by ROS results in damage to
proteins and the inactivation of critical enzymes.
 These cumulative long-term effects of ROS can cause loss of heart
contractile function and alterations in the cardiovascular system

13. Mitochondria as targets of ROS
 Mitochondrial proteins, lipids, and mtDNA become
nonfunctional due to their oxidative modifications.
 The most affected mitochondrial enzymes or enzyme
complexes include aconitase, ketoglutarate dehydrogenase,
pyruvate dehydrogenase, and complexes I, II, and III.
 Oxidative inactivation of mtDNA polymerase slows mtDNA
replication and thus leads to inhibition of oxidative
phosphorylation.
 This would lead to decreased supply of ATP to all energy-
dependent processes in the cell.

14.  Atherogenesis
 Plaque vulnerability
 Ischemic reperfusion injury

15.  According to the theory of oxidative stress, atherosclerosis is the
result of the oxidative modification of low density lipoproteins
(LDL) in the arterial wall by reactive oxygen species (ROS).
 Common risk factors for atherosclerosis increase the risk of the
production of free ROS, not only from the endothelial cells, but
also from the smooth muscle cells and the adventitial cells.
 Thus, hypercholesterolemia, diabetes mellitus (DM), arterial
hypertension, smoking, age, and nitrate intolerance increase the
production of free ROS.
 Oxidative stress triggers atherosclerosis by
 Endothelial dysfunction
 Modification of LDL
 Expression of adhesion molecules

17. Endothelial dysfunction
 Endothelial function is impaired in the earlier stages of atherogenesis
and is strongly correlated with several risk factors.
 Endothelial dysfunction predisposes to long-term atherosclerotic lesions
and has been proposed as an important diagnostic and prognostic
factor for coronary syndromes.
 The production of free oxidative radicals is believed to induce
endothelial dysfunction, as an initial step of atherogenesis.
 The increased production of ROS reduces the production and
consequently the bioavailability of NO, leading to vasoconstriction,
platelet aggregation and adhesion of neutrophils to the endothelium.
 Oxidative stress by hydrogen peroxide (H2O2) increases
phosphorylation of tyrosin kinases, which leads to stronger binding of
neutrophil cells on endothelium and alteration of vessel permeability.

18. Modification of LDL
 Oxidative stress leads to oxidation of LDL (ox-LDL),
whose uptake by macrophages is easier compared
to non-oxidized lipoproteins.
 The main sources of oxidative substances and
ROS in atherosclerotic vessels are macrophages
and smooth muscle cells.
 Hypercholesterolemia stimulates the production of
superoxide anion radicals from the smooth muscle
cells of vessels, an event that leads to increased
oxidation of LDL

19. Expression of adhesion molecules
 Oxidative stress (by H2O2) causes
atherogenesis by increasing the production of
transcription factors such as nuclear factor ÎB
(NF-ÎB) and activator protein 1 (AP-1), which
participate in the expression of adhesion
molecules-
 vascular cellular adhesion molecules (VCAM1),
 intracellular adhesion molecules (ICAM-1),
 E-selectin and other cytokines.

20.  Thus, it seems that atherosclerosis is an inflammatory
process strongly affected by oxidative stress.

21. PLAQUE VULNERABILITY AND
PRECIPITATION OF MYOCARDIAL INFARCTION (MI)
 Oxidative stress and inflammation are positively associated
with the instability of atherosclerotic plaque and the
incidence of acute coronary syndrome (ACS)
 ROS-induced initiation of inflammatory cascades and low-
density lipoprotein (LDL) oxidation leads to the formation of
macrophage-derived foam cells, differentiation and
proliferation of vascular smooth muscle cells, activation of
vascular matrix metalloprotein-ases and impairment of the
extracellular matrix (ECM) of the affected site. This may
culminate in atherosclerotic plaque rupture
 Ehara et al demonstrated increased plasma levels of
oxidized LDL in cases of ACS.

