1. PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM DISORDERS
Mehtap KACAR KOÇAK M.D. PhD
Pathophysiologist

2. Learning Objectives Describe to Cell adhesion molecules
Describe to injury of ischemia-reperfusion
Describe to atherosclerosis
Describe to hypertension
Ischemic heart diseases
Myocardial infarction
Heart failure
Cor pulmonale (right heart failure)
Rheumatic Heart Disease

3. INTEGRATING CELLS INTO TISSUES
Junctions:
Cell to cell
Gap junction
Tight junction
Anchoring junction
Cell to matrix
Focal adhesions
Hemidesmosomes

4. The appearance of multicellular organisms allows specialization of cells and formation of organs.
A special matrix, the extracellular matrix, ECM, fills out the space between cells
ECM also binds cells together, acts as reservoir for growth factors and hormones, and creates an environment in which molecules and cells can migrate.
By means of cell adhesion molecules, CAMs, cells are capable of recognizing each other
Plasma membrane receptors take care of cell-ECM interactions

5. Junctions
Figure 3-14: Types of cell junctions

6. Key Junction Proteins: Connexin, cadherins, occludin & integrins

8. CELL-CELL ADHESION MOLECULES (NONJUNCTIONAL MECHANİSM)
Cadherins
Ig superfamily CAMs
Selectins
Integrins

9. CADHERINS A family of Ca2+-dependent CAMs
Ca2+ causes dimerization of Cadherins
The binding is homophilic

10. IMMUNOGLOBULİN (Ig) FAMİLY MEMBERS:
Include:
* ICAM-1(Intracellular adhesion molecule 1),
* ICAM-2 (Intracellular adhesion molecule 2),
* VCAM-1 (Vascular cell adhesion molecule-1)
* PECAM-1(Platelet Endothelial Cell adhesion molecule 1)
Structure: type 1 transmembrane glycoproteins
containing Ig homology domains

11. Expression patterns of Ig adhesion molecules:
IL-1 and TNF upregulate ICAM-1 and VCAM-1 expression on endothelium.
ICAM-2 is expressed constitutively on the endothelial surface.
PECAM-1 is expressed constitutively on endothelial cells at intercellular junctions and on leukocytes.

12. Ligands of Ig adhesion molecules:
ICAM-1, ICAM-2 and VCAM-1 bind leukocyte integrins.

13. Selectins: Three highly homologous members:
endothelial (E), platelet (P) and leukocyte (L)
Structure: type 1 transmembrane glycoproteins
E- and P-selectins are expressed by endothelial cells.
L-selectin is expressed by leukocytes.
P- and L-selectins are expressed constitutively.
Cytokines (IL-1 and TNF) upregulate the transcription of E- and P-selectins.
P-selectin is stored in cytoplasmic granules and a variety of stimuli can induce rapid translocation to the cell surface (within seconds).

14. Expression patterns of endothelial cell adhesion molecules:
Inducible Stored in Constitutively
expression cytoplasm expressed
E-selectin P-selectin ICAM-2
VCAM-1 PECAM-1
ICAM-1

15. (Leukocyte) integrins:
Integrins are heterodimeric transmembrane proteins composed of alpha and beta chains.
Integrins provide a link between the cell cytoskeleton and the extracellular matrix.
Integrins are clustered in focal adhesion complexes.

16. Adhesion molecules relevant to inflammation:
Adhesion molecules are proteins with structural domains that mediate the adhesion of leukocytes to endothelial cells.
Adhesion molecules are proteins that contain structural domains.
Each adhesion molecule can bind one or several ligands or counter-receptors.

17. Leukocyte integrin ligands:
Leukocyte integrins bind members of the Ig gene superfamily as well as other proteins.
Integrin Counter-receptors
L2 ICAM-1, ICAM-2
(LFA-1, CD11a/CD18)
M2 ICAM-1, fibrinogen, iC3b
(Mac-1, CD11b/CD18)
41 VCAM-1, fibronectin CS-1
(VLA-4, CD49d/CD29)

18. Endothelial Cell Activation
Inflammatory cytokines (e.g., IL-1 or TNF) activate endothelial cells to express adhesion molecules.
Unactivated
Activated
nonadhesive for leukocytes
hyperadhesive for leukocytes

19. Integrin activation during inflammation
NORMAL
INFLAMMATION

20. Leukocyte adhesion cascade
A sequence of activation and adhesion events leading to the extravasation of leukocytes at the site of inflammation.
Capture and Rolling (Fast-slow)-Selectins
Firm Adhesion-Integrins
Transmigration
Block in any one of them greatly reduces leukocyte accummulation in the damaged tissue.

23. Leukocyte Adhesion Cascade. Capture and Rolling
Cytokines released by injury activate venular endothelial cells and induce them to express P-selectin (stored in Weibel-Palade bodies) on their surface which interacts with a glycoprotein on leukocytes.
As a result the leukocytes roll along the endothelium forming bonds at the leading edge and breaking them at the trailing one.
L-selectin expressed by leukocytes also participates in the rolling process. It may be necessary for the initial attachment to the endothelium. In absence of P-selectin rolling is less efficiently mediated by L-selectin.
E-selectin expressed by activated endothelial cells is required to slow down rolling of leukocytes and initiates stronger adhesion.

