Group M1445

CardioVascular Pathophysiology

1.In what pathologic situation develops heart overload with resistence?

The work that the heart performs consists mainly of ejected blood that has returned to the
ventricles during diastole into the pulmonary or systemic circulation, or what are called the preload
and afterload. Cardiac work overload may become evident due to increase of volume and pressure.

Overload factors

Factors, which increase preload Factors, which increase afterload

Arterial Aorta and

Hypervolemia Polycythemia hypertension pulmonary
artery stenosis

Cardiac valve
insufficiency Hemoconcentration Atrioventricular orifice
stenosis

Afterload represents the force of heart contraction that must generate blood ejection from the
filled heart. The main components of afterload are the systemic (peripheral) vascular resistance and
ventricular wall tension. When the systemic vascular resistance is elevated, as with arterial
hypertension, an increased left intraventricular pressure must be generated to first open the aortic
valve and then move blood out of the ventricle and into the systemic circulation. This increased
pressure equates to an increase in ventricular wall stress or tension. As a result, excessive afterload
may impair ventricular ejection and increase wall tension.
Preload reflects the volume or loading conditions of the ventricle at the end of diastole, just
before the onset of systole. It is the volume of blood stretching the heart muscle at the end of
diastole and is normally determined by the venous return to the heart. During any given cardiac
cycle, the maximum volume of blood filing the ventricle is present at the end of diastole. Known as
the end-diastolic volume or preload increases, this volume causes an increase in the length of the
myocardial muscle fibers. Within limits, as end-diastolic volume or preload increases, the stroke
volume increases in accord with the Frank-Starling mechanism.
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In case of chronic cardiac overload compensatory mechanisms are activated, which are
directed towards maintaining level of blood flow according to metabolic needs. In such cases,
cardiac pathology is compensated, and circulatory shock doesnt develop. Only in case of impaired
compensatory abilities, heart failure develops, and, as a consequence, circulatory shock is
developed.
During circulatory shock and decrease of oxygen supply in tissues, extracardiac (peripheral)
compensatory mechanisms are activated, and are directed towards oxygen supply of the tissues.
In case of acute work overload (e.g. multiple pulmonary embolisms) compensatory mechanisms
dont manage to develop themselves and are inefficient, and, as a result, cardiac failure develops
spontaneously, and acute circulatory shock sets up.

2. In what pathologic condition develop overload of the heart with volume?

Refer to Question 1.

3. In what disorders develop dysmetabolic heart failure?

Factors that cause direct damage of the myocardium and subsequent decrease of heart contractility;
(systolic and metabolic heart failure):
a. physical factors (myocardial trauma, action of the electric current );
b. chemical factors, including biochemical (increased concentrations of biologically
active substances (adrenaline, thyroxin);
c. overdoses of drugs, substances that impair coupling of oxidation and phosphorylation
processes in mitochondria;
d. enzymes inhibitors or inhibitors of trans membrane transport of Ca2+ ions in
cardiomyocytes,
e. sympathomimetic drugs;
f. electron transport blockers in mitochondrial respiratory chain);
g. biological factors (microorganisms and/or their toxins, parasites);
h. lack of factors which are necessary for normal functioning of the heart: oxygen,
substrates for oxidation, enzymes, vitamins.

4. In what disorders develop hemodynamic heart failure?

Factors that cause the myocardium work overload (pressure - afterload and volume - preload);
(hemodynamic heart failure):
a. Factors that increase afterload: arterial hypertension, aorta and pulmonary artery
stenosis, hemoconcentration.
b. Factors that increase preload: hypervolemia, mitral or aortic regurgitation, ventricular
septal defect.
There are also mixed forms when myocardium injury (e.g. myocarditis) is accompanied by
cardiac work overload (e.g. valve insufficiency).
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5. In what disorders develop diastolic heart failure?

Factors that cause direct damage of the heart and disturb the diastolic filling;(diastolic heart
failure):
a. myocardium (infiltrative diseases, cardiac fibrosis, cardiac amyloidosis,
hemochromatosis, cardiac hypertrophy),
b. endocardium (fibroelastosis),
c. pericardium with impaired cardiac filling during diastole, in case of constrictive
pericarditis, cardiac tamponade.

6. What are possible causes for right heart failure? (Also Refer to Next Question)

The most common cause of right-sided heart failure is actually left-sided heart failure (either
systolic or diastolic heart failure).

While left-sided heart failure is typically the cause of right-sided heart failure, other conditions, such
as certain lung diseases, can cause the right ventricle to fail even when there is no problem with your
left ventricle.

Causes of right-sided heart failure

Cause What is it? How does it cause right-sided
heart failure?

Left-sided The left ventricle does not pump blood Blood backs up behind the left
heart failure efficiently, leading to pressure buildup ventricle into the left atrium, in
behind the left side of the heart that the lungs, and then eventually
eventually causes the right side of the heart to in to the right ventricle, which
fail. also eventually fails, allowing
blood to then back up farther
into the extremities, the liver,
and the other organs.
Chronic lung Includes emphysema, pulmonary embolism, High blood pressure in the
disease and other causes of pulmonary hypertension pulmonary arteries increases
the workload of the right
ventricle, eventually causing
the right ventricle to fail.
Coronary Blockage of the arteries that supply blood to CAD can cause left-sided heart
artery disease your heart failure leading to right-sided
heart failure or can directly
cause right-sided heart failure
by blocking blood supply to the
right ventricle.
Pulmonic Narrowing of the pulmonic valve that limits Increases the work of the right
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stenosis blood flow out of the right ventricle ventricle; similar to chronic
lung disease
Tricuspid Narrowing of the tricuspid valve Limits blood flow out of the
stenosis right atrium, causing
enlargement of the right atrium
and backup of blood flowing to
it
Tricuspid Tricuspid valve doesn't close properly, Causes volume overload of the
regurgitation causing blood in the right ventricle to flow right ventricle, which
back into the right atrium eventually causes right
ventricular dilatation and
failure
Pericardial The pericardium is a membrane sac around A thickened pericardium
constriction the heart. Repeated or ongoing inflammation restricts the heart's ability to
of it causes stiffening and thickening and pump effectively.
prevents the heart from expanding normally
to pump.
Left-to-right An abnormal connection between the left and Causes a volume overload of
shunt right side of the heart, usually present from the right ventricle, similar to
birth tricuspid regurgitation

7. What are possible causes for left heart failure?

Most patients who present with significant heart failure do so because of an inability to provide
adequate cardiac output in that setting. This is often a combination of the causes listed below in the
setting of an abnormal myocardium. The list of causes responsible for presentation of a patient with
heart failure exacerbation is very long, and searching for the proximate cause to optimize therapeutic
interventions is important.
From a clinical standpoint, classifying the causes of heart failure into the following 4 broad
categories is useful:
Underlying causes: Underlying causes of heart failure include structural abnormalities
(congenital or acquired) that affect the peripheral and coronary arterial circulation, pericardium,
myocardium, or cardiac valves, thus leading to increased hemodynamic burden or myocardial or
coronary insufficiency
Fundamental causes: Fundamental causes include the biochemical and physiologic mechanisms,
through which either an increased hemodynamic burden or a reduction in oxygen delivery to the
myocardium results in impairment of myocardial contraction
Precipitating causes: Overt heart failure may be precipitated by progression of the underlying
heart disease (eg, further narrowing of a stenotic aortic valve or mitral valve) or various
conditions (fever, anemia, infection) or medications (chemotherapy, NSAIDs) that alter the
homeostasis of heart failure patients
Genetics of cardiomyopathy: Dilated, arrhythmic right ventricular and restrictive
cardiomyopathies are known genetic causes of heart failure.
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Underlying causes:
Specific underlying factors cause various forms of heart failure, such as systolic heart failure (most
commonly, left ventricular systolic dysfunction), heart failure with preserved LVEF, acute heart
failure, high-output heart failure, and right heart failure.
Underlying causes of systolic heart failure include the following:
Coronary artery disease
Diabetes mellitus
Hypertension
Valvular heart disease (stenosis or regurgitant lesions)
Arrhythmia (supraventricular or ventricular)
Infections and inflammation (myocarditis)
Peripartum cardiomyopathy
Congenital heart disease
Drugs (either recreational, such as alcohol and cocaine, or therapeutic drugs with cardiac side
effects, such as doxorubicin)
Idiopathic cardiomyopathy
Rare conditions (endocrine abnormalities, rheumatologic disease, neuromuscular conditions)
Underlying causes of diastolic heart failure include the following:
Coronary artery disease
Diabetes mellitus
Hypertension
Valvular heart disease (aortic stenosis)
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy (amyloidosis, sarcoidosis)
Constrictive pericarditis
Underlying causes of acute heart failure include the following:
Acute valvular (mitral or aortic) regurgitation
Myocardial infarction
Myocarditis
Arrhythmia
Drugs (eg, cocaine, calcium channel blockers, or beta-blocker overdose)
Sepsis
Underlying causes of high-output heart failure include the following:
Anemia
Systemic arteriovenous fistulas
Hyperthyroidism
Beriberi heart disease
Paget disease of bone
Albright syndrome (fibrous dysplasia)
Multiple myeloma
Pregnancy
Glomerulonephritis
Polycythemia vera
Carcinoid syndrome
Underlying causes of right heart failure include the following:(Questuin 6)
Left ventricular failure
Coronary artery disease (ischemia)
Pulmonary hypertension
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Pulmonary valve stenosis
Pulmonary embolism
Chronic pulmonary disease
Neuromuscular disease.

8. What are characteristic manifestations in left heart failure?

The clinical features of left-sided heart failure primarily result from a diminished cardiac output
with a resultant decrease in peripheral blood flow and a progressive accumulation of blood within
the pulmonary circulation. With impairment of left ventricular function, there is a decrease in
ejection of blood into the systemic circulation, an increase in left ventricular and left atrial end-
diastolic pressures, and congestion of the pulmonary circulation.When the filtration pressure in the
pulmonary capillaries (normally approximately 10 mm Hg) exceeds the capillary osmotic pressure
(normally approximately 25 mm Hg), there is a shift of intravascular fluid into the interstitium of the
lung and development of pulmonary edema. An episode of pulmonary edema often occurs at night,
after the person has been reclining for some time and the gravitational forces have been removed
from the circulatory system. It is then that the edema fluid that had been sequestered in the lower
extremities during the day is returned to the vascular compartment and redistributed to the
pulmonary circulation. The most common causes of left ventricular dysfunction are hypertension
and acute myocardial infarction. Left ventricular heart failure and pulmonary congestion can
develop very rapidly in persons with acute myocardial infarction. Even when the infarcted area is
small, there may be a surrounding area of ischemic tissue. This may result in large areas of
ventricular wall hypokinesis or akinesis and rapid onset of pulmonary congestion and edema.
Another cause of left heart failure is valvular defects such as stenosis or regurgitation of the aortic or
mitral valve. These valvular defects increase the work of the left heart and eventually lead to heart
failure if untreated.

9. What are characteristic manifestations in right heart failure?

The major clinical features of right heart failure differ from those of left heart failure in that
pulmonary congestion is minimal, while engorgement of the systemic and hepatic venous systems is
pronounced. Right-sided heart failure is usually the consequence of left-sided heart failure, in which
an increase in pulmonary blood volume eventually produces an increased burden on the right side of
the heart. Isolated right-sided heart failure is less common and occurs in persons with intrinsic lung
disease or pulmonary vasculature resistance that results from pulmonary hypertension. It can also
occur in persons with pulmonic or tricuspid valvular disease, right ventricular infarction, and
cardiomyopathy. Congenital heart defects with right to- left cardiac shunt can cause isolated right
heart failure as well. When the right heart failure occurs in response to chronic pulmonary disease, it
is referred to as cor pulmonale. Right heart failure impairs the ability to move blood from the
systemic venous circulation into the pulmonary circulation. Consequently, when the right ventricle
fails, there is a reduction in the amount of blood that is moved forward from the systemic venous
circulation into the pulmonary circulation and then into the left side of the heart. This causes an
increase in right ventricular enddiastolic, right atrial, and systemic venous pressures. A major effect
of right-sided heart failure is the development of peripheral edema (see Fig.10). Because of the
effects of gravity, the edema is most pronounced in the dependent parts of the bodyin the lower
extremities when the person is in the upright position and in the area over the sacrum when the
person is supine. The accumulation of edema fluid is evidenced by a gain in weight (i.e., 1 pint [568
mL] of accumulated fluid results in a 1-lb [0.45-kg] weight gain). Daily measurement of weight can
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be used as a means of assessing fluid accumulation in a patient with chronic heart failure. As a rule,
a weight gain of more than 2 lb (0.91 kg) in 24 hours or 5 lb (2.25 kg) in 1 week is considered a sign
of worsening failure. Right-sided heart failure also produces congestion of the viscera. As venous
distention progresses, blood backs up in the hepatic veins that drain into the inferior vena cava and
the liver becomes engorged. This may cause hepatomegaly and right upper quadrant pain. In severe
and prolonged right-sided failure, liver function is impaired and hepatic cells may die. Congestion of
the portal circulation also may lead to engorgement of the spleen and the development of ascites.
Congestion of the gastrointestinal tract may interfere with digestion and absorption of nutrients,
causing anorexia and abdominal discomfort. In severe right-sided failure, the external jugular veins
become distended and can be visualized when the person is sitting up or standing.

