JP Advis DVM, Ph.D. Bartlett Hall, Animal Sciences, Cook...

Pathophysiology 13 • JP Advis DVM, Ph.D.

Bartlett Hall, Animal Sciences, Cook,

932 - 9240, [email protected]

• Course website: rci.rutgers.edu/~advis

• Lectures, tests, grades, office hours, textbook,

• Material to

be covered:

• About

lecture

slides:

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• Slides are good to review the course material after you have study your course textbook

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Lectures 1-2: Introduction to Pathophysiology (2) Lectures 3-4: Mechanisms of Self-Defense and Stress (2)

Lectures 5-8: Endocrine and Nervous System Dysfunctions (4) Lecture 9: Alterations of Skeletal Muscle Function (1)

REVIEW AND TEST #1 Lectures 12-18: Cardiovascular, Respiratory and Renal Dysfunctions (7)

REVIEW AND TEST #2

Lectures 21-24: Alterations of Digestive Function and Intermediary Metabolism (4) Lectures 25-26: Alterations of the Reproductive System (2)

REVIEW AND TEST #3

Arteriosclerosis

Arteriosclerosis

arteriosclerosis, athero-sclerosis, fibrous plaque

Coronary artery disease myocardial isquemia, myocardial infarction

Heart wall disorders

pericardial, valvular stenosis/regurgitation, rheumatic heart disease, infective endocarditis

Heart failure

congestive heart failure (left failure), cor pulmonale (right failure)

Shock cardiogenic, hypovolemic, neurogenic, anaphylactic, septic, and multiple organ dysfunction (MODS)

Arteriosclerosis, is a chronic disease of the arterial system

characterized by abnormal thickening and hardening of vessel

walls. Smooth muscle cells and collagen fibers migrate into the tunica intima, causing it to stiffen and thicken, thus decreasing

the artery’s ability to change lumen size.

Atherosclerosis, is the common form of arteriosclerosis in

which thickening of vessel walls is caused by hardening of soft deposits of intra-arterial fat and fibrin that reduces lumen size. It

is the leading contributor to coronary artery & cerebrovascular

disease.

The process leading to atherosclerosis (atherogenesis), begins with injury to endothelial cells and their inability to produce anti-

thrombic and vasodilating cytokines. Macrophages adhere to

injured endothelial cells and release O2 radicals that result in

oxidation of LDL. When this are engulfed by macrophages are

called “foam cells”, which accumulate to form the “fatty streak”.

Arteriosclerosis, a chronic disease of arteries is characterized by

abnormal thickening and hardening of vessel walls.

Arteriosclerosis

Arteriosclerosis





Heart failure



The lesions of atherosclerosis occur primarily within the tunica

intima or the innermost layer. They include fatty streaks, fibrous

plaquse, and the complicated lesions. The early fatty streak is a flat, yellow, lipid-filled smooth muscle cell that causes no

obstruction of the affected vessel.

Fibrous plaque, the characteristic lesion of advancing athero-

sclerosis consist of lipid-laden smooth muscle cell surrounded by collagen, elastic fibers, and mucoprotein matrix. The lesion is

elevated and protrudes into the lumen of the artery, it fixes to the

inner wall of the tunica intima, and may invade the muscular

tunica media. It probably originates from fatty streaks, and has

lipids and debris from cellular necrosis caused by insufficient blood supply. It occludes arterial lumen at arterial bifurcations,

curves, or regions were arteries taper.

Complicated lesions occurs as fibrous plaques are altered by

hemorrhage, calcification, cell necrosis, and blood clots and the intima layer becomes rigid causing extensive vascular occlusion.



Arteriosclerosis

Arteriosclerosis





Heart failure





normal artery diseased occluded artery

adventitia

tunica intima

tunica

media

Atherosclerosis Progression

Arteriosclerosis





Heart failure



Atherosclerosis is the most common form of arteriosclerosis


Arteriosclerosis arteriosclerosis, athero-sclerosis, fibrous plaque




Heart failure

congestive heart failure (left

failure), cor pulmonale (right failure)


Progression of atherosclerosis: Basic physiology on the endo-

thelium regulation of vasomotion (constriction and dilation) and

platelet aggregation


Arteriosclerosis





Heart failure



Progression of atherosclerosis: Basic physiology on the factors that

cause endothelium – dependent vasodilation. Injured endothelial

cells do not make normal amounts of antithrombic and vasodilating cytokines.

Smooth muscle relaxation

Smooth muscle relaxation






Heart failure




Progression of atherosclerosis: low density lipoprotein (LDL)

enters the arterial intima through an intact endothelium. In hyper-

cholesterolemia, influx of LDL exceeds the eliminating capacity and an ECF pool is formed. Intima LDL is oxidized by action of

free O2 radicals and generate pro-inflammatory lipids.