24. General mechanism of cell injury
The three common forms of cell injury are;
1- hypoxic injury (and following reperfusion injury)
2- reactive oxygen species (ROS) and free radical-induced injury
3- chemical injury (CCl4)

26. ISCHEMIA - REPERFUSION INJURY
Hypoxia, or lack of sufficient oxygen, is the single most common cause of cellular injury.
Hypoxia can result from:
a decreased amount of oxygen in the air ,
loss of Hb or Hb function,
decreased production of red blood cells,
diseases of the respiratory and cardiovascular system,
poisoning of the oxidative enzymes (cytochromes) within the cells.
The most common cause of hypoxia is ischemia (reduced blood supply).

27. Ischemic injury is often caused by gradual narrowing of arteries (arteriosclerosis), and complete blockage by blood clots (thrombosis).
Cellular responses to hypoxic injury have been extensively studied in heart muscle.
Within 1 minute after blood supply to the myocardium is interrupted, the heart becomes pale.
Within 3 to 5 minutes, the ischemic portion of the myocardium ceases to contract.

28. The abrupt lack of contraction is caused by a rapid decrease in mitochondrial phosphorylation, which results in insufficient ATP production.
Lack of ATP leads to an increase in anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen.

30. Irreversible damage characterized by two events:
1- lack of ATP generation because of mitochondrial dysfunction,
2- major disturbances and damage in membrane function.
Acid hydrolases from leaking lysosomes are activated in the reduced pH of the injured cell and they digest cytoplasmic and nuclear components.
Leakage of intracellular enzymes into the peripheral circulation provides a diagnostic tool for detecting tissue-specific cellular injury and death using blood samples (troponin-MI, liver transaminases-hepatic injury)

31. Reperfusion injury
Restoration of oxygen, however, can cause additional injury called reperfusion injury.
Xanthine dehydrogenase, an enzyme which normally utilizes oxidized nicotinamide adenine dinucleotid (NAD+) as an electron acceptor, is converted during reperfusion with oxygen to xanthine oxidase.

32. During ischemic period, excessive ATP consumption leads to the accumulation of the purine catabolites hypoxanthine and xanthine ;
Which upon subsequent reperfusion and influx of oxygen are metabolized by xanthine oxidase to make massive amounts of superoxide and hydrogen peroxide.
In addition the highly reactive free radical nitric oxide is generated.

33. These radicals can all cause membrane damage and mitochondrial calcium overload.
Neutrophils are especially affected with reperfusion injury, and neutrophil adhesion to the endothelium enhances the process.

35. Free radicals and reactive oxygen species-induced injury
An important mechanism of membrane damage is injury induced by free radicals, especially ROS called oxidative stress.
Oxidative stress occurs when excess ROS overwhelms endogenous antioxidant systems.
Free radicals may be initiated within cells by :
1- the absorption of extreme enerjy sources (UV, x-ray)
2- endogenous (during normal metabolic process)
3- enzymatic metabolismof exogenous chemicals or drug.

37. Free radicals and ROS, three are particularly important in regard to cell injury:
1- lipid peroxidation
2- alterations of proteins causing fragmentation of polypeptide chains,
3- alterations DNA, including breakage of single strands..

40. CARDIOVASCULAR DISORDERS: Vascular Disease
Outlines:
Pathophysiology of Atherosclerosis
Pathophysiology of Hypertension

41. Arteriosclerosis
Arteriosclerosis is a chronic disease of arterial system characterized by abnormal thickening and hardening of the vessel walls.
In arteriosclerosis the tunica intima undergoes a series of changes that decrease the artery’s ability to change lumen size.
Smooth muscle cells and collagen fibers migrate into the tunica intima, causing it to stiffen and thicken.

42. Arteriosclerosis: Pathophysiology
General term for all types of arterial changes
Best for degeneration in small arteries and arterioles
Loss of elasticity, walls thick and hard, lumen narrows

43. Atherosclerosis
Atherosclerosis is a form of arteriosclerosis in which the thickening and hardening of the vessel is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called plaque.
It is leading contributor to coronary artery and cerebrovascular disease.

44. Atherosclerosis: Pathophysiology
Presence of atheromas
Plaques
Consist of lipids, cells, fibrin, cell debris
Lipids usually transported with lipoproteins

45. Consequences of Atherosclerosis

46. Lipoproteins and Transport

47. Atherosclerosis--Diagnosis
Analysis of serum lipids:
Total cholesterol, triglycerides, LDL, HDL
LDL
High cholesterol content
Transports cholesterol liver  cells
Dangerous component
HDL
“good”
Low cholesterol content
Transports cholesterol cells  liver

48. Atherosclerosis—Risk Factors
Age
Gender (Male)
Genetic factors
Obesity, diet high in cholesterol, animal fats
Cigarette smoking
Sedentary life style
Diabetes mellitus
Poorly controlled hypertension
Smoking
LDL↑
HDL↓
hyperhomocystinemia
CRP ↑
Serum fibrinogen ↑
Oxidative stress
Peridontal disease

49. Pathophysiology of atherosclerosis
Atherosclerosis is an inflammatory disease.
Atherosclerosis begins with injury to the endothelial cells that line artery walls. (Risk factors!!!) (remember leukocyte adhesion)
Pathologically the lesions progress from: endothelial injury and dysfunction to fatty streak to
fibrotic plaque to
complicated lesions.

50. Once injury has occured, endothelial dysfunction and inflammation lead to the following events:
1. injured ECs become inflamed and cannot make normal amounts of antithrombotic and vasodilating cytokines.
2. numerous inflammatory cytokines are released, including TNF-α, IF-γ, IL-1, toxic oxygen radicals, and heat shock proteins.

51. 3. growth factors are also released, including AngII, FGF, PDGF, which stimulate smooth muscle cell proliferation in the affected vessels.
4. macrophages adhere to injured endothelium by way of adhesion molecules such as VCAM-1.
5. these macrophages then release enzymes and toxic oxygen radicals that create oxidative stress, oxidize LDL, and further injure the vessel wall.