10. What are immediate cardiac compensatory reactions in heart failure?

1.Tachycardia (increased heart rate) is the most quick to act compensatory mechanism. It is
mainly due to reflexive stimulation of baroreceptors in vena cava and due to increased pressure in
atria (Bainbridge reflex) and also as a consequence of sympathetic stimulation. Tachycardia is the
faster mechanism than others that compensates decreased stroke volume ( 70ml) and to maintain
the optimal cardiac output (CO SVHR). In such cases that stroke volume is decreased, the
cardiac output, as a result of increased heart contraction frequency, is maintained on normal level.
Thereby compensation is realized and circulatory shock doesnt develop. However, tachycardia is
less effective compensatory mechanism and energetic expansive, because with increasing heart rate,
increases the O2 consumption in myocardium. In addition, as the heart rate increases, the time spent
in diastole is reduced, and there is less time for the ventricles to fill. In normal condition at a heart
rate of 75 beats per minute, one cardiac cycle lasts 0,8 second, of which approximately 0,3 second is
spent in systole and approximately 0,5 second in diastole. In severe tachycardia (more than 150
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beats/min), with shortening of the diastole, decrease the diastolic filling of the ventricles ( normal
end-diastolic volume 120 -140 ml). These leads to decreased stretching of muscle fibers in diastole,
as the result, decrease the effectiveness of systole, of SV and consecutively CO. So tachycardia, for
one hand, in certain limits maintains CO, but for the other hand, is unfavorable, with limited
effectiveness and uneconomically.
2.Heterometric compensatory mechanism (Frank-Starling). The Frank-Starling mechanism
describes the process whereby the heart increases its stroke volume through an increase in end-
diastolic volume or preload, is inserted in blood volume overload. With increased diastolic filling,
there is increased stretching of the myocardial fibers, more optimal approximation of the actin and
myosin filaments, and a resultant increase in the force of the next contraction (tonogenic dilation).
As a result, increase SV and CO. It is known that in physiological conditions the EDV (end-diastolic
volume 120- 140 ml), and after ejection, at the end of the systole, the ventricular volume is
reduced with 70% but volume of the residual blood is 40-50 ml (ESV).
When the heart contracts stronger, is ejected much more quantity of blood, due what ESV
decreased till 10 -20 ml, the ejection fraction increase (EF more than 70%). In physiological
conditions the EDV can increase till 160 180 ml. These lead to double increased of stroke volume,
so is realized compensation. But this compensatory mechanism is limited by the optimal length of
sarcomeres (2,2 -2,3 m). If their lengthening not exceeds 25% from the initial value, we observe
equilibrium between diastolic feeling and contractile forces of the heart. But in case of exceeding
this optimal limits of sarcomeres, lead to uncoupling of actin and myosin filaments with decreasing
contractile forceses.
3.Homeometric compensation mechanism works during the increase of resistance to cardiac output
(increased afterload - aortic stenosis, pulmonary artery stenosis, atrio-ventricular orifice
stenosis). Length of muscle heart fibers during diastole augments not so significant change in this
case, but high intraventricular pressure and effort that happened by reason of contraction of muscle
at the end of systole. Force of cardiac contractions augments not at once, but gradually
with each following heart contraction, while will not arrive at level, necessary for safety
of constancy of minute volume-heart. Although in lesser degree, in homeometric hyperfunction, is
included the Frank Starling mechanism. In case of essential hypertension the pressure in aorta
during diastole remains elevated. As a consequence, normal systole of left ventricle will not eject a
normal stroke volume, due what will increase end-systolic volume. As venous return is stable, end-
diastolic volume will increase evident with every subsequent systole. So, adaptation to the overload
by resistance is realized also on account of Frank-Starling mechanism. But unlike work overload by
volume, in this case greater stretching of fibrils leads to a more powerful contraction.
From the point of view of energy consumption, these mechanisms (homeometric and
heterometric) are not identically. At the same volume of work heart consumes much more oxygen in
case of hyperfunction by resistance (increased afterload), than in case of increased volume with
normal resistance (increased preload). For example, if volume of work was doubled due to double
increasing of end-diastolic volume; oxygen utilization by myocardium will increase about 25%. If
volume of work will increase due to double increasing of resistance against ejection, the oxygen
utilization will increase with 200%. These is explained by way that homeometric compensatory
mechanism to exceed resistance against ejection needs a grater systolic pressure, which can be
achieved by increasing degree and speed myofibril tension development. So, homeometric
contraction, which is the most energy expansive, represents the main factor which determines
increased consumption of ATP and oxygen utilization by myocardium. Thus, heterometric
compensatory mechanism is more economically than homeometric mechanism. This explains the
favorable clinical evolution of cardiac disease, where is included Frank-Starling mechanism, for
example, valvular insufficiency in comparison with orifice stenosis.
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11. What are late cardiac compensatory reactions in heart failure?

1.Redistribution of cardiac output and circulatory centralization:

In heart failure cardiac output and arterial pressure decrease, due what will be activated SNS
via baroreceptors. As vessels that supply muscles, organs, skin have sympathetic enervation, mostly
1- adrenoreceptors, activation of SNS leads to vasoconstriction of these regions and redistribution
of cardiac output concomitant with blood supplying of main important organs predominantly with
adrenoreceptors (brain, heart). Increased blood influx of these vital organs ensures their metabolic
needs in these conditions.

2.Increase of oxyhemoglobin dissociation:

As a result of decreased cardiac output, blood circulation disturbance occurs, with
subsequent circulatory hypoxia. Oxygen insufficiency in tissues leads to metabolic disturbances and
raises of H+ ions concentration, which increases oxyhemoglobin dissociation and stimulates more
effective oxygen utilization by the tissues.

3.Pulmonary hyperventilation:
As a result of cardiac insufficiency, in the body develops circulatory hypoxia that leads to
increase concentration of carbon dioxide and hydrogen ions. These factors directly and reflexively
stimulate respiratory center with development of lung hyperventilation. Thereby, is restored balance
between metabolic needs and oxygen supply.

4.Pulmonary arterioles constriction:

This mechanism is activated in case of left ventricle insufficiency, and is one of the main
mechanisms, which are directed to prevention of pulmonary edema development in such situations.
As a result of increased pressure in the left atrium and pulmonary veins, will be activated
baroreceptors from these areas that lead to reflexive constriction of pulmonary arterioles. As a
consequence of reflector pulmonary arterioles spasm, the blood volume, which flows to the left
atrium decreases, so, preload of functionally weakened heart decreases, too (F. Kitaev reflex). At
the same time this reflex increases pressure in pulmonary artery and stimulates the overload of right
ventricle.

12. What are late extracardiac compensatory reactions in heart failure?

1.Increases of erythropoiesis:
Tissular hypoxia in heart failure leads to synthesis of erythropoietin (80 -90% are synthesized in the
kidney), that increases production of erythrocytes. As a consequence, oxygenic capacity of the blood
increases oxygen concentration in the arterial blood increases, so ensure the compensation of
circulatory hypoxia. But also this mechanism is relative useful. Concomitantly with increasing
number of erythrocytes, increases also hematocrit and blood viscosity that lead to additional
overload of the heart.

2.Retention of water and salts (Renin-Angiotensin-Aldosterone) mechanism:

One of the most important effects of lowered cardiac output in heart failure is a reduction in renal
blood flow and glomerular filtration rate, which leads to sodium and water retention. With decreased
renal blood flow, there is a progressive increase in renin secretion by the kidneys with parallel
increases in circulating levels of angiotensin II. The increased concentration of angiotensin II
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contributes directly to a generalized and excessive vasoconstriction, as well as facilitating
norepinephrine release and inhibiting reuptake of norepinephrine by the sympathetic nervous
system. Angiotensin II also provides a powerful stimulus for aldosterone production by the adrenal
cortex. Aldosterone increases tubular reabsorption of sodium, with an accompanying increase in
water retention. Because aldosterone is metabolized in the liver, its levels are further increased when
heart failure causes liver congestion. Angiotensin II also increases the level of antidiuretic hormone
(ADH), which serves as a vasoconstrictor and inhibitor of water excretion. In addition to their
individual effects on sodium and water balance, angiotensin II and aldosterone are also involved in
regulating the inflammatory and reparative processes that follow tissue injury. They stimulate
inflammatory cytokine production (e.g., tumor necrosis factor [TNF] and interleukin-6), attract
inflammatory cells (e.g., neutrophils and macrophages), activate macrophages at sites of injury and
repair, and stimulate the growth of fibroblasts and synthesis of collagen fibers. Fibroblast and
collagen deposition results in ventricular hypertrophy and myocardial wall fibrosis, which decreases
compliance (i.e., increases stiffness), ultimately causing inappropriate remodeling of the heart and
progression of both systolic and diastolic ventricular dysfunction.

3.Natriuretic Peptides:
The heart muscle produces and secretes a family of related peptide hormones, called the natriuretic
peptides (NPs) ,that have potent diuretic, natriuretic, vascular smooth muscle, and other
neurohumoral actions that affect cardiovascular function. Two of the four known NPs most
commonly associated with heart failure are atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP). As the name indicates, ANP is released from atrial cells in response to atrial stretch,
pressure, or fluid overload. BNP, so named because it was originally found in extracts of the porcine
brain, is primarily secreted by the ventricles as a response to increased ventricular pressure or fluid
overload. Although the NPs are not secreted from the same chambers in the heart, they have very
similar functions. In response to increased chamber stretch and pressure, they promote rapid and
transient natriuresis and diuresis through an increase in the glomerular filtration rate and an
inhibition of tubular sodium and water reabsorption. The NPs also facilitate complex interactions
with the neurohormonal system, inhibiting the sympathetic nervous system, the renin-angiotensin-
aldosterone system, and vasopressin. In addition, the NPs directly affect the central nervous system
and the brain, inhibiting the secretion of the antidiuretic hormone (ADH) and the function of the salt
appetite and thirst center. Circulating levels of both ANP and BNP are elevated in persons with heart
failure. The concentrations are well correlated with the extent of ventricular dysfunction, increasing
up to 30-fold in persons with advanced heart disease. Assays of BNP are used clinically in the
diagnosis of heart failure and to predict the severity of the condition. Human BNP, synthesized by
recombinant deoxyribonucleic acid (DNA) technology, is now available for treatment of persons
with acutely decompensated heart failure.

4.Endothelins:
The endothelins, released from the endothelial cells throughout the circulation, are potent
vasoconstrictors. Like angiotensin II, endothelin can also be synthesized and released by a variety of
cell types, such as cardiac myocytes. Four endothelin peptides (endothelin-1 [ET-1], ET-2, ET-3,
and ET-4) have been identified. In addition to vasoconstrictor actions, the endothelins induce
vascular smooth muscle cell proliferation and cardiac myocyte hypertrophy; increase the release of
ANP, aldosterone, and catecholamines; and exert antinatriuretic effects on the kidneys. They also
have been shown to have a negative inotropic action in patients with heart failure. Production of ET-
1 is regulated by many factors that are significant for cardiovascular function and have implications
for heart failure; for example, it is enhanced by angiotensin II, ADH, and norepinephrine and by
factors such as shear stress and endothelial stretching.21 Plasma ET-1 levels also correlate directly
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with pulmonary vascular resistance, and it is thought that the peptide may play a role in mediating
pulmonary hypertension in persons with heart failure. An endothelin receptor antagonist is now
available for use in persons with pulmonary arterial hypertension due to severe heart failure.

5.Neurohumoral compensatory mechanisms (Sympathetic Nervous System Activity):

Stimulation of the sympathetic nervous system plays an important role in the compensatory response
to decreased cardiac output and in the pathogenesis of acute heart failure (fig.10). Both cardiac
sympathetic tone and catecholamine (epinephrine and norepinephrine) levels are elevated during the
late stages of most forms of heart failure. By direct stimulation of heart rate and cardiac contractility
(via - adrenoreceptors), regulation of vascular tone, and enhancement of renal sodium and water
retention, the sympathetic nervous system initially helps to maintain perfusion of the various body
organs. In persons who progress to more severe heart failure, blood is diverted to the more critical
cerebral and coronary circulations. Although the sympathetic nervous system response is meant to
maintain blood pressure and cardiac output, it quickly becomes maladaptive and contributes to the
deterioration of heart function. An increase in sympathetic activity can lead to tachycardia,
vasoconstriction, and cardiac arrhythmias. Acutely, tachycardia significantly increases the workload
of the heart, thus increasing myocardial oxygen demand and leading to cardiac ischemia, myocyte
damage, and decreased contractility (inotropy). An increase in systemic vascular resistance causes
an increase in cardiac afterload and ventricular wall stress. By promoting arrhythmias, the
catecholamines released with sympathetic nervous system stimulation also may contribute to the
high rate of sudden death seen with heart failure. Other effects include decreased renal perfusion and
additional augmentation of the renin-angiotensin-aldosterone system, as well as decreased blood
flow to skin (the symptom being pallor), muscle (the symptom being fatigue), and abdominal
organs.

13. What are immediate extracardiac compensatory reactions in heart failure?

1.Redistribution of cardiac output and circulatory centralization:

In heart failure cardiac output and arterial pressure decrease, due what will be activated SNS
via baroreceptors. As vessels that supply muscles, organs, skin have sympathetic enervation, mostly
1- adrenoreceptors, activation of SNS leads to vasoconstriction of these regions and redistribution
of cardiac output concomitant with blood supplying of main important organs predominantly with
adrenoreceptors (brain, heart). Increased blood influx of these vital organs ensures their metabolic
needs in these conditions.

2.Increase of oxyhemoglobin dissociation:

As a result of decreased cardiac output, blood circulation disturbance occurs, with
subsequent circulatory hypoxia. Oxygen insufficiency in tissues leads to metabolic disturbances and
raises of H+ ions concentration, which increases oxyhemoglobin dissociation and stimulates more
effective oxygen utilization by the tissues.