22.  Oxidative stress plays a key role in ischemia-reperfusion
injury and subsequent cardiac repair.
 During ischemia-
 cellular defenses against oxidative injury are impaired,
with lower activities of antioxidants such as superoxide
dismutase and glutathione peroxidase.
 Greater amounts of ROS are produced, for example, by
xanthine dehydrogenase, which is converted to xanthine
oxidase, a potent generator of O2
− and hydrogen peroxide

23. Mechanism of ischemic reperfusion injury
 During acute myocardial ischemia, the absence of oxygen switches cell
metabolism to anaerobic respiration, resulting in the production of
lactate and a drop in intracellular pH.
 This induces the Na+-H+ exchanger to extrude H+ and results in
intracellular Na+ overload, which activates the 2Na+-Ca2+ exchanger to
function in reverse to extrude Na+ and leads to intracellular
Ca2+ overload. The Na+-K+ ATPase ceases to function in ischemia,
exacerbating intracellular Na+ overload.
 The acidic conditions during ischemia prevent the opening of the MPTP
and cardiomyocyte hypercontracture at this time.
 During reperfusion, the electron transport chain is reactivated,
generating ROS. Other sources of ROS include xanthine oxidase
(endothelial cells) and NADPH oxidase (neutrophils).

24.  ROS mediate myocardial reperfusion injury by inducing the opening of
the MPTP, acting as a neutrophil chemoattractant, and mediating
dysfunction of the sarcoplasmic reticulum (SR).
 This contributes to intracellular Ca2+ overload and damages the cell
membrane by lipid peroxidation, inducing enzyme denaturation and
causing direct oxidative damage to DNA.
 Reperfusion and reactivation of the Na+-H+ exchanger result in washout
of lactic acid, resulting in the rapid restoration of physiological pH,
which releases the inhibitory effect on MPTP opening and
cardiomyocyte contracture.
 The restoration of the mitochondrial membrane potential drives calcium
into the mitochondria, which can also induce MPTP opening.
 Several hours after the onset of myocardial reperfusion, neutrophils
accumulate in the infarcted myocardial tissue in response to the
release of the chemoattractants ROS, cytokines, and activated
complement.

26.  The four recognized forms of myocardial reperfusion injury
are-
1. Reperfusion induced arrhythmias.
2. Myocardial stunning-The reversible post-ischemic contractile
dysfunction that occurs on reperfusing acute ischemic
myocardium is referred to as myocardial stunning.
3. Microvascular obstruction–
 inability to reperfuse a previously ischemic region.
 major contributing factors include capillary damage with impaired
vasodilatation, external capillary compression by endothelial cell
and cardiomyocyte swelling, micro-embolization of friable
material released from the atherosclerotic plaque, platelet micro-
thrombi, the release of soluble vasomotor and thrombogenic
substances, and neutrophil plugging.

27. 4. Lethal myocardial reperfusion injury
 Reperfusion-induced death of cardiomyocytes
that were viable at the end of the index
ischemic event is defined as lethal myocardial
reperfusion injury.
 major contributory factors include oxidative
stress, calcium overload, mitochondrial
permeability transition pore (MPTP) opening.
 lethal myocardial reperfusion injury may
account for up to 50% of the final MI size.

29. Long-term effects of oxidative stress-
ventricular remodelling
 There is a correlation among oxidative stress, ventricular remodelling and
progressive dilation leading to end-stage heart failure.
 The remodelling process in postischemic myocardium is the result of multiple
underlying structural and signalling changes comprising myocardial cell
contractile dysfunction, necrosis, apoptosis, inflammation, microvascular
dysfunction and ECM changes.
 Following myocardial infarction, ROS-activated matrix metalloproteinases and
fibroblast proliferation lead to structural and functional rearrangement of the
ECM.
 The migration of cytokine-attracted neutrophils and macrophages producing
additional free radicals is facilitated.
 The neuroendocrine system, ROS and inflammatory cytokines are important
regulators of the remodelling process.

30. Heart failure
 Heart failure under both acute and chronic conditions is
associated with increased levels of oxidative markers (eg,
malonyldialdehyde, glutathione peroxidase, thioredoxin or
superoxide dismutase.
 Mitochondria damaged by ischemia-reperfusion injury are
one of the sources of persistently elevated ROS levels.
 Increased renin-angiotension-aldosterone system activity
stimulates NADH/NADPH oxidase, as shown by
Griendling et al and Rajagopalan et al.

31.  Vitamins (A, E, C) reduce LDL oxidation and
preserve vasoreactivity by increasing
endothelial nitric oxide release and reducing
thrombogenicity.
 Antioxidant vitamins may also reduce the
risk of plaque progression and rupture.