52. The oxidation of LDL is an important step in atherogenesis
The oxidation of LDL is an important step in atherogenesis. (smoking, diabetes, hypertension…)
Inflammation with oxidative stress and activation of macrophages is the primary mechanism.
The oxidized LDL penetrates into the intima of the arterial wall and is engulfed by macrophages. Macrophages filled with oxidized LDL are called foam cells.
Once these lipid-laden foam cells accumulate in significant amounts, they form a lesion called a fatty streak.
At this point SMCs proliferate, produce collagen, and migrate over the fatty streak forming a fibrous plaque.
Plaques that have ruptured are called complicated plaques.

57. Clinical manifestations of atherosclerosis
Coronary artery disease (CAD) (major cause of myocardial ischemia)
Stroke
Hypertension

58. HYPERTENSION
Hypertension is defined as a sustained elevation of systemic arterial blood pressure.
Hypertension is caused by increases in cardiac output, total peripheral resistance, or both.

60. Classification of hypertension
Primary hypertension (essential or idiopathic hypertension): most cases of combined systolic and diastolic hypertension have no known cause and are diagnosed as primary hypertension. This type affects 90% to 95% of hypertensive individuals.
Secondary hypertension: It is caused by altered hemodynamics associated with a primary disease, such as renal disease. (5%to 8% of cases)

61. Classification of hypertension
Isolated systolic hypertension: It is elevated SBP accompained by normal DBP. This type is a manifestation of increased cardiac output or rigidity of the aorta or both.
Malignant hypertension (rapidly progressive hypertension in which diastolic pressure is usually above 140 mmHg) can cause encephalopathy, cerebral edema.

62. Factors associated with primer hypertension
Family history of hypertension,
Advancing age,
Gender (male),
Black race,
High dietary sodium intake,
Glucose intolerance (diabetes mellitus),
Smoking,
Obesity,
Heavy alcohol consumption,
Low dietary intake of potassium, calcium, magnesium.

63. Pathophysiology of primary hypertension
Primary hypertension is the result of a complicated interaction between genetics and environment and their effects on vascular and renal function.
Multiple pathophysiologic mechanism mediate these effects including the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAA), adductin, and natriuretic peptides.
Inflammation, endothelial dysfunction and insulin resistance also contribute to both increased peripheral resistance and increased blood volume.

65. In the healty indivudial, the Symphatetic NS contributes to the maintenance of adequate blood pressure and tissue perfusion
by promoting cardiac contractility and heart rate (maintenance of adequate cardiac output) and,
by inducing arteriolar vasoconstruction (maintenance of adequate peripheral resistance).

66. In indivudials with hypertension, over-activity of the SNS can result from increased productionof catecholamines (E, NE) or from increased receptor activity involving these neurotransmitters.
Increased SNS activity causes heart rate and systemic vasoconstruction, thus raising the blood pressure.

67. Dysfunction of the RAA system in the hypertensive indivudual can lead to persistent increases in peripheral resistance and renal salt retention.
Angiotensin II also causes structural changes in blood vessels (remodeling) that contribute to permanent increases in peripheral resistance and make vessels more vulnerable to endothelial dysfunction and platelet aggregation.
Angiotensin II is also responsible for the hypertrophy of the myocardium associated with hypertension.
Aldosterone not only contributes to sodium retention by the kidney but also has further deleterious effects on the cardiovascular system.

69. Natriuretic hormones modulate renal sodium excretion and include;
Atrial natriuretic peptide (ANP),
Brain natriuretic peptide (BNP),
C-type natriuretic peptide (CNP),
Urodilanton.
The function of these hormones can be effected by excessive sodium intake; inadequate dietary intake of K, Mg, Ca and obesity.
Therefore; salt retention leads to water retention and increased blood volume, which contributes to an increasein blood pressure.

70. Inflammation plays a role in the pathogenesis of hypertension.
Endothelial injury and tissue ischemia result in the release of vasoactive inflammatory cytokines.
Endothelial dysfunction in primary hypertension is characterized by
a decreased production of vasodilators, such as nitric oxide, and
increased production of vasoconstructors, such as endothelin.
Insulin resistance is associated with endothelial dysfunction in primary hypertension even without overt diabetes.

71. Diabetes and insuline resistance also cause changes in SNS and RAA activity, cause renal glomerular dysfunction and contributeto the target organ effects.
Primary hypertension is the result of an interaction between many of the above-describes processes.
The majority of these factors influence renal sodium excretion and shift the pressure-natriuresis relationship.

73. Secondary hypertension
Secondary hypertension is caused by a systemic disease process that raises peripheral vascular resistance or cardiac output.
If the cause is identified and removed before permanent structural changes occur, blood pressure returns to normal.

75. Isolated systolic hypertension
Elevations of systolic pressure are caused by increases in cardiac output or total peripheral vascular resistance or both.
For example; aortic valve insufficiency, arterioventricular fistula, thyrotoxic crisis, paget disease of the bone and beriberi.

76. Complicated hypertension
Chronic hypertension damages the walls of systemic blood vessels.
Within the walls of arteries and arterioles, smooth muscle cells undergo hypertrophy and hyperplasia with associated fibrosis of the tunica intima and media in a process called “vascular remodeling” .

78. Endothelial dysfunction, angiotensin II, catecholamines, insulin resistance, and inflammation all contribute this process.
Once significant fibrosis has occured, reduced blood flow and dysfunction of the organs perfused by these affected vessels is inevitable.
Target organs for hypertension include the kidney, brain, heart, extremities and eyes.