3.Pulmonary hyperventilation:
As a result of cardiac insufficiency, in the body develops circulatory hypoxia that leads to
increase concentration of carbon dioxide and hydrogen ions. These factors directly and reflexively
stimulate respiratory center with development of lung hyperventilation. Thereby, is restored balance
between metabolic needs and oxygen supply.
 Group M1445
4.Pulmonary arterioles constriction:
This mechanism is activated in case of left ventricle insufficiency, and is one of the main
mechanisms, which are directed to prevention of pulmonary edema development in such situations.
As a result of increased pressure in the left atrium and pulmonary veins, will be activated
baroreceptors from these areas that lead to reflexive constriction of pulmonary arterioles. As a
consequence of reflector pulmonary arterioles spasm, the blood volume, which flows to the left
atrium decreases, so, preload of functionally weakened heart decreases, too (F. Kitaev reflex). At
the same time this reflex increases pressure in pulmonary artery and stimulates the overload of right
ventricle.

14. What is pathogenesis of homeometric heart hyperfunction?

Refer to Question 10.

15. What is pathogenesis of heterometric heart hyperfunction?

Refer to Question 10.

16. For what heart defects there is characteristic homeometric hyperfunction?

Factors which increase Afterload such as aortic stenosis, pulmonary artery stenosis, atrio-
ventricular orifice stenosis, Hemoconcentration, Arterial hypertension.

Afterload represents the force of heart contraction that must generate blood ejection from the filled
heart. The main components of afterload are the systemic (peripheral) vascular resistance and
ventricular wall tension. When the systemic vascular resistance is elevated, as with arterial
hypertension, an increased left intraventricular pressure must be generated to first open the aortic
valve and then move blood out of the ventricle and into the systemic circulation. This increased
pressure equates to an increase in ventricular wall stress or tension. As a result, excessive afterload
may impair ventricular ejection and increase wall tension.

17. For what heart defects there is characteristic heterometric heart hyperfunction?

Factors which increase preload such as 1.Cardiac valve insufficiency.2. Hypervolemia.3.

Polycythemia.

Preload reflects the volume or loading conditions of the ventricle at the end of diastole, just before
the onset of systole. It is the volume of blood stretching the heart muscle at the end of diastole and is
normally determined by the venous return to the heart. During any given cardiac cycle, the
maximum volume of blood filing the ventricle is present at the end of diastole. Known as the end-
diastolic volume or preload increases, this volume causes an increase in the length of the myocardial
muscle fibers. Within limits, as end-diastolic volume or preload increases, the stroke volume
increases in accord with the Frank-Starling mechanism.
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18. How myocardial structure is changed in hypertrophy?

By Long term (late) compensatory mechanisms develop hypertrophy which have three basic
steps in the molecular pathogenesis of cardiac hypertrophy (fig.8):
The integrated actions of mechanical sensors (that are triggered by increased workload),
growth factors (including TGF-, insulin-like growth factor 1 [IGF1], fibroblast growth factor
(FGF), platelet-derived growth factor (PDGF), insulin in type II diabetes)), and vasoactive agents
(e.g., -adrenergic agonists, endothelin-1, and angiotensin II, ADH,) and decrease in growth
inhibitors (NO and PGI2). Indeed, mechanical sensors themselves induce production of growth
factors and agonists.
These signals originating in the cell membrane activate a complex web of signal transduction
pathways. Two such biochemical pathways involved in muscle hypertrophy are the
phosphoinositide 3-kinase (PI3K)/ AKT pathway (postulated to be most important in physiologic,
e.g., exercise-induced, hypertrophy) and signaling downstream of G-proteincoupled receptors
(induced by many growth factors and vasoactive agents, and thought to be more important in
pathologic hypertrophy).
These signaling pathways activate a set of transcription factors such as GATA4, nuclear
factor of activated T cells (NFAT), and myocyte enhancer factor 2 (MEF2). These transcription
factors work coordinately to increase the synthesis of muscle proteins that are responsible for
hypertrophy. Hypertrophy is also associated with a switch of contractile proteins from adult to fetal
or neonatal forms. For example, during muscle hypertrophy, the isoform of myosin heavy chain is
replaced by the isoform, which has a slower, more energetically economical contraction. In
addition, some genes that are expressed only during early development are reexpressed in
hypertrophic cells, and the products of these genes participate in the cellular response to stress. For
example, the gene for atrial natriuretic factor is expressed in both the atrium and the ventricle in the
embryonic heart, but it is down-regulated after birth. Cardiac hypertrophy is associated with
increased atrial natriuretic factor (ANF) gene expression. Atrial natriuretic factor is a peptide
hormone that causes salt secretion by the kidney, decreases blood volume and pressure, and
therefore serves to reduce hemodynamic load.
Emergency stage, that develops imme Although ventricular hypertrophy improves the work
performance of the heart, it is also an important risk factor for subsequent cardiac morbidity and
mortality. Inappropriate hypertrophy and remodeling can result in changes in structure (i.e., muscle
mass, chamber dilation) and function (i.e., impaired systolic or diastolic function) that often lead to
further pump dysfunction and hemodynamic overload. The dynamics of these changes could be
defined in 3 main stages (according to F. Meerson):
1. diately, concomitantly with increased workload.
During this period the intensity of myocardial functional structure (MFS) increases, due to
hyperfunction without hypertrophy. Because of increased MFS, energy formation is intensified,
cellular genetic apparatus is activated, and simultaneously synthesis of nucleic acids increases and
protein synthesis occurs. The consumption of oxygen by myocardium units increases, oxidative
phosphorylation increases, resynthesis of ATP by aerobe pathway. Though, this elevation of ATP
synthesis doesnt cover myocardial necessities in oxygen, because energy is also used for increased
function supply, and for accelerated protein synthesis supply. Also are activated anaerobic ways of
energy re-synthesis. Glycogen is removed from cardiomyocytes, phosphocreatine level decreases,
intracellular potassium concentration decreases, and sodium is accumulated into cell. As a result of
anaerobic glycolysis, lactate is accumulated in myocardium. Direct consequence of increased
protein synthesis, during several weeks, rises hearts mass and function that is distributed to much
more area of effector structures, thats why MFS gradually returns to its normal level. Cardiac
hypertrophy leads to decrease of functional overload, which is gained by every myocardium unit till
 Group M1445
its normal indices. MFS returns to its initial level, as a result, metabolic processes in myocardium
become normal.
2. Stage of completed hypertrophy and relative stable hyperfunction.
This stage is characterizes by ending of hypertrophy process. Myocardium mass is increased
above 100-200%. MFS becomes normal. Pathologic changes in heart muscle metabolism and
structure arent revealed, oxygen consumption, energy synthesis, concentration of high-energy
compounds dont differ from normal evidence. Hemodynamic signs are normal. MFS normalization
allows hypertrophic heart to resist high overloads and to compensate blood circulation (e.g. during
compensated cardiac defects).
Hypertrophic heart differs from normal one by series of metabolic, functional, and structural
peculiarities, which on one hand, allow it to compensate increased overload for a long period of
time, but on other hand, create conditions for some pathologic processes. In the hypertrophic
heart growth of different morpho-functional structures are disturbed.
In case of myocardium hypertrophy development, cardiac nervous apparatus is engaged. Is
noticed the functioning of intra- and extracardiac nervous elements will increase, but the growth of
nervous endings slows down as contractile myocardium mass increases. Trophic influences are
disturbed, noradrenaline concentration in myocardium is decreased, that leads to worsening of
contractile properties cardiac reserves mobilization is slowed down.
Increasing of muscular fibers mass is not preceded by adequate rising of coronary capillary
network, due what installs relative coronary insufficiency, and respectively relative hypoxia
coronary reserve at effort decreases.
Growth of heart mass occurs as a result of increased each muscular fibers volume that is
associated with changes of correlation between intracellular structures. Cellular volume increases
proportionally to cube and cellular membrane surface proportionally to linear cell size square
(refashion between fiber volume and surface is increased), that leads to cellular surface decrease,
related to cell mass unit. Considering that in sacolema are localized protein receptors, enzymes that
ensure transmembrane transport of cations and metabolic substrates, indicated changes lead to ionic,
metabolic and functional imbalance.
Cellular membrane has a great importance in propagation of excitation, in coupling processes
of excitation and contraction, realized through the tubular system and sarcoplasmic reticulum.
Because their growth also is decreased, will be disturb processes of contraction and relaxation of
cardiomyocytes: as a result of decreased outflow of Ca2+ is disturb contraction, but due to hardly
reuptake of Ca2+ in sarcoplasmic reticulum will be disturb relaxation.
During developing of hypertrophy, in the initial phase, the mitochondrial mass increases
faster than mass of contractile proteins. So, is created conditions for sufficient energy supplying of
the functional overload heart. But, with progressing process, growth of mitochondrial mass lags
behind of cytoplasm mass growing. Mitochondria start to work with a maximum overload, inside of
them occurs destructive changes, their functional effectiveness decreases and oxidative
phosphorylation is disturbed. These lead to diminishes energy supply of hypertrophic cell.
The hypertrophy heart, at the initial phases, has a powerful contractile apparatus and with
energy well supplied. This is making possible for a long time to work with a higher performance, at
a normal metabolic rate. But adaptive capacity for overload working is limited in the hypertrophy
heart. Unbalanced intracellular and tissular structures make the hypertrophy heart to become more
vulnerable in unfavorable conditions, that could lead to reducing contractile cardiac forces and in
turn to cardiac insufficiency.
3. Stage of gradual exhaustion and progressive cardiosclerosis.
This stage is characterized by profound metabolic and structural changes, which in turn
accumulates in contractile and energo -generative elements of cardiomyocytes. As was mentioned
 Group M1445
previously, the muscular mass growths more than capillary network, the same increases the
distance between capillary and oxygen using elements. Increases consumption of oxygen in
condition of unchanged coronary meshwork, due what in the myocardium installs a relative
hypoxia. Hypoxia is one of the most important factors that will lead to metabolic and structural
changes, characteristic or this phase. In cardiomyocytes will develop pathological process like
dystrophy, necrobiosis and necrosis. One part of muscular fibers die and they are replaced by
connective tissue, that is the main mechanism of cardiosclerosis.
As a result of cardiosclerosis, the mass of contractile elements decreases, due what MFS again
increases, that once more will cause hypertrophy of still functional cardiomyocytes. In finally, these
will lead to progressive exhaustion of compensatory mechanisms that in turn will lead to chronic
heart failur

Compensatory myocardium hypertrophy

Imbalance of myocardium structures and its consequences

Microvascular Mitochondrial quantity Myosin ATP-ase Intensified cardiac

growth lags behind growth lags behind activity lags hystiocytes structure
myocardium mass myofibril mass growth behind synthesis dont supply
growth myocardium needs of the cell
energy necessities
Recent research has focused on the type of hypertrophy that develops in persons with heart failure.
At the cellular level, cardiac muscle cells respond to stimuli from stress placed on the ventricular
wall by pressure and volume overload by initiating several different processes that lead to
hypertrophy. These include stimuli that: produce a symmetric hypertrophy with a proportionate
increase in muscle length and width, as occurs in athletes. Concentric hypertrophy occurs in
hypertension (stimulus for hypertrophy is pressure overload) leads to parallel replication of
myofibrils, thickening of the individual myocytes. Concentric hypertrophy may preserve systolic
function for a time, but eventually the work performed by the ventricle exceeds the vascular reserve,
predisposing to ischemia. And eccentric hypertrophy as occurs in dilated cardiomyopathy or
ventricular volume overload, the increase in wall stress leads to replication of myofibrils in series,
elongation of the cardiac muscle cells, and eccentric hypertrophy. Eccentric hypertrophy leads to a
decrease in ventricular wall thickness with an increase in diastolic volume and wall tension

19. What are mechanisms for functional exhaustion and cardiosclerosis in hypertrophied
myocardium?

Refer to Question 18.

 Group M1445

20. What are mechanisms for relative hypoxia in hypertrophied myocardium?

Due to muscular mass growths more than capillary network result increase in the distance
between capillary and oxygen using elements and Increase consumption of oxygen in condition of
unchanged coronary meshwork, due what occur in the myocardium installs a relative hypoxia.
Hypoxia is one of the most important factors that will lead to metabolic and structural changes,
characteristic or this phase.

21. How are changed systolic volume and circulatory blood volume in heart failure?

works during the increase of resistance to cardiac output (increased afterload - aortic stenosis,
pulmonary artery stenosis, atrio-ventricular orifice stenosis). Length of muscle heart fibers during
diastole augments not so significant change in this case, but high intraventricular pressure
and effort that happened by reason of contraction of muscle at the end of systole. Force
of cardiac contractions augments not at once, but gradually with each following heart contraction,
while will not arrive at level, necessary for safety of constancy of minute volume-heart. Although in
lesser degree, in homeometric hyperfunction, is included the Frank Starling mechanism. In case of
essential hypertension the pressure in aorta during diastole remains elevated. As a consequence,
normal systole of left ventricle will not eject a normal stroke volume, due what will increase end-
systolic volume. As venous return is stable, end-diastolic volume will increase evident with every
subsequent systole. So, adaptation to the overload by resistance is realized also on account of Frank-
Starling mechanism. But unlike work overload by volume, in this case greater stretching of fibrils
leads to a more powerful contraction.
From the point of view of energy consumption, these mechanisms (homeometric and heterometric)
are not identically. At the same volume of work heart consumes much more oxygen in case of
hyperfunction by resistance (increased afterload), than in case of increased volume with normal
resistance (increased preload). For example, if volume of work was doubled due to double
increasing of end-diastolic volume; oxygen utilization by myocardium will increase about 25%. If
volume of work will increase due to double increasing of resistance against ejection, the oxygen
utilization will increase with 200%. These is explained by way that homeometric compensatory
mechanism to exceed resistance against ejection needs a grater systolic pressure, which can be
achieved by increasing degree and speed myofibril tension development. So, homeometric
contraction, which is the most energy expansive, represents the main factor which determines
increased consumption of ATP and oxygen utilization by myocardium. Thus, heterometric
compensatory mechanism is more economically than homeometric mechanism. This explains the
favorable clinical evolution of cardiac disease, where is included Frank-Starling mechanism, for
example, valvular insufficiency in comparison with orifice stenosis.

