PATHOPHYSIOLOGY OF

CARDIOVASCULAR
SYSTEM DISORDERS
Prof. Dr. Mehtap KAÇAR
MD, PhD
Yeditepe University, Faculty of Medicine, Department of Physiology & Pathophysiology, İstanbul,
2022
 Dyslipidemias

Hypertension

Atherosclerosis
OUTLINES Coronary Heart Disease

Myocardial Infarction

Heart Failure

Acute Rheumatic Fever & Rheumatic Heart Disease

DYSLIPIDEMIAS
LIPOPROTEIN

 The term lipoprotein refers to lipids, phospholipids, cholesterol,

and triglycerides bound to carrier proteins.

 Lipids (cholesterol in particular) is required by most cells for

the manufacture and repair of plasma membranes.

 Cholesterol is also a necessary component for the manufacture

of such essential substances as bile acids and steroid hormones.
Dyslipidemias
 Dyslipidemia (or dyslipoproteinemia) refers to abnormal
concentrations of serum lipoproteins.
 Dyslipidemias are important risk factors for cardiovascular diseases.
 Primary or familial dyslipoproteinemias result from genetic defects that
cause abnormalities in lipid-metabolizing enzymes and abnormal cellular
lipid receptors
 Secondary causes of dyslipidemia include several common systemic
disorders, such as diabetes, hypothyroidism, pancreatitis, and renal
nephrosis, as well as the use of some medications such as certain
diuretics, beta-blockers, glucocorticoids, interferons, and antiretrovirals.
ATHEROSCLEROSIS
Atherosclerosis
 Arteriosclerosis is a chronic disease of the arterial system
characterized by abnormal thickening and hardening of the
vessel walls.
 Atherosclerosis is a form of arteriosclerosis in which the
thickening and hardening of the vessel are caused by the
accumulation of lipid-laden macrophages within the arterial
wall, which leads to the formation of a lesion called plaque.
 It is a leading contributor to the coronary artery and
cerebrovascular disease.
Atherosclerosis—Risk Factors
 Age  LDL↑
 Gender (Male)
 HDL↓
 Genetic factors
 Obesity, diet high in cholesterol, animal
 hyperhomocystinemia
fats  CRP ↑
 Cigarette smoking
 Serum fibrinogen ↑
 Sedentary lifestyle
 Diabetes mellitus  Oxidative stress
 Poorly controlled hypertension  Peridontal disease
10

 Smoking
Lipid-Related Risk Factors: Importance of
LDL

 LDL is a major atherogenic  Genetic studies have

lipoprotein and;
 There is a strong
contributory relationship
between elevated LDL and
CHD.
concluded that high LDL
levels, even in the
absence of other known
risk factors, increase the
incidence of advanced
coronary atherosclerosis
and premature CHD.
Lipid-Related Risk Factors: Role of
Triglycerides and HDL

 While LDL has proven to be the greatest indicator

of CHD risk,
 it is evident that other circulating lipoproteins,
specifically triglycerides and HDL, also play
important roles in predisposing patients to
cardiovascular-related diseases
Atherosclerosis—Pathophysiology

 Atherosclerosis is an inflammatory disease.

 Atherosclerosis begins with injury to the endothelial cells

that line artery walls.

 Pathologically the lesions progress from endothelial injury

and dysfunction  fatty streak  fibrotic plaque 
complicated lesions. 13
 (1) LDL enters the arterial intima through an intact endothelium.
 (2) and (3) Inflammation and oxidized LDL cause endothelial cells to express adhesion molecules that bind monocytes and other inflammatory and immune
cells. Monocytes penetrate the vessel wall, becoming macrophages.
 (4) Lipid-laden macrophages are called “foam cells.”
 (5) Foam cells accumulate and form the fatty streak, and many inflammatory cytokines and enzymes are released that injure the vessel wall.
COMPLICATIONS OF
ATHEROSCLEROSIS
Atherosclerosis—Management
 The first step of the treatment is lifestyle changes !!!
 Losing weight and maintaining weight at healthy levels reduces
atherosclerosis.
 General weight reduction decreases the workload on the heart.
 Waist measurements below 87.5 cm in females and below 100 cm in
males are considered healthy benchmarks.
 Lowering serum cholesterol and LDL levels by substituting non-
hydrogenated vegetable oils for trans fats and saturated fats has been well
promoted as an effective means of slowing the progress of atherosclerosis.
 High dietary fiber intake also appears to decrease LDL levels.
Atherosclerosis—Management
 Cease smoking.
 Exercise appropriate for age and health status will promote collateral
circulation and reduce LDL levels.
 Control of primary disorders such as diabetes or hypertension is important.
 Sodium intake should be minimized.
 Lipid-reducing (cholesterol or LDL) lovastatin may help in resistant cases.
 If thrombus formation is a concern, oral anticoagulant therapy may be
required.
 When atheromas are advanced, surgical intervention may be required.
HYPERTENSION
 Hypertension is defined as
a sustained elevation of
systemic arterial blood
pressure.
HYPERTENSION
Hypertension is caused by
increases in cardiac
output, total peripheral
resistance, or both.
23
Criterias of Hypertension for Adults
Classification of Hypertension
 Primary hypertension (essential or idiopathic
hypertension)

 Secondary hypertension

 Isolated systolic hypertension

 Malignant hypertension
 Classification of Hypertension

 Primary hypertension (essential or idiopathic

hypertension): most cases of combined systolic and
diastolic hypertension have no known cause and are
diagnosed as primary hypertension.
This type affects 90% to 95% of hypertensive
individuals.
26
Primer Hypertension- Risk Factors

 Family history of (diabetes mellitus),

hypertension,  Smoking,
 Advancing age,  Obesity,
 Gender (male),  Heavy alcohol
 Black race, consumption,
 High dietary sodium  Low dietary intake of
intake, potassium, calcium, and
 Glucose intolerance magnesium.
27
Primer Hypertension-
Pathophysiology
 Primary hypertension is the result of a
complicated interaction between genetics and
environment and their effects on vascular and
renal function.