80. Clinical manifestations of hypertension
The early stages of hypertension have no clinical manifestations other than elevated blood pressure.
Most important no signs and symptoms cause the individual to seek health care; thus hypertension is called a lanthanic (silent) disease.
Initial signs vague, nonspecific
Fatigue, malaise, morning headache

81. Coronary Artery Disease, Myocardial Ischemia
Coronary artery disease (CAD) is a condition in which the blood supply to the heart muscle is partially or completely blocked.

82. CAD is almost always due to the build-up of cholesterol and other fatty materials (called atheromas or atherosclerotic plaques) in the wall of a coronary artery.
Occasionally CAD results from a spasm of an artery, and rarely, the cause is a birth defect, or an infection leading to inflammation of the arteries (arteritis), or physical damage (from an injury or radiation therapy).

83. CAD is the most common cause of myocardial ischemia
CAD is the most common cause of myocardial ischemia. The major complications of coronary artery disease are chest pain due to myocardial ischemia (angina) and heart attack (myocardial infarction).
CAD is the most common type of cardiovascular disease, occurring in about 5 to 9% of people aged 20 and older. The death rate increases with age and overall is higher for men than for women. After age 55, the death rate for men declines, and the rate for women continues to climb. After age 70 to 75, the death rate for women exceeds that for men who are the same age.

84. Risk factors of CAD A- Nonmodifiable (major) risk factors:
1- Advanced age
2- Male gender or woman after menopause,
3- Family history (Genetics)

85. Risk factors of CAD B- Modifiable risk factors: 1- Dyslipidemia,
2- Hypertension
3- Cigarette smoking,
4- Diabetes and insulin resistance,
5- Obesity,
6- Sedentary life-style,
7- Atherogenic diet.

86. Risk factors of CAD C- Novel risk factors:
1- Markers of inflammation and thrombosis,
2- Hyperhomocysteinemia,
3- Infection.

87. Dyslipidemia and CAD
The strong link between CAD and elevated plasma Lipoprotein concentrations (lipids, phospholipids, cholesterol, and triglycerides) is well documented.
Dyslipidemia refers to abnormal concentrations of serum lipoproteins. These abnormalities are the result of a combination of genetic and dietary factors.

88. Criteria for dyslipidemia
Optimal
Near optimal
Desirable
Low
Borderline
High
Very High
Total cholesterol
< 200
≥240
LDL
<100
≥190
Triglycerides
<150
≥500
HDL
<40
≥60
Data from expert panel on detection, eveluation, and treatment of high blood cholesterol in adults, JAMA 285: , 2001)

89. Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipid-metabolizing enzymes and abnormal cellular lipid receptors.
Secondary causes of dyslipidemia include several common systemic disorders such as diabetes, hypothyroidism, pancreatitis and renal nephrosis.

91. An increased levels of LDL is a strong indicator of coronary risk.
(remember to atherosclerosis!!!)
Low levels of HDL also are strong indicator of coronary risk, and high levels of HDL may be more protective for the development of atherosclerosis than low levels of LDL.
HDL responsible for “reverse cholesterol transport”, which returns excess cholesterol from into the tissues to the liver for metabolism.
HDL also participate in endotheial repair and decreases thrombosis.

92. Exercise, weight loss, fish oil consumption can result in modest increases in HDL.
Niacin, fibrates, and statins are drugs that can cause modest increases in HDL.
Other lipoproteins associated with increased cardiovascular risk include elevated serum VLDL (triglycerides) and lipoprotein (a).

93. Hypertension and CAD
Hypertension is responsible for a twofold to threefold increased risk of atherosclerotic cardiovascular disease.
A reduction in systolic blood pressure of only mmHg can reduce the risk of CAD by as much as 21%.
It contributes to endothelial injury a key step in atherogenesis and causes myocardial hypertrophy, which increases myocardial demand for coronary flow.

94. Smoking and CAD
Studies indicate that 20% of the annual mortality from CAD is traceable to cigarette smoking.
Nicotine stimulates the release of catecholamines (E, NE), which increase heart rate and peripheral vascular constriction. As a result, blood pressure increases, as do cardiac workload and oxygen demand. Elevated catecholamines also stimulated release of free fatty acids.
Cigarette smoking is associated with an increase in LDL, a decrease in HDL, an induction of a prothrombotic state, as well as increases in inflammatory markers of CAD such as CRP and fibrinogen.
After smoking is disconytinued, the risk associated with CAD may decrease as much as 50% in 1 year.

95. Diabetes mellitus and CAD
DM is an extremely important risk factor for CAD.
DM is associated with a two fold increase in the risk for CAD death and up to a sixfold risk for stroke.
Diabetes and insulin resistance have multiple effects on the cardiovascular system throıgh the production of toxic ROS taht alter vascular cell function.
These effects can include endothelial damage, thickening of the vessel wall, increased inflammation and leukocyte adhesion, increased thrombosis, glycation of vascular proteins, and decreased production of endothelial-derived vasodilators such as nitric oxide.

96. Obesity and CAD
Obesity is caused by genetics, diet and inadequate physical exercise.
Abdominal obesity has the strongest link with increased CAD risk and is related to insulin resistance, decreased HDL, increased blood pressure.
A sedentary life-style not only increases the risk of obesity but also has an independent effect on increasing CAD risk.