22. What are mechanisms of hypervolemia in chronic heart failure?

Hypo perfusion of kidney lead to secretion of Renin which lead to Retention of water and salts
(Renin-Angiotensin-Aldosterone) mechanism

Explanation: One of the most important effects of lowered cardiac output in heart failure is
a reduction in renal blood flow and glomerular filtration rate, which leads to sodium and water
retention. With decreased renal blood flow, there is a progressive increase in renin secretion by the
kidneys with parallel increases in circulating levels of angiotensin II. The increased concentration of
 Group M1445
angiotensin II contributes directly to a generalized and excessive vasoconstriction, as well as
facilitating norepinephrine release and inhibiting reuptake of norepinephrine by the sympathetic
nervous system. Angiotensin II also provides a powerful stimulus for aldosterone production by the
adrenal cortex. Aldosterone increases tubular reabsorption of sodium, with an accompanying
increase in water retention. Because aldosterone is metabolized in the liver, its levels are further
increased when heart failure causes liver congestion. Angiotensin II also increases the level of
antidiuretic hormone (ADH), which serves as a vasoconstrictor and inhibitor of water excretion. In
addition to their individual effects on sodium and water balance, angiotensin II and aldosterone are
also involved in regulating the inflammatory and reparative processes that follow tissue injury. They
stimulate inflammatory cytokine production (e.g., tumor necrosis factor [TNF] and interleukin-6),
attract inflammatory cells (e.g., neutrophils and macrophages), activate macrophages at sites of
injury and repair, and stimulate the growth of fibroblasts and synthesis of collagen fibers. Fibroblast
and collagen deposition results in ventricular hypertrophy and myocardial wall fibrosis, which
decreases compliance (i.e., increases stiffness), ultimately causing inappropriate remodeling of the
heart and progression of both systolic and diastolic ventricular dysfunction.

23. What are consequences of venous stasis in circulatory failure?

slow blood flow in the veins, usually of the legs. Venous stasis is a risk factor for forming blood
clots in veins (venous thrombosis), as with the deep veins of the legs (deep vein thrombosis or
DVT).[1]

Causes

Venous valves
CVI in the leg may be caused by the following:

Blood clots in the deep veins. This is called Deep vein thrombosis, or DVT. CVI caused by
DVT may be described as postthrombotic syndrome
Arteriovenous fistula (an abnormal connection or passageway between an artery and a vein).
Phlebitis
Thrombophilia
Obesity
MayThurner syndrome. This is a rare condition in which blood clots occur in the iliofemoral
vein due to compression of the blood vessels in the leg. The specific problem is compression of
the left common iliac vein by the overlying right common iliac artery. Many May-Thurner
compressions are overlooked when there is no blood clot. More and more of them get nowadays
diagnosed and treated (by stenting) due to advanced imaging techniques
 Group M1445

24. In what anatomic regions develops venous stasis in left ventricular failure?

Refer to Left Heart Failure Manifestations Question 10.

25. What are consequences of venous stasis in the liver?

Refer to Right Heart Failure Manifestations Question 9.

26. What are causes of portal hypertension in hepatic cirrhosis?

Venous blood from the gastrointestinal tract empties into the portal vein and travels through the liver
before moving into the general venous circulation, Obstruction of blood flow (due to damage of
sinusoidal capillaries) in the portal vein produces an increase in the hydrostatic pressure within the
peritoneal capillaries, contributing to the development of ascites, splenic engorgement with
sequestration and destruction of blood cells and platelets, and shunting of blood to collateral venous
channels causing varicosities of the hemorrhoidal and esophageal veins.

27. What are consequences of portal hypertension?

Complications of portal hypertension arise from the increased pressure and dilation of the venous
channels behind
the obstruction. In addition, collateral channels open that connect the portal circulation with the
systemic circulation. The major complications of the increased portal vein pressure and the opening
of collateral channels are ascites, congestive splenomegaly (splenomegaly consequences are
Anemia, Leukopenia, Thrombocytopenia which may associated with bleeding), increased pressure
in splenic vein, hepatic encephalopathy, and the formation of portosystemic shunts with
development of esophageal varices bleeding from esophageal varices, hemorrhoids, periumblical
venous collaterals(Caput medusa).
Note: Bleeding can be caused by liver dysfunction due to decreased liver of coagulation factors.
 Group M1445

28. In what pathologic conditions develops venous stasis in the liver?

1.Congestive Hear failure, Right Heart Failure.

2.Venous thrombosis such as Budd-Chiarri

syndrome.

3.Liver inflammation due to various factors.

4.liver cirrhosis.

5.Conditions related to blood dynamic and viscosity like polycythemia

29. In what conditions develop porto-caval anastomosis?

Due to various factors related to Portal hypertension.

30. What are pathogenetic mechanisms in development of cardiac edema?

When the heart ceases to meet the requirements of the body for oxygen, the sympathetic-adrenal
system is activated. This occurs in people with a healthy heart when the demands for oxygen are
excessivefor example, in heavy muscular workand in subjects with a failing heart when the
demands are normal or small. Eventually, when the heart is unable to meet even the ordinary
requirements of everyday life, the sympathetic activity becomes more or less continuous. It may
 Group M1445
lessen during rest at night, but with a further failing of the heart its output may become inadequate
even in complete rest.
The sympathetically-medicated renal vasoconstriction, with reduction of the glomerular sodium
load, redistribution of the blood flow in the renal cortex to the juxtamedullary glomeruli, and the
mobilization of the renin-angiotensin-aldosterone system, is responsible for the salt and water
retention which will ultimately become clinically manifest as oedemaespecially when it is no
longer counteracted by the tidal output of water and sodium at night. A by-product of this continuing
dehydration reaction is a cumulative potassium loss which may lead to disastrous consequences if
untreated.
Many of the manifestations of heart failure result from the increased capillary pressures (increased
hydrostatic pressures) that develop in the peripheral circulation in people with right-sided heart
failure and in the pulmonary circulation in people with left-sided heart failure. The increased
capillary pressure reflects an overfilling of the vascular system because of increased sodium and
water retention and venous congestion, referred to earlier as backward failure, resulting from
impaired cardiac output.
Nocturia is a nightly increase in urine output that occurs relatively early in the course of heart
failure. It occurs because of the increased cardiac output, renal blood flow, and glomerular filtration
rate that follow the increased blood return to the heart when the person is in a supine position.
Oliguria, which is a decrease in urine output, is a late sign related to a severely reduced cardiac
output and resultant renal failure.
Transudation of fluid into the pleural cavity (hydrothorax) or the peritoneal cavity (ascites) may
occur in people with advanced heart failure. Because the pleural veins drain into both the systemic
and pulmonary venous beds, hydrothorax is observed more commonly in persons with hypertension
involving both venous systems.
Pleural effusion occurs as the excess fluid in the lung interstitial spaces crosses the visceral pleura,
which in turn overwhelms the capacity of the pulmonary lymphatic system. Ascites occurs in people
with increased pressure in the hepatic veins and veins draining the peritoneum. It usually reflects
right ventricular failure and long-standing elevation of systemic venous pressure in chronic heart
failure.

31. What is pathogenetic role of renal hypoperfusion in development of edema?

Simply due to RAAS system,

RAAS SYSTEM: The renin-angiotensin-aldosterone system contributes to the regulation of

arterial pressure primarily via the vasoconstrictor properties of angiotensin II and the
sodium-retaining properties of aldosterone. Renin is an aspartyl protease that is synthesized
as an enzymatically inactive precursor, prorenin. Most renin in the circulation is synthesized
in the renal afferent renal arteriole. Prorenin may be secreted directly into the circulation or
may be activated within secretory cells and released as active renin. Although human plasma
contains two to five times more prorenin than renin, there is no evidence that prorenin
contributes to the physiologic activity of this system. There are three primary stimuli for
renin secretion: (1) decreased NaCl transport in the distal portion of the thick ascending limb
of the loop of Henle that abuts the corresponding afferent arteriole (macula densa), (2)
decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism),
and (3) sympathetic nervous system stimulation of renin-secreting cells via 1
 Group M1445
adrenoreceptors. Conversely, renin secretion is inhibited by increased NaCl transport in the
thick ascending limb of the loop of Henle, by increased stretch within the renal afferent
arteriole, and by 1 receptor blockade. In addition, angiotensin II directly inhibits renin
secretion due to angiotensin II type 1 receptors on juxtaglomerular cells, and renin secretion
increases in response to pharmacologic blockade of either ACE or angiotensin II receptors.
Once released into the circulation, active renin cleaves a substrate, angiotensinogen,
to form an inactive decapeptide, angiotensin I. A converting enzyme, located primarily but
not exclusively in the pulmonary circulation, converts angiotensin I to the active octapeptide,
angiotensin II, by releasing the C-terminal histidyl-leucine dipeptide. The same converting
enzyme cleaves a number of other peptides, including and thereby inactivating the
vasodilator bradykinin (Fig.3). Acting primarily through angiotensin II type 1 (AT1)
receptors on cell membranes, angiotensin II is a potent pressor substance, the primary tropic
factor for the secretion of aldosterone by the adrenal zona glomerulosa, and a potent mitogen
that stimulates vascular smooth muscle cell and myocyte growth. Independent of its
hemodynamic effects, angiotensin II may play a role in the pathogenesis of atherosclerosis
through a direct cellular action on the vessel wall. An angiotensin II type 2 (AT2) receptor
has been characterized. It is widely distributed in the kidney and has the opposite functional
effects of the AT1 receptor. The AT2 receptor induces vasodilation, sodium excretion, and
inhibition of cell growth and matrix formation. Experimental evidence suggests that the AT2
receptor improves vascular remodeling by stimulating smooth muscle cell apoptosis and
contributes to the regulation of glomerular filtration rate. AT1 receptor blockade induces an
increase in AT2 receptor activity.

Fig. 3 Renin-angiotensin-aldosterone axis.

(From Harrison's Principles of Internal Medicine, 18th Edition)
 Group M1445
Angiotensinogen, renin, and angiotensin II are also synthesized locally in many tissues,
including the brain, pituitary, aorta, arteries, heart, adrenal glands, kidneys, adipocytes, leukocytes,
ovaries, testes, uterus, spleen, and skin. Angiotensin II in tissues may be formed by the enzymatic
activity of renin or by other proteases (tonin, chymase, and cathepsins). In addition to regulating
local blood flow, tissue angiotensin II is a mitogen that stimulates growth and contributes to
modeling and repair. Excess tissue angiotensin II may contribute to atherosclerosis, cardiac
hypertrophy, and renal failure.

Angiotensin II is the primary tropic factor regulating the synthesis and secretion of
aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone is a potent mineralocorticoid
that increases sodium reabsorption by amiloride-sensitive epithelial sodium channels on the apical
surface of the principal cells of the renal cortical collecting duct. Mineralocorticoid receptors also
are expressed in the colon, salivary glands, and sweat glands. Aldosterone also has effects on non-
epithelial targets. Aldosterone and/or mineralocorticoid receptor activation induces structural and
functional alterations in the heart, kidney, and blood vessels, leading to myocardial fibrosis,
nephrosclerosis, and vascular inflammation and remodeling, perhaps as a consequence of oxidative
stress. These effects are amplified by a high salt intake and can contribute to development of
hypertension.

32. What is pathogenetic role of secondary hyperaldosteronism in circulatory failure?

Its related to hypervolemia due to hyperaldosteronism and sodium and water retention which will
cause overload and heart failure which may be complicated by circulatory failure.

33. What are metabolic changes in the myocardium in the first stage of hypertrophy?

34. How arterial pressure and central venous pressure are changed in heart failure?

35. How systolic volume and end-systolic volume are changed in heart failure?

36. What are manifestations of conductibility disorders in the heart?

Conductivity represent the ability of cardiac tissue to conduct action potentials.

Under normal conditions, the AV junction, which consists of the AV node with its
connections to the entering atrial internodal pathways, the AV bundle, and the non-branching
portion of the bundle of His, provides the only connection for transmission of impulses between the
atrial and ventricular conduction systems. Junctional fibers in the AV node have high-resistance
characteristics that cause a delay in the transmission of impulses from the atria to the ventricles. This
delay provides optimal timing for atrial contribution to ventricular filling and protects the ventricles
from abnormally rapid rates that arise in the atria. Conduction defects of the AV node are most
commonly associated with fibrosis or scar tissue in fibers of the conduction system. Conduction
defects also may result from medications, including digoxin, -adrenergicblocking agents, calcium
channelblocking agents, and class 1A antiarrhythmic agents. Additional contributing factors
include electrolyte imbalances, inflammatory disease, or cardiac surgery.
 Group M1445
Heart block refers to abnormalities of impulse conduction. It may be normal, physiologic
(vagal tone), or pathologic. It may occur in the AV nodal fibers or in the AV bundle (bundle of His),
which is continuous with the Purkinje conduction system that supplies the ventricles. The PR
interval on the ECG corresponds with the time it takes for the cardiac impulse to travel from the SA
node to the ventricular pathways. Normally, the PR interval ranges from 0.12 to 0.20 second.

First-degree AV block is characterized by a prolonged PR interval 0.20 second The prolonged PR

interval indicates delayed AV conduction, but all atrial impulses are conducted to the ventricles.
This condition usually produces a regular atrial and ventricular rhythm. Clinically significant PR
interval prolongation can result from conduction delays in the AV node itself, the His Purkinje
system, or both.17 When the QRS complex is normal in contour and duration, the AV delay almost
always occurs in the AV node and rarely in the bundle of His. In contrast, when the QRS complex is
prolonged, showing a bundle branch block pattern, conduction delays may be in the AV node or the
HisPurkinje system. First-degree block may be the result of disease in the AV node, such as
ischemia or infarction, or of infections such as rheumatic fever or myocarditis. Isolated first-degree
heart block usually is not symptomatic, and temporary or permanent cardiac pacing is not indicated,
but should be monitored.