33. Verlangieri,
et al.
United
States
Inverse association between fruit and vegetable
consumption and CHD mortality
Riemersma,
et al.
110
angina
patients
and 394
control
subjects
Lower plasma vitamin E levels in angina patients than in
control subjects
Luoma, et al. Northern
Finland
Inverse association of plasma vitamin E level and CHD
mortality

34.  The National Health and Nutrition Examination Survey-
cohort study found an inverse relationship between the
highest vitamin C intake (diet and supplements) and CHD
risk over 10 years in 11,349 U.S. men and women 25 to 74
years of age.
 The primary prevention Alpha-Tocopherol, Beta-Carotene
Cancer Prevention (ATBC) study (1998) examined
cardiovascular disease as a secondary outcome in 29,133
male smokers randomized to α-tocopherol, β-carotene, a
combination of the two, or placebo. At 8 years follow-up,
neither antioxidant was found to decrease cardiovascular
disease.

35.  The Cambridge Heart Antioxidant Study (CHAOS) randomized 2,002
individuals with angiographically proven coronary artery disease to α-
tocopherol (800 IU/day) or placebo. After a median follow-up of 510
days, patients randomized to α-tocopherol were found to have a
reduction in the combined primary endpoint of cardiovascular death
and nonfatal myocardial infarction) that was driven mainly by a
reduction in myocardial infarction.
 The Women’s Health Study randomized 39,876 individuals in a 2 × 2
factorial design to α-tocopherol or placebo and aspirin or placebo and
followed participants for an average of 10.1 years. In this study, α-
tocopherol supplementation decreased cardiovascular mortality in
healthy women but had no effect on the incidence of myocardial
infarction or stroke.

36.  In order to reconcile all the available data from clinical studies,
several meta-analyses were performed.
 One analysis included data from 188,209 individuals that
participated in 15 placebo-controlled clinical trials. Overall, this
study found that antioxidant vitamins had no effect on major
adverse cardiovascular events .
 Another meta-analysis identified 50 randomized controlled trials
that included 294,478 subjects (156,663 in the treatment or
intervention group and 137,815 in the control or referent group)
to evaluate the effect of antioxidants on cardiovascular disease,
the primary analysis found that vitamins or antioxidant
supplements did not reduce the risk of major cardiovascular
events leading to the conclusion that antioxidant vitamins or
supplements had no beneficial effect in the primary or
secondary prevention of cardiovascular disease.

37.  The beneficial antioxidant effects of diet have been examined extensively in the
PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter,
randomized, controlled, clinical trial that evaluated the effects of a Mediterranean
diet on cardiovascular outcomes in individuals without cardiovascular disease.
 Participants were randomized to a Mediterranean diet supplemented with nuts or
extra-virgin olive oil, or a control low-fat diet.
 After a median of 4.8 years, there was a 28-30% reduction in major adverse
cardiovascular events in individuals randomized to the supplemented
Mediterranean diet.
 These findings were attributed, in part, to a reduction in oxidant stress as
markers of oxidant stress (i.e., oxidized low-density lipoproteins and
malondialdehyde) were decreased in individuals assigned to the Mediterranean
diet.
 While it is not clear what dietary antioxidants are responsible for the
cardiovascular risk reduction, it is evident that dietary intervention with the
Mediterranean diet offered the best possible outcomes of all the antioxidants
studied.

39.  that may provide protection against CHD include selenium,
bioflavonoids and ubiquinone.
 One study found that selenium levels are inversely
associated with CHD mortality.
 Flavonoids are antioxidants found in tea, wine, fruits and
vegetables. These antioxidants reduce platelet activation,
but studies do not yet support an associated reduction in
CHD. One epidemiologic study found an inverse
correlation between dietary flavonoid intake and CHD.

40. Recommendations for Patient Care
Patients should consume a varied diet that contains five to seven servings of
fruits and vegetables each day.
Patients should receive lifestyle counseling and continue cholesterol treatment
when indicated.
Patients with known CHD should probably take vitamin E in a dosage of 400
IU per day and vitamin C in a dosage of 500 to 1,000 mg per day.
Supplementation of β-carotene for CHD prevention is not routinely
recommended.
Patients at high risk for CHD and low-density lipoprotein cholesterol oxidation
(i.e., those with diabetes or hypertension, and those who smoke) may benefit
from supplementation of vitamin E in a dosage of 400 IU per day and vitamin
C in a dosage of 500 to 1,000 mg per day.
Supplements of other antioxidant nutrients are not recommended at this
time.
Physicians should watch for results of upcoming clinical trials on
vitamin supplements.