Heart failure




Progression of atherosclerosis: a summary, slide

Damaged endothelium:

Chronic endothelial injury

Hypertensiom

Smoking

Hyperlipidemia

Hyperhomocystinemia

Hemodynamic factors Toxins

Viruses

Immune reactions

Fatty streak

Fibrous plaque

Complicated

lesion

Coronary Artery Disease

Arteriosclerosis





Heart failure



Coronary artery disease, myocardial ischemia and myocardial

infarction impair heart’s pumping ability by depriving it of O2 &

nutrients

Coronary artery disease (CAD), diminishes myocardial blood

supply until deprivation impairs myocardial metabolism. Myo-

cardial cells remain alive but are unable to function normally. Persistent ischemia or complete occlusion of a coronary artery

causes acute coronary syndromes including infarction or death.

Myocardial ischemia, is due predominantly to atherosclerosis.

The growing mass of plaque, platelets, fibrin, and cellular debris can eventually narrow the coronary artery lumen enough to

impede blood flow. Platelet aggregation release thromboxane

A2, a potent vasoconstrictor capable of causing spasm of

coronary arteries and promote further platelet aggregation.

Myocardial infarction, occurs when coronary arteries can not

compensate for lack of O2 caused by myocardial ischemia. As a

marker of inflammation and thrombosis, C-reactive protein rises

shortly after infarction. A common complication of myocardial

infarction are dysrhythmias, arrhythmias, and sudden death.

Coronary Artery Disease

Arteriosclerosis





Heart failure



Cycle of ischemic events

Myocardial Ischemia

Arteriosclerosis





Heart failure



The ischemic cost of aggravation, angiogram of coronary

arteries, electrocardiogram (EKG) and ischemia

Normal

Myocardial

Ischemia

Myocardial Ischemia

Arteriosclerosis





Heart failure



Pathophysiology model of the effects of acute stress

as a trigger of cardiac clinical events

VF = ventricular fibrillation

VT = ventricular tachicardia

MI = Myocardial infarction

VF = ventricular fibrillation

VT = ventricular tachicardia

MI = Myocardial infarction

Myocardial Ischemia

Arteriosclerosis





Heart failure



Pathophysiology of acute coronary syndrome

Myocardial Ischemia

Arteriosclerosis





Heart failure



Pathogenesis of unstable plaques and thrombus formation

Myocardial Infarction

Arteriosclerosis





Heart failure



Plaque disruption and myocardial infarction


Arteriosclerosis





Heart failure



EKG alterations associated with the three zones of myocardial

infarction


Arteriosclerosis





Heart failure



Three interacting factors related to sudden cardiac death

Pericarditis

Arteriosclerosis





Heart failure



Disorders of the pericardium includes acute pericarditis,

pericardial effusion, and constrictive pericarditis

Pericardial disease is often a localized manifestation of another

disorder. Infection, trauma or surgery, neoplasm, or metabolic,

immunologic, or vascular disorders can elicit a pericardial response. Pericarditis, pericardial effusion, and constrictive

pericarditis are the consequences of the elicited response.

Acute pericarditis, although idiopathic, is commonly caused by

infection, connective tissue disease, or radiation therapy. Peri-cardium becomes inflamed, roughened, & exudate may develop.

Among its symptoms are sudden chest pain that worsen with

respiration, dysphagia, restlesness, irritability, weakness, and

malaise. A friction rub or scratchy grating sound in the cardiac

apex and left sternal border is pathognomonic. Its treatment, if uncomplicated, is antiinflammatory drugs to relieve symptoms.

Pericardial effusion, is accumulation of fluid in the pericardial

cavity. It is possible with all type of pericarditis. The fluid might

be transudate or an exudate and suggest an underlying disorder.

Pericarditis

Arteriosclerosis





Heart failure



Pericardial tamponede is when pericardial fluid creates sufficient

pressure to cause cardiac compression, equal diastolic pressure,

decrease atrial and ventricular filling, SV and CO, and circulatory collapse may develop. The most significant clinical finding of

tamponade is pulsus paradoxus, when arterial pressure during

expiration exceeds that of inspiration by more than 10 mm Hg.

Constrictive pericarditis, is either idiopathic or associated with radiation exposure, rheumatoid arthritis, uremia, or coronary

artery bypass graft. Fibrous scarring & occasional calcification

causes visceral and parietal layers to adhere obliterating the

pericardial cavity and reducing CO. It develops gradually, unlike

the tamponade that has a more sudden onset. Among its symptoms are exercise intolerance, dyspnea on exertion,

anorexia, weight loss, edema, distention of the jugular vein, and

hepatic congestion. Chest X-rays show prominent pulmonary

vessels and pericardium calcification. Therapy involves digitalis

glycosides and even removal of the pericardium.