Second-degree AV block. Second-degree AV block is characterized by intermittent failure of

conduction of one or more impulses from the atria to the ventricles. The non-conducted P wave can
appear intermittently or frequently. A distinguishing feature of second-degree AV block is that
conducted P waves relate to QRS complexes with recurring PR intervals; that is, the association of P
waves with QRS complexes is not random. Second-degree AV block has been divided into two
types: type I (Mobitz type I or Wenckebachs phenomenon) and type II (Mobitz type II). A Mobitz
type I AV block is characterized by progressive lengthening of the PR interval until an impulse is
blocked and the sequence begins again. It frequently occurs in persons with inferior wall myocardial
infarction, particularly with concomitant right ventricular infarction. The condition usually is
associated with an adequate ventricular rate and rarely is symptomatic. It usually is transient and
does not require temporary pacing. In the Mobitz type II AV block, an intermittent block of atrial
impulses occurs, with a constant PR interval. It frequently accompanies anterior wall myocardial
infarction and can require temporary or permanent pacing. This condition is associated with a high
mortality rate. In addition, Mobitz type II AV block is associated with other types of organic heart
disease and often progresses to complete heart block.

Third-degree AV block. Third-degree, or complete, AV block occurs when the conduction

link for all impulses from the SA node and atria through the AV node is blocked, resulting in
depolarization of the atria and ventricles being controlled by separate pacemakers. The atrial
pacemaker can be sinus or ectopic in origin. The ventricular pacemaker usually is located just below
the region of the block. The atria usually continue to beat at a normal rate, and the ventricles
develop their own rate, which normally is slow (30 to 40 beats per minute). The atrial and
ventricular rates are regular but dissociated. Third-degree AV block can result from an interruption
at the level of the AV node, in the bundle of His, or in the Purkinje system. Third-degree blocks at
the level of the AV node usually are congenital, whereas blocks in the Purkinje system usually are
acquired. Normal QRS complexes, with rates ranging from 40 to 60 complexes per minute, usually
are displayed on the ECG when the block occurs proximal to the bundle of His. Complete heart
 Group M1445
block causes a decrease in cardiac output with possible periods of syncope (fainting), known as a
Stokes-Adams attack. Other symptoms include dizziness, fatigue, exercise intolerance, or episodes
of acute heart failure. Most persons with complete heart block require a permanent cardiac
pacemaker.

37. For what disorders there is characteristic sinus bradycardia?

Sinus bradycardia describes a slow (<60 beats per minute) heart rate.

ECG: In sinus bradycardia, a P wave precedes each QRS. A normal P wave and PR interval (0.12 to
0.20 second) which indicate that the impulse originated in the SA node rather than in another area of
the conduction system that has a slower inherent rate.

Vagal stimulation decreases the firing rate of the SA node and conduction through the AV node to
cause a decrease in heart rate.

This rhythm may be normal in trained athletes, who maintain a large stroke volume, and during
sleep.

Sinus bradycardia may be an indicator of poor prognosis when it occurs in conjunction with acute
myocardial infarction, particularly if associated with hypotension.

38. For what disorders is characteristic sinus tachycardia?

Sinus tachycardia refers to a rapid heart rate (>100 beats per minute) that has its origin in the
SA node.

ECG: A normal P wave and PR interval should precede each QRS complex.

The mechanism of sinus tachycardia is enhanced automaticity related to sympathetic

stimulation or withdrawal of vagal tone (Both Conditions Change Membrane Potential toward more
excitable).

Sinus tachycardia is a normal response during fever and exercise and in situations that incite
sympathetic stimulation.

It may be associated with congestive heart failure, myocardial infarction, and

hyperthyroidism.

Pharmacologic agents such as atropine, isoproterenol, epinephrine, and quinidine also can
cause sinus tachycardia.

39. For what extrasystole is characteristic complete compensatory pause?

Premature ventricular contractions (ventricular extrasystole). A premature ventricular

contraction (PVC) is caused by a ventricular ectopic pacemaker. After a PVC, the ventricle usually
 Group M1445
is unable to repolarize sufficiently to respond to the next impulse that arises in the SA node. This
delay is commonly referred to as a compensatory pause, occurs while the ventricle waits to
reestablish its previous rhythm. When a PVC occurs, the diastolic volume usually is insufficient for
ejection of blood into the arterial system. As a result, PVCs usually do not produce a palpable pulse,
or the pulse amplitude is significantly diminished. In the absence of heart disease, PVCs typically
are not clinically significant. The incidence of PVCs is greatest with ischemia, acute myocardial
infarction, history of myocardial infarction, ventricular hypertrophy, infection, increased
sympathetic nervous system activity, or increased heart rate. PVCs also can be the result of
electrolyte disturbances or medications.

A special pattern of PVC called ventricular bigeminy is a condition in which each normal
beat is followed by or paired with a PVC. This pattern often is an indication of digitalis toxicity or
heart disease. The occurrence of frequent PVCs in the diseased heart predisposes the patient to the
development of other, more serious arrhythmias, including ventricular tachycardia and ventricular
fibrillation.

40. What is pathogenesis of excitability disorders in the heart?

1.A less negative diastolic membrane potential which can be correlated with sympathetic
stimulation, congestive heart failure, myocardial infarction, and hyperthyroidism and pharmacologic
agents such as atropine, isoproterenol, epinephrine, and quinidine.

2.Afterdepolarizations and triggered automaticity. Triggered automaticity or activity refers to

impulse initiation that is dependent on afterdepolarizations. Afterdepolarizations are membrane
voltage oscillations that occur during an action potential (early afterdepolarizations) or after it
(delayed afterdepolarizations).

Early afterdepolarizations (EAD) occur during the action potential and interrupt the orderly
repolarization of the myocyte. EADs occur when the AP duration is markedly prolonged, which
registers in the ECG as a prolonged QT interval (long QT syndrome). Causes of EAD are
bradycardia (ex in hypothyroidism, 1 block), hypokalemia, hypomagnesemia (loop diuretics), and
certain drugs such as the Na+ channel blockers quinidine, procainamide, and disopyramide, as well
as the Ca2+ channel blockers verapamil and diltiazem. Certain genetic defects in the Na+ channels or
in one of the K+ channels lead to EAD due to a lengthening of the QT interval. If such EAD occur in
the Purkinje cells, they trigger ventricular ES in the more distal myocardium (the myocardium has a
shorter AP than the Purkinje fibers and is therefore already repolarized when the DAP reaches it).
Traditionally, EADs have been thought to arise from action potential prolongation and
reactivation of depolarizing currents, but more recent experimental evidence suggests a previously
unappreciated interrelationship between intracellular calcium loading and EADs. Cytosolic calcium
may increase when action potentials are prolonged. This, in turn, appears to enhance L-type Ca
current, further prolonging action potential duration as well as providing the inward current driving
EADs. The interrelationship among intracellular [Ca2+] and EADs may be one explanation for the
susceptibility of hearts that are calcium loaded (e.g., in ischemia or congestive heart failure) to
develop arrhythmias, particularly on exposure to action potentialprolonging drugs.
 Group M1445
Structural heart disease such as cardiac hypertrophy and failure may also delay ventricular
repolarization (so-called electrical remodeling) and predispose to arrhythmias related to
abnormalities of repolarization. The abnormalities of repolarization in hypertrophy and heart failure
are often magnified by concomitant drug therapy or electrolyte disturbances.

The delayed afterdepolarizations (DADs) are usually preceded by posthyperpolarization that

changes into postdepolarization. If the amplitude of the latter reaches the threshold potential, a new
AP is triggered. The cellular feature common to the induction of DADs is the presence of an
increased Ca2+ load in the cytosol and sarcoplasmic reticulum. Digitalis glycoside toxicity,
catecholamines, and ischemia all can enhance Ca2+ loading sufficiently to produce DAD.
Accumulation of lysophospholipids in ischemic myocardium with consequent Na+ and Ca2+
overload has been suggested as a mechanism for DADs and triggered automaticity. Cells from
damaged areas or cells that survive a myocardial infarction may display spontaneous release of
calcium from the sarcoplasmic reticulum, and this may generate "waves" of intracellular calcium
elevation and arrhythmias.

41. What are manifestations of heart excitability disorders?

Excitability describes the ability of a cell to respond to an impulse and generate an action potential,
abnormalities in Excitability can lead to extra systole.

A premature contraction or extra systole which occurs when an ectopic pacemaker initiates a beat or
it can be in healthy hearts in response to sympathetic nervous system stimulation or other stimulants
such as caffeine.

Premature contractions do not follow the normal conduction pathways, they are not coupled with
normal mechanical events, and they often render the heart refractory or incapable of responding to
the next normal impulse arising in the SA node.

Etiology: disorders of excitability,

1.A less negative diastolic membrane potential in the cells of the conduction system or
myocardium. This is because depolarization also results in the potential losing its stability and
depolarizing spontaneously.
2.Afterdepolarizations and triggered automaticity or depolarizing after-potentials which can
occur during repolarization (early) or after its end (late).

42. How manifest disorders of automatism in the heart?

Automaticity refers to the ability of pacemaker cells in the heart to spontaneously generate an action
potential. Normally, the SA node is the pacemaker of the heart because of its intrinsic automaticity,
SA node has an inherent discharge rate of 60 to 100 times per minute. It normally acts as the
pacemaker of the heart because it reaches the threshold for excitation before other parts of the
conduction system have recovered sufficiently to be depolarized. If the SA node fires more slowly
or SA node conduction is blocked, another site that is capable of automaticity takes over as
pacemaker. Other regions that are capable of automaticity include the atrial fibers that have plateau-
 Group M1445
type action potentials, the AV node, the bundle of His, and the bundle branch Purkinje fibers. These
pacemakers have a slower rate of discharge than the SA node. The AV node has an inherent firing
rate of 40 to 60 times per minute, and the Purkinje system fires at a rate of 20 to 40 times per
minute. The SA node may be functioning properly, but because of additional precipitating factors,
other cardiac cells can assume accelerated properties of automaticity and begin to initiate impulses.
These additional factors might include injury, hypoxia, electrolyte disturbances, enlargement or
hypertrophy of the atria or ventricles, and exposure to certain chemicals or drugs.

The heart rate is lower if:

1. The rise of the slow depolarization becomes less steep,
2. The TP becomes less negative,
3.The MDP becomes more negative so that spontaneous depolarization begins at a
lower level;
4.Repolarization in an AP starts later or is slower.
What the first three processes have in common is that the threshold is reached later than
before.
The heart rate is higher if:
Augmentation of sympathetic nervous system tone increases myocardial catecholamine
concentrations, which activate both and adrenergic receptors.

The effect of 1-adrenergic stimulation predominates in pacemaking cells, augmenting L-type in

addition to other factors.

During sleep and in trained athletes at rest (vagotonia) and also in hypothyroidism, the rate can drop
below 60 per minute (sinus bradycardia), while during physical exercise, excitement, fever or
hyperthyroidism it may rise to well above 100 per minute (sinus tachycardia).

Sinus node arrhythmias:

1)Respiratory sinus arrhythmia is a cardiac rhythm characterized by gradual lengthening

and shortening of RR intervals. This variation in cardiac cycles is related to intrathoracic
pressure changes that occur with respiration and resultant alterations in autonomic
control of the SA node. Inspiration causes acceleration of the heart rate, and expiration
causes slowing. Respiratory sinus arrhythmia accounts for most heart rate variability in
healthy individuals. Decreased heart rate variability has been associated with altered
health states, including myocardial infarction, congestive heart failure, hypertension,
diabetes mellitus, and prematurity in infants.

2)Sinus bradycardia

3)Sinus tachycardia.

4)Sinus arrest. Sinus arrest refers to failure of the SA node to discharge and results in an
irregular pulse. An escape rhythm develops as another pacemaker takes over.
 Group M1445
Sinus arrest may result in prolonged periods of asystole and often predisposes to other
arrhythmias.

Causes of sinus arrest include disease of the SA node, digitalis toxicity, myocardial
infarction, acute myocarditis, excessive vagal tone, quinidine, acetylcholine, and hyperkalemia or
hypokalemia.

43. What are pathogenetic mechanisms of renal hypertension in kidney disorders?

Its related to 2 main mechanism:

1)Due to Hypoperfusion of kidney develop Increased Renin secretion which is related to increased
levels of angiontesion II which is a potent vasoconstrictor and aldosterone which is related to
sodium and water retention.

2)The kidney also produces a variety of vascular relaxing, or antihypertensive, substances (including
prostaglandins PGA and PGE and NO), which presumably counterbalance the vasopressor effects of
angiotensin. PGA and PGE are produced at the level of kidney medullary interstitium. Renal
disorders associated with loss of renal parenchyma like, glomerulonephritis, chronic renal disease,
polycystic disease can be associated with renal hypertension so-called renoprive renal
hypertension, due to inability of the kidney to produce vasodilator biological substances. PGA has
predominantly a local vasodilator effects, controlling the level of perfusion. PGE can have a general
vasodilatatory effect. Lack of local vasodilatatory biological substances increases vasoconstriction
of afferent arteriole with hypoperfusion and release of renin from the juxtaglomerular cells.

44. Hyperfunction of what heart compartment is attested in hypertensive disease?

45. In what endocrine disorders can develop arterial hypertension?

Endocrine hypertension can develop in a number of endocrine disorders due to hypersecretion of

hormones.