97. Markers of inflammation and thrombosis and CAD
CRP is an indirect measure of atherosclerotic plaque; related inflammation and is an important indicator of CAD risk.
Elevated levels of CRP are associated with CAD.
Other markers of inflammation associated with CAD include the erytrocyte sedimentation rate, von Willebrand factor concentration, IL-6, IL-18, fibrinogen.

98. Hyperhomocysteinemia and CAD
Hyperhomocysteinemia occurs because of a genetic lack of the enzyme that break down homocysteine (an amino acid) or because of nutritional deficiency of folate, cobalamin (vit B12), or pyridoxine (vit B6).
Mechanism by which it contributes to coronary disease include associated increases in LDL, decreases in endogenous vasodilators, and an increased tendency for thrombosis.

99. Infection and CAD
Emerging is evidence that infection may play role in atherogenesis and CAD risk.
Studies have found that several microorganisms, especially Chlamydia pneumonae, and Helicobacter pylori are often present in atherosclerotic lesions.
Serum antibodies to microorganisms have been linked to an increased risk for CAD as has the presence of periodontal disease.

100. Myocardial ischemia
The coronary arteries normally supply blood flow sufficient to meet demands of the myocardium as it labors under varying workloads.
Oxygen extraction from these vessels occurs with maximal efficiency.
If efficient exchange meet myocardial oxygen needs, healthy coronary arteries are able to dilate to increase the flow of oxygenated blood to the myocardium.

101. Myocardial ischemia develops if the supply of coronary blood cannot meet the demand of the myocardium for oxygens and nutrients.
Imbalances between coronary blood supply and myocardial demand can result from a number of conditions.
The most common cause of decreased coronary blood flow and resultant myocardial ischemia is the formation of atherosclerotic plaques in the coronary circulation.

102. As the plaque increases in size, it may partially occlude vessel lamina, thus limiting coronary flow and causing ischemia especially during exercise.
Some plaques are “unsatble”, meaning they are prone to ulceration or rupture.
When this occurs, underlying tissues of the vessel wall are exposed resulting in platelet adhesion and thrombus formation.
This can suddenly cut off blood supply to the heart muscle resulting in acute myocardial ischemia and, if the vessel obstruction cannot be reversed rapidly, ischemia progress to infarction.

103. Myocardial ischemia also can result from other causes of decreased blood and oxygen delivery to the myocardium, such as coronary spasm, hypotension, arrhythmias, and decreased oxygen-carrying capacity of the blood (anemia, hypoxemia).

104. Myocardial cells become ischemic within 10 seconds of coronary oclusion.
After several minutes the heart cells lose the ability to contract, and cardiac output decreases.
Ischemia also causes conduction abnormalities that lead to chnages in the electrocardiogram and may initiate dysrhythmias.
Anaerobic processes take over, and lactic acid accumulates.

105. Cardiac cells remain viable for approximately 20 min under ischemic conditions.
If blood flow is restored, aerobic metabolism resumes, contractility is restored and cellular repair begins.
If perfusion is not restored within min, an irreversible stage of injury characterized by diffuse mitochondrial swelling, damage to cell membrane and marked depletion of glycogen begins.

106. Clinical manifestations of myocardial ischemia
Stable angina,
Prinzmetal angina,
Silent ischemia and mental stress

107. Stable angina
Chronic coronary obstruction result in recurrent predictable chest pain called stable angina.
Angina pectoris is chest pain caused by myocardial ischemia.
The discomfort is usually transient lasting approximately 3 to 5 minutes.
Angina pectoris is typically experienced as substernal chest discomfort, ranging from a sensation of heaviness or pressure to moderately severe pain.

108. The pain is presumably caused by the buildup of lactic acid or abnormal stretching of the ischemic myocardium that irritates myocardial nerve fibers.
Pallor, diaphoresis, and dyspnea may be associated with the pain.
Stable angina is caused by gradual luminal narrowing and hardening of the arterial walls, so affected vessels cannot dilate in response to increased myocardial demand associated with physical exertion ar emotional stress.
The pain is usually relieved by rest and nitrates.

109. Prinzmetal angina
Prinzmetal angina is chest pain attributable to transient ischemia of the myocardium that occurs unpredictably and almost exclusively at rest.
Pain is caused by vasospasm of one or more major coronary arteries with or without associated atherosclerosis.
The pain often occurs at night during rapid eye movement sleep and may have a cyclic pattern of occurence.

110. Silent ischemia
Myocardial ischemia often does not cause detectable symptoms such as angina. Ischemia can be totally asymptomatic and referred to as silent ischemia.
Another area that receiving renewed interest is the lack of angina even though an artery is occluded, in some individuals during mental stress.
The increases in blood pressure induced by mental stress and increases in myocardial oxygen demand may play role in the pathophysiology of myocardial ischemia induced by mental stress.
Chronic stress has been linked to a hypercoagulable state that may contribute to acute ischemic events.

113. Clinical manifestations and evaluation
Physical examination may disclose extra, rapid heart sounds (S3).
The presence of xanthelasmas (small fat deposits) around the eyelids or arcus senilis of the eyes ( a yellow lipid ring around the cornea) suggest dyslipidemia and possible atherosclerosis.
ECG,
Coronary angiography,
SPECT (single-photon emission computed tomography)

115. Acute Coronary Syndromes:
Unstable angina,
Myocardial infarction

117. Unstable angina
Unstable angina is a form of acute coronary syndrome that result in reversible myocardial ischemia.
A fairly small fissuring or superficial erosions of the plaque leads to transient episodes of thrombotic vessels occlusion and vasoconstruction at the site of plaque damage.
This thrombus is labile, and occludes the vessel for no more than 10 to 20 min, with return of perfusion before significant myocardial necrosis occurs.