Disorders of the pericardium includes acute pericarditis,

pericardial effusion, and constrictive pericarditis

Pericarditis

Arteriosclerosis





Heart failure



B

C D

Disorders of the pericardium includes acute pericarditis (B),

pericardial effusion (C), and constrictive pericarditis (D)

Acute

pericarditis

Pericardial

effusion

Constrictive

pericarditis

Valvular Dysfunctions

Arteriosclerosis





Heart failure



Disorders of the endocardium includes valvular dysfunctions,

acute rheumatic fever and rheumatic heart disease, and

infective endocarditis

Valvular dysfunctions include stenosis and regurgitation.

In valvular stenosis, the valve orifice is constricted or narrowed. This impedes the forward flow of blood and

increases the workload of the cardiac chamber “in front”

or before the diseased valve. Increased volume and

pressure causes the myocardium to work harder and

myocardial hypertrophy develops.

In valvular regurgitation, also known as insufficiency or

incompetence, the valve leaflets or cusps fail to close

completely. This permits blood to continue even when the

valve should be closed. During systole some blood leaks into the atrium, thus increasing the workload of atrium and

ventricle. Increased volume leads to chamber dilation, and

increased workload leads to hypertrophy. Left valves are

more commonly affected than right valves.


Arteriosclerosis





Heart failure



Valvular stenosis and regurgitation

A

C

B

D

Normal valve

(open)

A B

D

Normal

valve

(open)

C


Arteriosclerosis





Heart failure



Mitral stenosis with “fish mouth” and vegetation (V) that (impair

blood flow into left ventricle, and mitral valve prolapse (valve

leaflets billow back into atrium during left ventricular systole)

Endocarditis

Arteriosclerosis





Heart failure



Disorders of the endocardium includes valvular dysfunctions,

acute rheumatic fever and rheumatic heart disease, and

infective endocarditis

Endocarditis

Arteriosclerosis





Heart failure



Pathogenesis of infective endocarditis

ENDOTHELIAL

DAMAGE

DEVELOPMENT OF THROMBI

NON-BACTERIAL THROMBOTIC ENDOCARDITIS

Genito-urinary instrumentation

Dental procedure Skin infection

hemodialysis

Intravenous drug abuse Cardiac surgery

PATHOGEN ENTRY INTO BLOODSTREAM

Failure of platelets

Inhibition causing platelet deposition Failure of mechanisms of self-defense

(serum complement, antibodies)

BACTEREMIA

BACTERIAL INFILTRATION OF PLATELET – FIBRIN THROMBI

COLONIZATION ON ENDOCARDIAL SURFACES

Adherences of more platelets Formation of more fibrin

GROWTH OF VEGATATION

INFECTIVE ENDOCARDITIS

Deposition of immune complex

(systemic lupus erythmatosus,

rheumatic heart disease)

Exposure to cold High altitude

Turbulent blood flow (valvular dysfunctions)

Stress

Cardiac catheterization

Endocarditis

Arteriosclerosis





Heart failure



Rheumatic heart disease (RHD) versus infective endocarditis

Cause Pathophysiology Manifestation Treatment

RHD, sequel to streptococus

pharingeal infection

Carditis of all 3 layers of heart wall,

endocardial inflammation and

vegetative growth on valves and valvular stenosis

Fever, lymphoadeno-

pathy, acute migrato-ry

polyarthritis, chrea,truncal rush, history of strepto


Antibiotics, NSAID,surgical valve

repair, continuos prophy-lactic

antibiotic therapy for as long as 5 years

Infective endocar-ditis,

staphyloco-cus followed by

strepto, virus, fungi, ricketsia

Prior endothelial damage to valves

leads to throm-botic endocarditis, blood-

borne microbes colonize damaged valve and form

endocardial vegetations

Fever, cardiac murmur, petechial

lesions of skin and mucosa,

bacteremia, prolonged PR

Antimicrobial therapy for 4-6

weeks, possible valve replacement

Cause Pathophysiology Manifestation Treatment

RHD, sequel

to streptococus


Carditis of all 3 layers of

heart wall, endocardial inflammation and

vegetative growth on valves and valvular

stenosis

Fever,

lymphoadeno-pathy, acute

migratory polyarthritis, chrea,

truncal rush, history

of strepto pharingeal infection

Antibiotics,

NSAID, surgical valve repair,

continuos prophy-lactic

antibiotic therapy

for as long as 5 years

Infective

endocarditis, staphylococu

s followed by strepto,

virus, fungi,

ricketsia

Prior endothelial

damage to valves leads to thrombotic

endocarditis, blood-borne microbes colonize

damaged valve and

form endocardial vegetations

Fever, cardiac

murmur, petechial lesions of skin and

mucosa, bacteremia,

prolonged PR

Antimicrobial

therapy for 4-6 weeks, possible

valve replacement

Ventricular Remodeling

Arteriosclerosis





Heart failure



Pathophysiology of ventricular remodeling

Heart failure are several types of cardiac dysfunction causing an

inadequate perfusion of tissues with vital blood-born nutrients.