Most frequently these are

1. Mineralocorticoid hypertension (due to hypersecretion of aldosteron in primary or secondary

hyperaldosteronism).
2. Glucocorticoid hypertension (due to hypersecretion of glucocorticoids, mainly cortisol).
3. Catecholaminic hypertension (hypersecretion of catecholamines in pheochromocytoma,
paragnagliomas).
4. Thyroid gland disorders(Mild diastolic hypertension may be a consequence of
hypothyroidism, whereas hyperthyroidism may result in systolic hypertension).
5. Hypersecretion of Growth Hormone(Acromegaly).

46. What are pathogenetic mechanisms of endocrine hypertension?

 Group M1445
1.Mineralocorticoid hypertension: increased aldosterone production is independent of the
renin-angiotensin system lead to sodium and water retention which lead to hypertension, and
hypokalemia.

Additionally, hypokalemic hypertension may be a consequence of secondary aldosteronism,

which is present in patients with liver cirrhosis, heart failure etc. High level of aldosteron in the
blood is due to activation of the renin-angiotensin-aldosteron system or insufficient degradation of
aldosteron in the liver. In these patients the plasma renin level is increased.

2.Glucocorticoid hypertension mechanism related to stimulation of mineralocorticoid

receptors by cortisol leading to increased water and salt retention and permissive effects of
glucocorticoids on adrenoreceptors with increased cardiac output (effect on 1 receptors) and
increased peripheral resistence (effects on 1 receptors). Additional mechanisms can be explained
by the fact that cortisol increase hepatic production of angiotensinogen, by this way also enhancing
the activity of renin-angiotensin-aldosteron system.

3.Catecholaminic hypertension:

1. Effects of Cathecolamines on Cardiovascular System.

2.High blood level of catecholamines leads to vasoconstriction of renal afferent arteriole by

this way activating the renin-angiotensin-aldosteron system, which is the other mechanism by which
hypercatecholaminemia lead to high blood pressure.

If there is predominant hypersecretion of adrenaline, the hypertension will be mainly

systolic associated with tachycardia.

If there is predominant hypersecretion of noradrenaline, the hypertension is systole-diastolic,

with less tachycardia.

4. hypersecretion of thyroid hormones is due to cardiogenic effects of T3 andT4 (positive

chronotron and inotropic effects). Mainly this is a form of hypertension due to increased cardiac
output (hemodynamic hypertension) which is associated with tachycardia (120 160/min) and
frequently with heart arrhythmias (mainly, atrial fibrillation).

Mild diastolic hypertension may be a consequence of hypothyroidism, whereas

hyperthyroidism may result in systolic hypertension.
 Group M1445

Pathophysilogy of Respiratory System

Answers and more details

1. What is hyperpnoea?
Increased depth and rate of breathing physiologic and pathologic (severe sepsis)
occur in asphyxia
increase breathing movement

2. What is polypnoea?
more than 20 breaths per minute (can be sign of pneumonia in children)
caused by Pulmonary embolism , pneumothorax

3. What is bradypnea?
decrease rate of breathing

4. What is hyperventilation?
physiologically caused by work
Pathologically caused by : metabolic acidosis, increase demand, hypoxemia and inappropriate
hyperactivity of the respiratory neurons
Hyperventilation increases the O2 partial pressure in the alveoli and blood
No significant increase in O2 uptake because of saturated hemoglobin
boosts CO2 release
factors acting on respiratory neurons in medulla causing hyperventilation :
acidosis, hypercapnia, hypoxia, decrease of Ca2+ and Mg2+ in cerebrospinal fluid (CSF), Pain,
intensive cold or heat stimuli to the skin, increase or moderate fall in body temperature,
drop in blood pressure, muscular activity (joint innervations), epinephrine and
norepinephrine in the blood, histamine, acetylcholine and prostaglandins in CNS,
progesterone, testosterone, and corticotropin.

5. What is hypoventilation?

causes : - respiratory failure due to : 1- drug overdose 2- neuromuscular diseases ( Guillain-Barr

syndrome) 3- chest wall deformities ( inflammation of joints
severe scoliosis) 4- pleural effusion 5- pneumothorax
6- restrictive and obstructive lung diseases
- Administration of high-flow oxygen to patient with chronic hypoxia
- Decrease of O2 demand

Factors acting on respiratory neurons in medulla causing hypoventilation :

Alkalosis, hypocapnia, peripheral hyperoxia, and Ca2+ and Mg2+ increase in the CSF,Hypoxia in
the CNS, deep hypothermia, rise in blood pressure, ganglion blockers, atropine, catecholamines,
endorphins and glycine in the CNS.
 Group M1445

6. What changes in the composition of alveolar air is found in hyperventilation?

High PO2
low PCO2

7. What changes in the composition of alveolar air is found in hypoventilation?

Less fresh air which means more CO2 and less O2

8. What changes in the gaseous composition of arterial blood is found in hyperventilation?

increases the O2 partial pressure in the blood

9. What changes in the gaseous composition of arterial blood is found in hypoventilation?

significant reduction in PaO2and increase inPaCO2

10. What changes in acid-base balance is found in hyperventilation?

 Group M1445
Reduce PCO2 hypocapnea Increase in PH Respiratory alkalosis

11. What changes in acid-base balance is found in hypoventilation?

raise PCO2 hypercapnea decrease in PH Respiratory acidosis

12. What changes in ventilatory parameters of the lung is found in hyperventilation?

13. What changes in ventilatory parameters of the lung is found in hypoventilation?

Euler-Liljestrand reflex which constrict the vessels of under ventilated alveoli( hypoxic vasoconstriction)

14. How do the intrathoracic pressure and venous return change to the heart in deep and accelerated
breathing?
intrathoracicpressure increases leading to impairing of venous return

15. How do the intrathoracic pressure and venous return change to the heart in shallow breathing?
intrathoracic pressure decreases leading to more of venous return

16. What is characteristic of dyspnea?

Represents changes of rhythm, amplitude and frequency of external breathing concomitantly with
increased effort of respiratory muscles associated with a characteristic subjective feeling of lack of
satisfaction from breathing process.
Persons perception of difficulty in breathing that includes the perception of labored breathing and
the reaction to that sensation.
Synonyms :breathlessness and shortness of breath

causes : respiratory like pneumonia, asthma, pulmonary Embolism, Sarcoidosis, Idopathic pulmonary
fibrosis, Bronchiectasis, pleural effusion, pneumothorax and emphysema
cardio : pulmonary congestion
neuromuscular : myasthenia gravis and muscular dystrophy
during exercise, particularly in untrained persons

Central dyspnea : due to changes in the excitability of respiratory center and interrelations between
inspiratory and expiratory neurons.
Pulmonary dyspnea : is due to changes at the level of the lung parenchyma (fibrosis, inflammation,
cancer) or airways (obstruction)
Extrapulmonary dyspnea :
- Cardiac by insufficiency of cardiac output (heart failure, heart defects with right-left shift etc)
- extracardiac which is characteristic for any type of hypoxia (except the cardiac hypoxia),
anemia, metabolic acidosis.
origin of the sensation :

1 - Stimulation of lung receptors by the contraction of bronchial smooth muscle, the

stretch of the bronchial wall (stretch receptors), pulmonary congestion, and conditions that
decrease lung compliance(juxtacapillary receptors or J receptors).
2 - Increased sensitivity to changes in ventilation perceived through central nervous
system mechanisms; focuses on central nervous system mechanisms that transmit information
 Group M1445
to the cortex regarding respiratory muscle weakness or a discrepancy between the increased
effort of breathing and inadequate respiratory muscle contraction. Chemoreceptors in the
carotid bodies and medulla are activated by hypoxemia, acute hypercapnia, and acidemia.
Stimulation of these receptors, as well as others that lead to an increase in ventilation,
produce a sensation of air hunger.

3 - Stimulation of neural receptors in the muscle fibers of the intercostals and

diaphragm and of receptors in the skeletal joints. Metaboreceptors, located in skeletal muscle,
are believed to be activated by changes in the local biochemical milieu of the tissue active
during exercise and, when stimulated, contribute to the breathing discomfort. These
receptors, once stimulated, transmit signals that bring about an awareness of the breathing
discrepancy.

17. What inspiratory dyspnea call?

deep and accelerated breathing (hyperpnea) with prevalence of inspiration

causes : Asphyxia(first stage) which is acute respiratory failure characterized by disorders in O2
uptake (hypoxemia) and CO2 release (hypercapnia).

18. What expiratory dyspnea call?

Reduction in respiratory rate but with preservation of maximal amplitude of breathing with
prevalence of expiration
causes :
- asphyxia (second stage)
-pleuritic pain caused by pulmonary infarction due to pulmonary embolism

19. What physical parameters of alveolar air slow the gas diffusion through alveolar-capillary barrier? ]
Fick law :SA x D(P1-P2)
T
SA= surface area D = diffusion coefficientP1-P2= pressure deference (gradient) T = Thickness.
slow diffusion : decreasing one or more of ( SA , D and P1)
increasing one or both of (P2 and T)

Characteristics of the gas and its molecular weight and solubility constitute the diffusion coefficient
and determine how rapidly the gas diffuses through the respiratory membranes

20. What conditions reduce the gas diffusion through alveolar-capillary barrier?
- Hypoventilation
- Diseases that destroy lung tissue
- increase the thickness of the alveolarcapillary membrane (pulmonary edema + pneumonia)
distance for diffusion (pulmonary edema + pneumonia )
- In interstitial lung fibrosis, the connective tissue forces alveoli and blood capillaries apart
increasing the distance.
- distance can also be slightly increased by vessel dilation (inflammation) or anemia.
reduction of the diffusion area:
- unilateral lung resection
- loss of alveolar septa: pulmonary emphysema, TB Pulmonary fibrosis
- alveolar collapse : atelectasis, pulmonary edema, or pulmonary infarction
 Group M1445
- Diffusion abnormalities can occur by increasing cardiac output (blood is more rapid to uptake O2)
at exercise (increasing O2 demand) the Cardiac output increases leading to diffusion
abnormality and these patients can get blue lips (central cyanosis)

21. What factors decrease the oxygen capacity of the blood?

Carbon monoxide
nitrates/nitrites
decrease in PH
increase in DPG
increase Temperature

22. What hemoglobin compounds decrease the oxygen capacity of the blood?
Methemoglobin (high concentration of nitrates produce methemoglobin)

23. What physico-chemical parameters prevent the oxygen association with hemoglobin in small
circulation?
anemia
any increasing in distance (recall question 20)
Carbon monoxide
nitrates/nitrites

24. What physico-chemical parameters prevent the oxygen association with hemoglobin in systemic
circulation?
Hypoxia
decrease in PH
increase in DPG
increase Temperature

25. What processes determine extra parenchymal pulmonary restriction?

is a term given to an anatomical or functional loss of gaseous exchange area

Chest wall disorders (neuromuscular diseases such as poliomyelitis, severe obesity, kyphoscoliosis),
pleural diseases like pneumothorax, hydrothorax, adhesion of both pleural layers as a result of
inflammation [pleural fibrosis]

Pleural effusion
Abnormal accumulation of fluids in pleural cavity
Causes: (1) increased capillary pressure, as in congestive heart failure;
(2) increased capillary permeability, which occurs with inflammatory conditions;
(3) decreased colloidal osmotic pressure, such as the hypoalbuminemia occurring with liver
disease and nephrosis;
(4) increased negative intrapleural pressure, which develops with atelectasis;
(5) impaired lymphatic drainage of the pleural space, which results from obstructive
processes such as mediastinal carcinoma.
Transudate : also called hydrothorax , serous fluid most commonly results by Congestive heart
failure, nephrosis, liver failure and malignancy

Exudates : can have one or more of :

- a pleural fluid protein to serum protein ratio greater than 0.5;
- a pleural fluid lactate dehydrogenase (LDH) to serum LDH ratio greater than 0.6;
- pleural fluid LDH greater than two thirds the upper limit of normal serum LDH.
- Sometimes, there is characteristic presence of inflammatory cells.
 Group M1445
Caused By: infections, pulmonary infarction, malignancies, rheumatoid arthritis, and SLE
Empyema :pus in the pleural cavitycaused by direct infection of the pleural space from an adjacent
bacterial pneumonia, rupture of a lung abscess into the pleural space, invasion from a
subdiaphragmatic infection, or infection associated with trauma.
Chylothorax: effusion of lymph in the thoracic cavity (fluid contains chylomichron) results from
trauma, inflammation, malignant infiltration, intrathoracic surgical procedures, and
use of the great veins for total parenteral nutrition and hemodynamic monitoring.
Hemothorax :is the presence of blood in the thoracic cavity Bleeding may arise from chest injury, a
complication of chest surgery, malignancies, or rupture of a great vessel such as an aortic aneurysm.