119. Clinical manifestations of unstable angina
Unstable angina presents as new onset angina, angina that is occuring at rest, or angina that increasing in severity or frequency.
Physical examination may reveal evidence of ischemic myocardial dysfunction such as tachycardia, S3 gallop, or pulmonary congestion.

121. Myocardial infarction (MI)
When coronary blood flow is interrupted for an extended period of time, myocyte necrosis occurs. This results in myocardial infarction.
Pathologically there are two major types of MI;
* subendocardial infarction,
* transmural infarction.

122. Coronary artery completely obstructed
Prolonged ischemia and cell death of myocardium
Most common cause is atherosclerosis with thrombus
3 ways it may develop:
Thrombus obstructs artery
Vasospasm due to partial occlusion
Embolus blocks small branch of coronary artery
Majority involve Left ventricle
Size and location of infarction determine severity of damage

123. Function of myocardium contraction and conduction quickly lost
Oxygen supplies depleted
1st 20 minutes critical
Time Line
1st 20 min critical
48 hrs inflammation begins to subside
7th day necrosis area replaced by fibrous tissue
6-8 weeks scar forms

124. Pathophysiologic changes in MI
1- cellular ınjury,
2- cellular death,
3- structural and functional changes,
4- repair

125. Cellular injury
Cardiac cells can withstand ischemic conditions for about 20 minutes before cellular death take place.
After only 30 to 60 second of hypoxia, ECG changes are visible.
After 8 to 10 seconds of decreased blood flow, the affected myocardium becomes cyanotic and cooler.
Myocardial oxygen reserves are used very quickly (about 8 s) after complete cessation of coronary flow.
Glycogen stores decrease and anaerobic metabolism begins.

126. Glycolysis can supply only 65% to 70% of the total myocardial energy requirement and produces much less ATP than aerobic process.
Hidrogen ions and lactic acid accumulate.
Oxygen deprivation also is accompained by electrolyte disturbances, spesifically loss of potassium, calcium and magnesium from cells.
Myocardial cells deprived of necessary oxygen and nutrients lose contractility, thereby diminishing the pumping ability of the heart.

127. Normally, the myocardium takes up varying quantities of catecholamines.
Significant arterial occlusioncauses the myocardial cells to release catecholamines, predisposing the individual to serious imbalances of sympathetic and parasympathetic function, irregular heartbeats (dysrhythmia) and heart failure.
Catecholamines mediate the release of glycogen, glucose and stored fat fom body cells.
Therefore plasma concentrations of free fatty acids and glycerol rise within 1 hour after onset of acute MI.
Excessive levels of free fatty acids can have a harmful detergent effects on cell membranes.
NE elevates blood sugar levels through stimulation of liver and skeletal muscle cells. (hyperglycemia is noted 72 hours after an acute MI)

128. Angiotensin II is released during myocardial ischemia and contributes to the pathogenesis of MI in several ways.
It result in the systemic effects of peripheral vasoconstruction and fluid retention.
These hemostatic responses are counter-productive in that they increase myocardial work and thus exacerbate the effects of the loss of myocyte contractility.
AngII is also released locally, where it is a growth factor for VSMC, myocytes and cardiac fibroblasts; promote catecholamines release; and causes coronary artery spasm.

129. Cellular death
After about 20 min of myocardial ischemia, irreversible hypoxic injury causes cellular death and tissue necrosis.
Necrosis of myocardial tissue result in the release of certain enzymes through the damaged cell membranes into the interstitial spaces.
The lymphatics pick up the enzymes and transport them into the bloodstream, where they can be detected by serologic tests.

130. Structural and functioanl changes

131. The severity of functional impairment depends on the size of the lesion and the site of infarction.
Functional changes can include:
1- decreased cardiac contractility with abnormal wall motion,
2- altered left ventricular compliance,
3-decreased stroke volume,
4- decreased ejection fraction,
5- increased left ventricular end-systolic pressure,
6- SA node malfunction.
Life-threatening dysrhythmias and heart failure often follow MI

132. Repair
MI causes a severe inflammatory response that ends with wound repair.
Repair consists of degradation of damaged cells, proliferation of fibroblasts, and synthesis of scar tissue.
Within 24 hours leukocytes infiltrate the necrotic area and proteolytic enzymes from scavenger neutrophils degrade necrotic tissue.
By the second week insulin secretion increases to mobilize glucose from the repair process.
After 6 weeks the necrotic area is completely replaced by scar tissue, which is strong but unable to contract and relax like healty myocardial tissue.

133. MI: signs and symptoms Pain
Sudden, substernal area
Radiates to left arm and neck
Less severe in females
Pallor, sweating, nausea, dizziness (vasovagal reflexs and catecholamines release)
Anxiety and fear
Hypotension, rapid and weak pulse (low Cardiac Output)
Low grade fever

134. MI—Diagnostic Tests ECG Serum enzyme and isoenzyme test
High serum levels of myosin and troponin
Abnormal electrolytes
Leukocytosis
Arterial blood gases
Pulmonary artery pressure measure
Determines ventricular function

135. MI—Complications Arrhythmias Cardiogenic shock CHF
25% pts sudden death after MI
Due to ventricular arrhythmias and fibrillation
Heart block
Premature ventricular contraction (PVCs)
Cardiogenic shock
CHF

136. Heart Failure
Heart failure is a disorder in which the heart pumps blood inadequately, leading to reduced blood flow, back-up (congestion) of blood in the veins and lungs, and other changes that may further weaken the heart.