Ventricular remodeling, a process leading to decrease contractility,

is caused by inflammatory, immune, and neurohumoral changes.

Ventricular remodeling results in hypertrophy and dilation of the

myocardium and causes progressive myocyte contractile dysfunc-tion over time. When contractility is decreased, stroke volume falls

and ventricular end-diastolic volume (VEDV) increases. This cause

dilation of the heart and increase preload, which might temporally

increase CO but eventually leads to sarcomere dysfunction. Most

rises in preload are related to intravenous fluid administration, renal failure, and mitral valvular disease. Increased afterload or

TPR is seen in hypertension, and aortic valvular disease. It also

causes myocardium hypertrophy, increase O2 demand and

ventricular remodeling. It has been linked to failed compensatory

mechanisms involving catecholamines, RAS, ANP, and AVP.


Arteriosclerosis





Heart failure



Pathophysiology of ventricular remodeling

Ventricular remodeling

due to myocardial

disfunction

Ventricular remodeling

due to myocardial

disfunction

MYOCARDIAL DYSFUNCTION

RENIN – ANGIOTENSIN – ALDOSTERONE SYSTEM ACTIVATED

VENTRICULAR REMODELING

Decreased perfusion to kidneys

Decreased CO

Decreased systemic BP

Myocardial infarction

Ischemic heart disease

Hypertension, others

Baroreceptors activated Left ventricle

Aotic arch Carotide sinus

Vasomotor regulatory centers in medula stimulated

Sympathetic nervous system activated

Increased Cas (Epi & Norepi)

Vasoconstriction Increased afterload Increased BP & HR

Increased AgII

Increased ALDO

Retain Na and water

AVP, endothelin, cytokines (TNF-alpha)

Hypertrophy & dilated ventricles

Geneticall large cells

Impaired contractility


Arteriosclerosis





Heart failure



Effect of elevated preload on myocardial O2 demand and supply

Increased preload (LVEDV)

Decreased lumen of

coronary arteries

Myocardial

ischemia

Stretching of

myocardium

Decreased

contractility


Arteriosclerosis





Heart failure



Role of increased afterload on yje pathogenesis of heart failure

Heart Failure

Arteriosclerosis





Heart failure



The vicious cycle of systolic heart failure

Renal failure hypertension

Decreased RBF

Increased renin

& AgII

Decreased EF

Increased

LVEDV

Decreased contractility

MYOCARDIAL INFARCTION

Right Heart Failure

Arteriosclerosis





Heart failure



Right hjeart failure

Right heart failure

Left Heart Failure

Arteriosclerosis





Heart failure



Left side failure (congestive heart disese)

High Output Heart Failure

Arteriosclerosis





Heart failure



High output failure, the heart is unable to supply nutrients despite

adequate blood volume and myocardial contractility. Common

causes are anemia, septicemia, hyperthyroidism, and beriberi

High output failure

Shock

Arteriosclerosis





Heart failure



Shock’s impairment of cellular metabolism

In shock, cardiovascular system fails to perfuse tissues adequately,

resulting in widespread impairment of cellular metabolism.

Tissue perfusion may be disrupted by any factor altering heart

function, thus shock has many causes and clinical manifestations.

Ultimately, shock progress to organ failure and death, unless

compensatory mechanisms reveres it or clinical treatment succeed.

Untreated severe shock overwhelms the body’s compensatory

mechanisms through positive feedback loops that initiate and

maintain a downward physiological spiral.

MODS or multiple organ dysfunction syndrome, describes failure of

two or more organ systems after severe illness and injury. It is a

frequent complication of severe shock. The disease process is

initiated and perpetuated by uncontrolled inflammatory and stress

responses. It is progressive & associated with significant mortality.

Shock and Cellular Metabolism

Arteriosclerosis





Heart failure



Shock’s impairment of cellular metabolism

Shock events, signs, symptoms

Arteriosclerosis





Heart failure



Events, signs and symptoms of shock

MODS

Arteriosclerosis





Heart failure



Pathogenesis of multiple organ disfunction syndrome (MODS)

Cardiogenic Shock

Arteriosclerosis





Heart failure




Cardiogenic shock

Hypovolemic shock

Arteriosclerosis





Heart failure




Hypovolemic shock

Neurogenic Shock

Arteriosclerosis





Heart failure




Neurogenic shock

Anaphylactic Shock

Arteriosclerosis





Heart failure




Anaphylactic shock

Septic Shock

Arteriosclerosis





Heart failure




Septic shock

JP Advis DVM, Ph.D. Bartlett Hall, Animal Sciences, Cook...

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