Minimal hemothorax300 to 500 mL

Moderate hemothorax 500-1000 mL
Large hemothorax more than 1000 mL

Moderate and large hemothorax can lead to fibrothorax (fusion of the pleural surfaces with
fibrin and hyaline and connective tissue and calcification of fibrous tissue).
Mediastianl shift contralateral (against) the abnormality

-Pneumothorax
refers to air or gas in the pleural cavities and may be spontaneous, traumatic, or therapeutic
and is most commonly associated with emphysema, asthma, and tuberculosis.
- Spontaneous pneumothorax: may complicate any form of pulmonary disease that causes
rupture of an alveolus.
Air may escape to pleural space by abscess which communicate directly or by
interstitium.
spontaneous idiopathic pneumothorax encountered in relatively young people, seems to be
due to rupture of small, peripheral, usually apical subpleural blebs, and usually subsides
spontaneously as the air is resorbed. Recurrent attacks are common and can be quite
disabling. Can result from Distal acinar/paraseptal emphysema .
-Traumatic pneumothorax:caused by some perforating injury to the chest wall, but sometimes
the trauma pierces the lung and thus provides two avenues for the accumulation of air within
the pleural spaces
-Tension pneumothorax :occurs when the intrapleural pressure exceeds atmospheric pressure.
It is a life-threatening condition and occurs when injury to the chest or respiratory
structures permits air to enter but not leave the pleural space
one direction of air entry valve-like. which is caused by burst alveoli
** Can be a result of trauma or mechanical ventilation

Pneumothorax leads to compression atelectasis and mediastinal shift toward the opposite site
which impair breathing in the other lung, leads also to compression of Vena Cava which
impair venous return to heart, asymmetrical chest, hypoxemia

26. What is the intra parenchymal pulmonary restriction?

is a term given to an anatomical or functional loss of gaseous exchange area and reduced lung
compliance
Chronic interstitial and infiltrative diseases, such as pneumoconiosis and interstitial fibrosis of
unknown etiology.
A functional decrease in exchange area occurs if plasma water is exuded into alveoli (pulmonary
edema, pneumonia)
causes a fall in :
- compliance (C)
- vital capacity (VC)
 Group M1445
- functional residual capacity (FRC)
- diffusion capacity
- Oxygen saturation SO2 (hypoxemia)
- Maximum breathing capacity (Vmax)
- forced expiration volume in 1 second (FEV1),

All these lead to increased work of breathing; V = ventilation flow. Increase pleural pressure
negativity , increasing vascular resistance (by compression ) resulting in hypertension in
pulmonary circulation and cor-pulmonale
- Atelectasis :
three types : 1 resorption : complete obstructionof an airway and is caused principally by
excessive secretions (e.g., mucus plugs) or exudates within smaller
bronchi and is therefore most often found in bronchial asthma, chronic
bronchitis, bronchiectasis, postoperative states, aspiration of foreign
bodies and, rarely, in bronchial neoplasms.
st
1 step there is decrease in blood O2
2nd more O2uptake from normal alveoli and less CO2 eliminated
(no significance increase of CO2 in contrast to decrease of O2)
rd
3 alveolar volume will fall leading to more concentrated N2there and more
uptake of N2to blood
th
4 entire alveolar air reabsorbtion(volume reduced)
5th hypoxic vasoconstriction (delay the fall in alveolar O2 concentration)
*ventilation with O2 can favor the atelectasis because 5thstep will not occur
2- Compression atelectasis results whenever the pleural cavity is partially or
completely filled by fluid exudates, tumor, blood, or air
causes mediastinal shift toward the atelectasis
3- Contraction atelectasis occurs when local or generalized fibrotic changes in
the lung or pleura prevent full expansion (this type is irreversible)
atelectasis reduces oxygenation and predisposes to infections.

- Pulmonary Edema : increase of filtration pressue pulmonary congestion interstitial

pulmonary edema alveolar pulmonary edema

Causes : carcinogenic, lymphatic, hypoproteinemia (liver failure. kidney failure) , hyper

hydration (in patient with impaired renal function), increasing of capillary
permeability ( inhalation of corrosive gasesprolonged inspiration of pure O2, in shock,
trauma, radiation, near-downing, effects of some drugs and toxins, transfusion)

Pulmonary edemas force the patient to breathe in the upright position (orthopnea)
this lead to decrease of hydrostatic pressure in Pulmonary capillary and increase
blood flow of upper part of lungs and facilitate the lymphatic drainage by decrease
venous pressure.

-Pulmonary Fibrosis :idiopathic pulmonary fibrosis (IPF)/cryptogenic fibrosingalveolitis

old pathogenic concept : in chronic inflammations Macrophages and Neutrophils migrate to
inflammation foci releasing oxidants and proteases leading to pneumocytes injury and
cytokines (IL-1; IL-4; TNF, INF, TGF- and ; FGF, PDGF) leading to development
of fibroblastic foci (activated fibroblast will produce collagen).
new pathogenic concept :repeated cycles of epithelial activation/injury by some unidentified
 Group M1445
agent, injured Pneumocytes release TGF-1 :
- high TGF-1 induces transformation of fibroblasts into myofibroblasts increase collagen
deposition
- high TGF-1reduce telomerase less epithelial regeneration
- high TGF-1 down regulate Caveolin-1 no endogenous inhibition of pulmonary fibrosis

27. What is pulmonary obstruction?

Usually measured by forced expiratory volume in 1 sec

Distinct anatomical lesions and different mechanisms of airflow obstruction.

Airway resistance :
Obstructive lung diseases are characterized by an increased flow resistance.
Airflow depends on the distending airway (intrapulmonary) pressures that hold the airways open and
the external (intrapleural or intrathoracic) pressures that surround and compress the airways. The
difference between these two pressures (intrathoracic pressure minus airway pressure) is called the
transpulmonary pressure.
Intrapulmonary pressure must be greater than the external one to permit air flow.
High drop in intrapulmonary pressure will cause a compression by intrathoracic pressure
leading to interruption of airflow and trapping of air in terminal airways.
Airway resistance is greater during expiration than inspiration

The total airway resistance is equal to the sum of the resistances in all three types of airways (large
medium and small )
Airway resistance measured According to Poiseuille law, the resistance to flow is inversely related to
the fourth power of the radius (R = 1/r4). If the radius is reduced by one half, the resistance increases
16-fold (2 2 2 2 =16). and because the respiratory airways situated in parallel so
the total airway resistance is equal to the sum of the resistances :
Total combined resistance = 1/R + 1/R, etc

Two types of air flow

Laminar : occur in small airways and in low flow velocity and rate
Turbulent : occur in large airways and in high flow velocity and rate (turbulence flow
contributes to respiratory sounds in auscultation).

Cystic Fibrosis can lead to obstructive lung disease :

No mucus clearing
Reduce lungs ability to retract (flaccid lung)
 Group M1445
decrease elastic recoil
requiringof more pressure during expiration.

In COPD there are :

- Increase ratio of expiration to inspiration
- Greater pressure is necessary because compliance and resistance are increased
- Increasing of functional residual capacity - FRC
- Reduce maximum breathing capacity Vmax and Force expiration volume FEV1
- Difference in ventilation of various alveoli abnormal distribution hypoxia
vasoconstriction in underventilated alveoli pulmonary hypertension increase right
ventricular load corpulmonale

28. What factors can cause the obstruction of upper airways?

Extrathoracic increase in resistance : (mainly affect inspiration)

paralysis of vocal cords
edema of glottis
external tracheal compression (tumor or goiter)
tracheomalacia collapse of trachea in inspiration due to wall softening

29. What factors can cause the obstruction of lower airways?

Intrathoracic increase in resistance : (mainly affect expiration)

- Cystic fibrosis
- Narrowing of bronchi by : thicking of mucus layer, external compression, contraction and
obstruction by mucus. Classically occur in asthma and chronic bronchitis

30. In which cases may occur the deep and accelerated breathing?
hyperpnoea ?if yes , physiological by exercises or pathological in case of sepsis

31. In which cases may shallow breathing occur?

32. In which cases may the deep and rare breathing occur?

33. In which cases may expiratory dispnea occur?

inPleuritic pain caused by pulmonary infarction due to pulmonary embolism

34. What active biologically substances posses the broncho constrictor effect?

Inhaled air pollutants, such as sulfur dioxide, ozone, andnitrogen dioxide, may also contribute to the
chronic airway inflammation and hyperreactivity that are present in some cases.
Drug-induced asthma :Aspirin-sensitive asthma and other NSAIDs so the lipoxganse activity raised
and more releasing of bronchoconstrictor leukotrienes
Occupational asthma.This form of asthma is stimulated by fumes (epoxy resins, plastics), organic \
and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals
(formaldehyde, penicillin products).
Bronchoconstriction is triggeredby direct stimulation of subepithelialvagal (parasympathetic)
receptors through both central and localreflexes (including those mediated by unmyelinated
sensory C fibers).
Eotaxin from esoniphils which stimulate late-phase in asthma and cause bronchoconstriction

35. What active biologically substances posses the broncho dilator effect?
 Group M1445
Corticosteroids ?

36. What biologically active substances increase the pressure in the lungs?

37. What biologically active substances decrease the pressure in the lungs?

38. What factors cause acute respiratory distress in adults?

** In infants its alveolar collapse caused by difficulty to produce enough surfactant factor
severe injury or infection in adults can Impair synthesis of Surfactant Factor leading to ARDS
Hamman Rich syndrome(acute interstitial pneumonia -AIP)
shock, oxygen therapy, and sepsis

39. What is pathogenesis of acute respiratory distress syndrome in adults?

Pro-inflammatory cytokines (IL-8, IL-1,TNF)released by macrophagescause neutrophils

adherence to pulmonary capillaries then undergo activationreleasing a variety of factors
(leukotrienes, oxidants, proteases, and platelet-activating factor PAF) whichcontribute tolocal
tissue damageand accumulation of edema fluid in the airspaces, surfactant inactivation, and hyaline
membrane formation.
Macrophages stimulate (by TGF- and PDGF) fibroblasts growth and collagen deposition.

Il-8 recruit neutrophils (sequestration of neutriphils done by upregulation of expression of adhesion

molecules and these activated neutrophils become stiff and less deformable which lead to their
trapping in the narrow capillary bed !!?)
Il-1 + TNF activate neutriphils and endothilum

in ARDS, lung injury is caused by an imbalance of pro-inflammatory and anti-inflammatory

mediators. NF-B shifting the balance in favor of a pro-inflammatory state.

- In ARDS the integrity of alveolar-capillary barrier is compromised by either endothelial or

epithelial injury orboth.
- endothelial injury leads to high endothilin and willebrand factor in serum
- increased vascular permeability
- alveolar flooding
- loss of diffusion capacity
- widespread surfactant abnormalities caused by damage to type II pneumocytes
- Endothelial injury also triggers the formation of microthrombi that add the insult of ischemic injury
- hyaline membrane by inspissations of protein rich edema fluidentraps debris of dead alveolar
epithelial cells.

40. What is pulmonary edema?

restrictive disease increase water in lungs causing less compliance
recall question 26

41. What is pulmonary emphysema?

- Obstructive lung disease (by reduction of elastic recoil and inflammation of small airways)
 Group M1445
-Irreversible enlargement of the airspaces distal to the terminal bronchiole.
-Destruction of alveolar walls and elastic tissue.
-Without obvious fibrosis.
- Reduction in elastic recoil (obstructive disease)patients try to raise the elastic recoil by
increasing inspiratory volume leading to shift position toward inspiration Barrel Chest
- increase FRV and FRC (if tidal volume remain constant)
- increase Dead Space
- Decrease expiratory Volume decrease vital capacity
-Increase compliance and air filling in lungs.
-loss of alveolar wall diminish diffusionarea .
- loss of pulmonary capillary increase in ( functional dead space, pulmonary artery pressure and
pulmonary vascularresistance) corpulmonale
-Types :
(1) Centriacinar/centrilobular :central or proximal parts of the acini, formed by respiratory
bronchioles, are affected, whereas distal alveoli are spared.
More common and usually more severe in the upper lobes.
Inflammation around bronchi and bronchioles is common.
Occurs predominantly in heavy smokers, often in association with chronic bronchitis.
Blue bloatersdue to abnormal distribution and hypoxemia
(2) Panacinar/panlobular :the acini are uniformly enlarged from the level of the respiratory
bronchiole to the terminal blind alveoli.
Occur more commonly in the lower zones and in the anterior margins of the lung.
Associated with 1-antitrypsin (1-AT) deficiency.
Pink puffersdue tofunctional dead spaceenlargement which force them to breathe deeply.
Hypoxemia develops just in increasing oxygen demand (e.g. during physical work) or
great reduction of diffusion capacity.
(3) Distal acinar/paraseptal:the proximal portion of the acinus is normal, and the distal part
is predominantly involved.
Is more striking adjacent to the pleura, along the lobular connective tissue septa, and at
the margins of the lobules.
It occurs adjacent to areas of fibrosis, scarring, or atelectasis
Is usually more severe in the upper half of the lungs.
The characteristic findings are of multiple, continuous, enlarged airspaces from less than
0.5 cm to more than 2.0 cm in diameter, sometimes forming cyst-like structures.
Underlines many cases of spontaneous pneumothorax in young adults .
(4) Airspace enlargement with fibrosis/Irregular: irregular involvement of acinus associated
with scaring.

Pathogenesis :
mild chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature
increasing in Macrophages, CD8+ and CD4+ T lymphocytesand neutrophils which release mediators
like :leukotriene B4, IL-8, TNF, and others leading to structural damage

The most plausible hypothesis is protease-antiproteasemechanism:

geneticdeficiency of the antiprotease 1-antitrypsin have a markedly enhanced tendency to develop
pulmonary emphysema

protease anti-protease imbalance hypothesis :

1-antitrypsinis a major inhibitor of proteases (particularly inhibits elastasewhich
secreted by neutrophils during inflammation) , 1-antitrypsinpresent in serum, tissue
fluids, and macrophages
steps :
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in inflammation , the neutrophils (major secretors of proteases) will gain access to
alveolar space, so any stimulus will lead to increase their number together with
macrophages and will both start secreting of their proteases-containing granules
increasing the proteolytic activity . and with any deficiency of 1-antitrypsin
(genetically ) or impaired function by smoking will decrease the anti-proteolytic
activity and exacerbate the proteolytic action on tissues leading to unchecked elastic
tissue destruction hence Emphysema !!