137. CHF—Etiology Increased demands on heart cause failure
Depends on ventricle most adversely affected
Ex: Hypertension increases diastolic bp
Requires L ventricle to contract more forcibly to open aortic valve
Ex: Pulmonary disease
Damages lung caps, increases pulm resistance
Increase work load to R vent

138. CHF—Etiology Causes of failure on affected side:
Infarction that impairs pumping ability or efficiency of conduction system
Valve defects
Congenital heart defects
Coronary artery disease

139. classification 1- congestive heart failure (left heart failure),
2- right heart failure,
3- high-output failure

140. congestive heart failure (left heart failure),
Congestive heart failure, is categorized as a systolic heart failure or diastolic heart failure.

142. Left Heart Failure
Systolic Dysfunction: Disorders that cause systolic dysfunction may impair the entire heart or one area of the heart. As a result, the heart does not contract normally. Coronary artery disease is a common cause of systolic dysfunction. It can impair large areas of heart muscle because it can reduce blood flow to large areas of heart muscle.
Diastolic Dysfunction: Inadequately treated high blood pressure is the most common cause of diastolic dysfunction. High blood pressure stresses the heart because the heart must pump blood more forcefully than normal to force blood into the arteries against the higher pressure. Eventually, the heart's walls thicken (hypertrophy), then stiffen. The stiff heart does not fill quickly or adequately, so that with each contraction, the heart pumps less blood than it normally does.

143. In systolic dysfunction, the heart contracts less forcefully and cannot pump out as much of the blood that is returned to it as it normally does. As a result, more blood remains in the lower chambers of the heart (ventricles). Blood then accumulates in the veins.
Cardiac output depends on heart rate and stroke volume.
Stroke volume is influenced by three major factor; contractility, preload, afterload.

144. In diastolic dysfunction, the heart is stiff and does not relax normally after contracting. Even though it may be able to pump a normal amount of blood out of the ventricles, the stiff heart does not allow as much blood to enter its chambers from the veins. As in systolic dysfunction, the blood returning to the heart then accumulates in the veins. Often, both forms of heart failure occur together.

149. Mechanisms and Examples that Cause Left Sided Heart Failure
Impaired Contractility
1. Myocardial infarction
2. Transient myocardial ischaemia
3. Chronic volume overload
a. Mitral regurgitation
b aortic regurgitation
4. Dilated cardiomyopathy
Increased Afterload
(Pressure Overload)
1. Aortic Stenosis
2. Uncontrolled hypertension
Impaired Ventricular
Relaxation
1. Left ventricular hypertophy
2. Hypertrophic cardiomyopathy
3. Restrictive cardiomyopathy
4, Transient myocardial ischaemia
1. Mitral Stenosis
2. Pericardial constriction or
tamponade
Left-sided
Heart Failure
Diastolic
Dysfunction
Systolic

151. Right ventricular failure
RVF can result from left HF when the increase in left ventricular filling pressure that is reflected back into the pulmonary circulation is severe enough.
As pressure in the pulmonary circulation rises, the resistance to right ventricular emptying increases.
The right ventricle is poorly prepared to compensate for this increased workload and will dilate and fail.

153. COR PULMONALE:
When RHF happens, pressure will rise in the systemic venous circulation, resulting in peripheral edema and hepatosplenomegaly.
When RHF occurs in the absence of LHF, it is caused most commonly by diffuse hypoxic pulmonary disases (COPD, ARDS, cystic fibrosis), and this type of right ventricular dysfunction is called
“COR PULMONALE”.

155. High-output heart failure
High-output failure is the inability of the heart to adequately supply the body with blood-borne nutrients, despite adequate blood volume and normal or elevated myocardial contractility.
In high-output failure the heart increases its output but the body’s metabolic needs are still not meet.
Common causes of high-output failure are anemia, septicemia, hyperthyroidism and beriberi.

157. CHF—Signs and Symptoms
Forward effects
Similar with failure on either side
Decrease blood supply to tissue and general hypoxia
Fatigue, weakness, dyspnea (breathlessness), cold intolerance, dizziness
Compensation mechanism
Indicated by tachycardia, pallor, daytime oliguira

158. CHF—Signs and Symptoms
Systemic backup effects of R-sided failure
Edema in feet, legs
Hepatomegaly, splenomegaly
Ascites
Acute R-sided failure
Increased pressure on SVC
Flushed face, distended neck veins, headaches, vision problems

159. CHF—Diagnostic Tests
Radiographs
Catheterization
Arterial blood gases

160. Diagnostic Tests for Cardiovascular Function
ECG
Monitors arrhythmias, MI, infection, pericarditis
Studies conduction activation and systemic abnormalities
Ausculation
Studies heart sounds using stethoscope
Exercise stress test
Assess general cardiovascular function
Checks for exercise-induced problems
Chest X-ray Film
Shows shape, size of heart
Evidence of pulmonary congestion associated with heart failure
Nuclear imaging

161. Diagnostic Tests Cardiac Catheterization
Visualize inside of heart, measure pressure, assess valve and heart function
Determine blood flow to and from heart

162. Diagnostic Tests Angiography
Visualization of blood flow in coronary artery
Obstruction assessed and treated
Basic catheterization
Balloon angioplasty

163. Diagnostic Tests Doppler Studies
Assessment of blood flow in peripheral vessels
Microphone records sounds of blood flow
Can detect obstruction
Blood tests
Assess triglyceride and cholesterol levels
Electrolytes
Hb, hematocrit, cbcs
Arterial Blood Gas Determination
Essential for pts with shock, MI
Check current oxygen levels, acid-base balance

164. General Treatment Measures for Cardiac Disorders
Dietary modification
Regular exercise program
Quit smoking
Drug therapy

165. ACUTE RHEUMATIC FEVER
Autoimmune consequence of infection with Group A streptococcal infection
Results in a generalised inflammatory response affecting brains, joints, skin, subcutaneous tissues and the heart.