Smoking induces emphysema by: (functional 1-antitrypsin deficiency)

1- Smoking leads to accumulate of neutrophils and macrophages in alveolar space:

direct chemoattractant of Nicotine and reactive oxygen species contained in
smoke, activation of NF-Bwhich switches on genes that encode TNF and
chemokines, including IL-8. These, in turn, attract and activate neutrophils.
2- Activated Neutrophils starts to secrete their proteases (neutrophil elastase,
proteinase 3, and cathepsin G)
3- Enhance macrophages elastase activity which itself is not affected by
1-antitrypsin and even can digest the 1-antitrypsin !
4- Smoking leads to Oxidant-Antioxidant imbalance :
Tobacco smoke contains reactive oxygen species (free radicals), which deplete the
antioxidant mechanisms of superoxide dismutase, glutathione and inactivate the
native antiproteases, thereby inciting tissue damage.

** in smoking dont cause deficiency in 1-antitrypsin but it makes it non-functional!

42. What factors cause pulmonary edema?

Recall question 26

43. What is the main pathogenetic link of emphysema?

Recall question 41

44. What are the sources of proteolytic enzymes that damage the alveoli?

Recall question 41

45. What are features of emphysema?

Recall question 41

Respiratory system more Details :

Lungs inactivate vasoactive substances such as bradykinin, convert angiotensin I to angiotensin II, and serve as a reservoir for
blood storage. Heparin-producing cells are particularly abundant in the capillaries of the lung, where small clots may be trapped.

Each unit contains :terminal bronchiole, an arteriole, pulmonary capillaries, and a venule

300 million alveoli In adult lung with total surface area 50-100 m2

Pores of kohn : small holes in alveolar wall contribute to air mixing

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Brush cell in alveoli are receptors for air quality

Type I alveolar cells : squamous cell non-regenerative , occupy 95% of alveolar surface joined by occluding junction and
forming a barrier between air and alveolar wall

Type II alveolar cells : cuboidal cells produce surfactant occupy 5% of the surface, progenitors for type I

Surfactant molecules : their function to reduce surface tension and modulate immune function of the lungs
Types : SP-A (surfactant protein A) : contribute to host defenses that protect against pathogens that have entered
the lung (collectin family) opsonize pathogens, produce inflammatory mediators and direct killers
SP-B : reduce surface tension, increase lung compliance and ease of lung inflation
generation of the surface-reducing film that makes lung expansion possible
SP-C : reduce surface tension, increase lung compliance and ease of lung inflation
SP-D :contribute to host defenses that protect against pathogens that have entered the lung (collectin
family) opsonize pathogens, produce inflammatory mediators and direct killers
Surfactant is a mixture of phospholipids, neutral lipids, and proteins
Alveolar Macrophages : some located in the airspace which remove inhaled particulate matter (dust and pollen) others are located
in the connective tissue which phagocyte materials and remain for life (smokers)

The bronchial circulation warming and humidifying incoming air, and they are the only vessels that undergo angiogenesis and
developing collateral circulation when there is obstruction (e.g PE)

Respiratory Center : The apneustic center (lower pons) has an excitatory effect on inspiration, tending to prolong inspiration
The pneumotaxic center in the upper ponsswitches inspiration off, assisting in the control of respiratory rate
and inspiratory volume
respiratory rhythm : automatic by chemoreceptors (CO2 O2 PH ) and lung and chest wall receptors(breathing pattern |
and lung function).Also by joints and tendons receptors in case of effort need for
respiration.
voluntary : like speaking blowing and singing performed by motor and premotor cortex these area
are also influenced by fever pain and emotions .
chemoreceptor :- centeral : which are influenced directly by CO2 and Indirectly by PH (note: chronical elevated PCO2
will no longer have sensitivity in center receptors for CO2 and the key role is the peripheral
sensitivity for o2 .
- peripheral : sensitive for PO2 more than PH and CO2
Lung receptors :monitor the status of breathing in terms of airway resistance and lung expansion
- stretch receptors : in Smooth muscle of airways respond to pressure changes and change the respiratory rate
corresponding to the pressure on the airway.
- irritant receptors : between airway and epithelial cells stimulated by noxious gases, cigarette smoke, inhaled
dust, and cold air leading to rapid shallow breathing responsible of bronchoconstriction in
asthmatic patients .
- juxtacapillary or J receptors : located in alveolar wall close to pulmonary arteries sense lung congestions and
responsible for rapid, shallow breathing in pulmonary Edema, Embolism and
Pneumonia .
Hering- Breuer inflation reflex. This reflex also increases therate of respiration is not activated until the tidal volume
increases to more than three times normal (by stretching receptors )

values : pressure at sea level = 1 atmosphere = 760 millimeters of mercury (mmHg) = 14.7 pounds per square (PSI)
atmosphere pressure assigned of ZERO when measuring respiratory pressures
respiratory pressure measured also by Cm H2O (1 mm Hg = 1.35 cm H2O pressure).
partial pressure = concentration of the gas multiplying by 760 mmHg (1 atmosphere)
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Warm air holds more moisture than cold air
The air in the alveoli, which is 100% saturated at normal body temperature, has a water vapor pressure of 47 mm Hg.
the total pressure of the other gases in the alveoli is 760 - 47 = 713 mm Hg (47 of water vapor)

the pressure of a gas varies inversely with the volume of its containerprovided the temperature remains constant.
hypoxemia :PaO2 less than 50-60 mmHg
cyanosis : 5 g/dL of deoxygenated hemoglobin in blood
hypercapnia PaCO2>46 mmHg
PaCO2 > 70 mmHg leads to paralysis of respiratory centre and arrest of ventilation
intrapleural pressure = -4
diaphragm movement 1cm in normal inspiration up to 10 in forced one
Tidal volume VT > Alveolar Volume VA (if not happened the alveoli are not ventilated by fresh air)

Barbiturates (soporific drugs) and chronic respiratory failure decrease the sensitivity of the
respiratory neurons to pH or CO2 in CSF.
decrease CO2 sensitivity can lead to : sleep apnea and respiratory acidosis

Pathological breathing :

Kussmaul breathingis an adequate response of the respiratory neurons to metabolic acidosis. The
depth of the individual breaths is greatly increased but breathing is regular.
CheyneStokes breathing is irregular. The depth of breathing periodically becomegradually deeper
and then gradually more shallow. It is caused by a delayed response of respiratory neurons to changes in
blood gases resulting in an overshooting reaction. It occurs when there is hypoperfusion of the brain, or
when breathing is regulated by a lack of oxygen.
Biot breathing consists of a series of normal breaths interrupted by long pauses. It is an expression of
damage to respiratory neurons.
Gasping also signifies a marked disorder in the regulation of breathing.

Pulmonary perfusion

The pulmonary blood vessels are thinner, are more compliant, and offer less resistance to flow than those in the systemic
circulation, and the pressures in the pulmonary system are much lower (e.g., 22/8 mm Hg versus 120/70 mm Hg) to
make it easier to flow and prevent congestion .
The volume in the pulmonary circulation is approximately 500 mL, 100 mL of this volume located in the pulmonary
capillary bed.
Same input in rt heart and output from left heart make pulmonary blood flow constant, any difference will affect the
blood flow in lungs and change the hydrostatic pressure leading to EDEMA in the lungs .
Blood flow to lungs is gravity and position dependent
Hypoxia induce vasoconstriction
Alveolar PO2 <60mm cause vasoconstriction (locally to these alveoli )
Generalized hypoxia causes vasoconstriction throughout all of the vessels of the lung (e.g high altitude or
chronic hypoxia of lung disease)
Chronic vasoconstriction- pulmonary hypertension increase rt heart workload rt ventricular hypertrophy
alveolar hypoxia low PH further vasoconstriction (e.g in circulatory shock)

Shunts :
Blood moves from pulmonary to systemic circulation without being oxygenated .
Types: :
- Anatomic shunts : blood moves before reaching the lung (heart defects)
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- Physiologic shunts : blood reaches the lung but is not oxygenated due to mismatch in ventilation and
perfusion within the lungs and results from destructive lung diseases or from
heart failure.
The pulmonary blood flow must be in a range to permit O2 uptake from alveoli (neither too high nor low)
For CO2 reduction in perfusion with constant CO2 production by cells and constant ventilation will lead to fall in
alveolar PCO2 and thus favor its uptake from blood and elimination
In raised lungs perfusion alveolar PCO2 will increase leading to decrease its uptake from blood
CO2 removal is less dependent on perfusion than O2 uptake
Pulmonary embolism :
mechanical obstruction of the pulmonary circulation which result in :
1- vasoconstriction (neurohormnal reflex)
2- bronchoconstriction (neurohormonal reflex )
3- Wasted ventilation and impaired gas exchange
4- Loss of alveolar surfactant ,
5- Pulmonary hypertension (if massive obstruction) which lead tort heart failure
6- small areas of infarction may occur (frank pulmonary infarction is uncommon)
Causes :
DVT , venous stasis, venous endothelial injury, surgery, hypercoagulability state, prolonged
bed rest, childbirth, fractures of the hip and femur, MI, congestive heart failure, and spinal
cord injury, orthopedic surgeries , gynecological and cancer surgire, cancer cells
production of thrombin, smoker women ( oral contraceptive, pregnancy and hormones
replacement therapy increase resistance to anticoagulants).
Manifestation : dyspnea and increased respiratory rate

Lung distribution
In the seated or standing position, gravity exerts a downward pull on the lung, causing intrapleural pressure at
the apex of the lung to become more negative
In the supine position, ventilation in the lowermost (posterior) parts of the lung exceeds that in the uppermost
(anterior) parts. In the lateral position (i.e., lying on the side), the dependent lung is better ventilated.
Air moves into the more compliant portions (base in standing , apex in supine)
Anatomic dead space + alveolar dead space = physiologic dead space
In normal person anatomic dead space = physiologic dead space (alveolar Dead space = zero)
Both dead air space and shunt produce a mismatching of ventilation and perfusion
Mismatching of ventilation and perfusion:
Shunt: perfusion without ventilation like in atelectasis
Dead air space: ventilation without perfusion like in pulmonary embolism
COPD there may be shunt in one area and dead air space another
abnormal distribution:
describes the condition when the ratio of ventilation to perfusion in Individual alveoli
deviates to a functionally significant extent from that in the whole lung :
Impaired perfusion : emphysema pulmonary embolism and pulmonary fibrosis
Compensated by deep breathing.
Impaired ventilation (alveolar shunt) : asthma, chronic bronchitis, tumor
pleural thickening, Diaphragmatic paralysis and Pulmonary fibrosis.

note: pulmonary fibrosis in both types of abnormailtiy

when their is inadequate ventilation hypoxemia occurs but hypercapnia hardly

ever occurs because the reduced CO2 release from underventilated alveoli can
be well compensated by increased release into hyperventilated alveoli. but
this hyperventilation which caused by hypoxemia can lead to hypocapnia then
respiratory alkalosis .
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Restrictive and obstructive diseases :

Obstructive disease :
Usually measured by forced expiratory volume in 1 sec
Distinct anatomical lesions and different mechanisms of airflow obstruction
Related to the resistance of the airflow which is determined by Poiseuille law :-
The resistance to flow is inversely related to the fourth power of the radius (R = 1/r4). If the
radius is reduced by one half, the resistance increases 16-fold (2 2 2 2 =16).
The total airway resistance is equal to the sum of the resistances in all three types of airways (large
medium and small ).

Restrictive disease :
reduced expansion of lung parenchyma and/or thorax with decreased total lung capacity
-extraparenchymatous restriction : chest wall disorders (poliomyelitis,obesity,
khyphoscoliosis pleural diseases)
- intraparenchymatous restriction Chronic interstitial and infiltrative diseases
pneumoconioses and interstitial fibrosis of unknown etiology
lung compliance :
normal compliance : 200 mL/cm H2O (in both lungs) every time the intrapulmonary pressure increases by 1
cm/H2O, the lung volume expands by 200 mL.
determined by the elastic properties of the lung, its water content, surface tension and thoracic cage.
Elastin increase compliance while collagen decrease so any tissue remolding which increase collagen like in
pulmonary fibrosis will reduce the compliance.
Pulmonary congestion increases waters quantity and reduce compliance
increase surface tension reduce lung compliance
In surgical and bed-ridden patients, shallow and quiet breathing often impairs the spreading of surfactant

respiratory failure
As a general rule, respiratory failure refers to a PaO2 level of 50 mm Hg or less and a PaCO2 level
greater than 50 mmHg

result of a number of conditions that impair ventilation, compromise the matching of ventilation and
perfusion, or disrupt blood flow in the lung. These conditions include impaired ventilation caused by
impaired function of the respiratory center, airway obstruction, weakness and paralysis of the
respiratory muscles, chest wall deformities, and disease of the airways and lungs. It may occur in
previously healthy persons as the result of acute disease or trauma involving the respiratory system,
or it may develop in the course of a chronic neuromuscular or respiratory disease.
Causes of respiratory failure

Impaired Ventilation (hypercapnic-hypoxemic respiratory failure)

- Upper airway obstruction - Drug overdose

- Infection (e.g., epiglottitis) - Muscular dystrophy
- Spinal cord injury - Weakness or paralysis of respiratory muscles
- Foreign body - Laryngospasm
- Brain injury - Chest wall injury

Impaired Matching of Ventilation and Perfusion

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- Chronic obstructive pulmonary disease
- Restrictive lung disease
- Severe pneumonia
- Atelectasis

Impaired Diffusion
- Pulmonary edema
- Acute respiratory distress syndrome

TYPE I : Hypoxemic respiratory failure

- Great Hypoxemia mild hypercapnia perfusion-ventilation mismatch (COPD)
Sedation and cardio-pathology can exaggerate this disorder
Administration of O2 can reduce the hypoxemia but decrease the respiratory drive leading to
more hypercapnia .
- Great hypoxemia no hypercapnia perfusion abnormalities
Administration of O2 is effective because the CO2 is not affected by the reduced perfusion

TYPE II : Hypercapnic respiratory failure

Great Hypoxemia great hypercapnia hypoventilation