166. RF is a delayed autoimmune response to Group A streptococcal pharyngitis. The clinical manifestation of the response and its severity in an individual is determined by host genetic susceptibility, the virulence of the infecting pathogen and a conducive environment.
RF is thought to occur only after GAS infection of the upper respiratory tract although this thinking has been challenged by those working in tropical areas where skin infections are rife.

167. ACUTE RHEUMATIC FEVER
The clinical presentation can be vague and difficult to diagnose.
Currently the modified Duckett-Jones criteria form the basis of the diagnosis of the condition.

168. It is thought that % of untreated group A beta haemolytic streptococcal infection progress to develop acute rheumatic fever.

169. Carapetis. Lancet 2005;366:155

171. RHEUMATIC HEART DISEASE
Rheumatic Heart Disease is the permanent heart valve damage resulting from one or more attacks of ARF.
It is thought that 40-60% of patients with ARF will go on to developing RHD.
Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.
Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, Durack DT; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group.
Circulation Oct 9;116(15): Epub 2007 Apr 19. Erratum in: Circulation Oct 9;116(15):e376-7.

172. RHEUMATIC HEART DISEASE
The commonest valves affecting are the mitral and aortic, in that order. However all four valves can be affected.
It is important to note that the natural history of valve disease can differ in the developed and developing world with the progression to mitral valve stenosis(for example) having a latency period of several decades as opposed to the early and aggressive presentation of the same lesion in developing countries.

173. RHEUMATIC HEART DISEASE
Sadly, RHD can go undetected with the result that patients present with debilitating heart failure.
At this stage surgery is the only possible treatment option.
It has been suggested that the medical management of RHD must defer to operative intervention according to echocardiographic and clinical guidelines. The absence of access to cardiac surgery, a reality for many parts of Africa, India and Pacific Islands, implies that patients present in advanced stages of the disease, with cardiac failure and with significant complications.
Cardiovasc J Afr Sep-Oct;18(5): Epub 2007 Oct 22.
Prevalence and pattern of rheumatic heart disease in the Nigerian savannah: an echocardiographic study.

174. RHEUMATIC HEART DISEASE
Patients living in poor countries have limited or no access to expensive heart surgery.
Prosthetic valves themselves are costly and associated with a not insignificant morbidity and mortality.
In 2000, the average cost of surgery for RHD in Africa was around US$5000;in low income countries of sub-Saharan Africa with a GDP per capita of less than US$500, such as Ghana, the cost of surgery is therefore prohibitive and would also adversely affect any poverty reduction strategies.
Rheumatic and nonrheumatic valvular heart disease: epidemiology, management, and prevention in Africa.
Essop MR, Nkomo VT.
Circulation Dec 6;112(23): Review

175. RHEUMATIC FEVER IS PREVENTABLE
Read more about the healthcare system in Cuba and the achievements in Cuba in the past decades.
Costa Rica
Cuba

176. The main content of the activities focused around early detection and treatment of sore throats and streptococcal pharyngitis.
The project also included primary and secondary prevention of RF/RHD, training of personnel, health education, dissemination of information, community involvement and epidemiological surveillance.
Nordet P, Lopez R, Duenas A, Sarmiento L
CVJSA 2008:19:

177. There was a progressive decline in the occurrence and severity of acute RF and RHD, with a marked decrease in the prevalence of RHD in school children.
A marked and progressive decline was also seen in the incidence and severity of ARF.
There was an even more marked reduction in recurrent attacks of RF as well as in the number and severity of patients requiring hospitalization and surgical care.
Nordet P, Lopez R, Duenas A, Sarmiento L
CVJSA 2008:19:

178. What are the clinical features of strep sore throat?

180. An Australian guideline for rheumatic fever and rheumatic heart disease: an abridged outline.
Carapetis JR, Brown A, Wilson NJ, Edwards KN; Rheumatic Fever Guidelines Writing Group.
Med J Aust Jun 4;186(11):581-6.

181. Hallmarks of STREP sore throat
Tender lymph nodes
Close contact with infected person
Scarlet fever rash
Excoriated nares( crusted lesions) in infants
Tonsillar exudates in older children
Abdominal pain
GOLD STANDARD: POSITIVE THROAT CULTURE
Management of group A beta-hemolytic streptococcal pharyngotonsillitis in children.
Brook I, Dohar JE.
J Fam Pract Dec;55(12):S1-11; quiz S12. Review.

182. Hallmarks of VIRAL sore throat
Coryza: runny nose or mouth ulcers
Other family with COLD symptoms
Evidence of another viral infection
Itchy watery eyes
Hoarseness and cough: non-specific
Fever: not specific
Red Throat: not specific

183. What are the treatment regimens of streptococcal sore throat?

184. Primary Prevention of Rheumatic Fever by treating sore throat
Antibiotic
Administration
Dose
Benzathine benzyl penicillin
Single IM injection
1.2 MU > 30kg
U < 30 kg
Phenoxymethyl penicillin
(Pen VK)
PO for 10 days
mg qds for 10 days
125mg qds X 10 if <30 kg
Erythromycin ethylsuccinate
Use same dose as above.
Oral penicillin is less efficacious than Penicillin IMI
Anaphylaxis is extremely unusual