28
Primer Hypertension-
Pathophysiology
 Multiple pathophysiologic mechanism mediate these effects
including:

 the sympathetic nervous system (SNS),

 the renin-angiotensin-aldosterone system (RAA), adductin,

and natriuretic peptides.
 Inflammation, endothelial dysfunction and insulin resistance
also contribute to both increased peripheral resistance and
increased blood volume.
 TABLE 19-2 Potential Mechanisms of Pathogenesis

Blood pressure (BP) is the mathematical product of cardiac output and peripheral
resistance. Elevated BP can result from increased cardiac output and/or increased
total peripheral resistance.
Increased cardiac output Increased cardiac preload:
•Increased fluid volume from excess sodium intake or
renal sodium retention (from reduced number of
nephrons or decreased glomerular filtration)
Venous constriction:
•Excess stimulation of the renin-angiotensin
aldosterone system (RAAS)
•Sympathetic nervous system overactivity

Increased peripheral Functional vascular constriction:

resistance •Excess stimulation of the RAAS
•Sympathetic nervous system overactivity
•Genetic alterations of cell membranes
•Endothelial-derived factors
Structural vascular hypertrophy:
•Excess stimulation of the RAAS
•Sympathetic nervous system overactivity
•Genetic alterations of cell membranes
•Endothelial-derived factors
•Hyperinsulinemia resulting from the metabolic
syndrome
32
Classification of Hypertension

 Secondary hypertension: It is caused by altered

hemodynamics associated with primary diseases, such as
renal disease. (5%to 8% of cases)

 Isolated systolic hypertension: It is elevated SBP

accompanied by normal DBP. his type is a manifestation
of increased cardiac output or rigidity of the aorta or both.
33
Secondary Hypertension

 Secondary hypertension is caused by a systemic disease

process that raises peripheral vascular resistance or
cardiac output.

 If the cause is identified and removed before permanent

structural changes occur, blood pressure returns to
normal.
34
35
Classification of Hypertension

 Malignant hypertension is rapidly progressive

hypertension in which diastolic pressure is usually
above 140 mmHg.

 If untreated, it is life-threatening.

 It can cause encephalopathy and cerebral edema.

37
Clinical Manifestations of
Hypertension
 The early stages of hypertension have no clinical
manifestations other than elevated blood pressure.
 Most important no signs and symptoms cause the
individual to seek health care; thus hypertension is
called a silent disease.
 Initial signs vague, nonspecific
Fatigue, malaise, morning headache

38
COMPLICATIONS
OF
HYPERTENSION
Management of Hypertension

 Lifestyle changes are the first treatment choice for primer

hypertension.

 In persistent cases, anti-hypertensive drugs can be used.

 For secondary hypertension, it is important to treat the

underlying disease.

 Malignant hypertension requires emergent treatment.

TABLE 19-4 Lifestyle Modifications to Prevent and Manage Hypertension
a
Effects of implementing these modifications are time- and dose-dependent and could be greater for some patients.
b
One drink equivalent is equal to 1.5 oz of 80-proof distilled spirits (e.g., whiskey), a 5 oz glass of wine (12%), or 12 oz of beer. The Dietary
Approaches to Stop Hypertension (DASH)

Approximate Systolic Blood

Modification Recommendation
Pressure Reduction (mm Hg)a

Weight loss Maintain normal body weight 5–20 per 10-kg weight loss
(body mass index, 18.5–24.9
kg/m2)
DASH-type dietary patterns Consume a diet rich in fruits, 8–14
vegetables, and low-fat dairy
products with a reduced
content of saturated and total
fat
Reduced salt intake Reduce daily dietary sodium 2–8
intake as much as possible,
ideally to ≈65 mmol/day (1.5
g/day sodium, or 3.8 g/day
sodium chloride)
Physical activity Regular aerobic physical 4–9
activity (at least 30
minutes/day, most days of the
week)
Moderation of alcohol intake Limit consumption to less than 2–4
or equal to 2 drink equivalents
per day in men and less than or
equal to 1 drink equivalent per
day in women and lighter
CORONARY HEART
DISEASE
Coronary Heart Disease
 Coronary heart disease (CHD) is also called ischemic
heart disease and coronary artery disease (CAD) in some
sources.
 These terms are related because CHD is characterized by
insufficient delivery of oxygenated blood to the
myocardium (ischemia) because of atherosclerotic
coronary arteries (CAD).
 CHD causes about one in six deaths in the United States.
 The main cause of premature death in industrialized
countries
Coronary Heart Disease
 Atherosclerosis of coronary arteries is the source of
nearly all CHD.
 Occasionally CAD results from a spasm of an artery,
and rarely, the cause is a birth defect, or an infection
leading to inflammation of the arteries (arteritis), or
physical damage (from an injury or radiation therapy).

46
Coronary Heart Disease
 CAD is the most common cause of myocardial
ischemia.
 CAD is the most common type of cardiovascular
disease, occurring in about 5 to 9% of people aged 20
and older.
 The death rate increases with age and overall is
higher for men than for women.
 After age 55, the death rate for men declines, and
the rate for women continues to climb.
 After age 70 to 75, the death rate for women exceeds
47

that for men who are the same age.

CHD—Risk Factors
 A- Nonmodifiable (major) risk factors:
 1- Advanced age: Men>45, Women >55
 2- Male gender or woman after menopause,
 3-
Family history (Genetics): CHD in first-degree
male relative <55, female <65

48
CHD—Risk Factors
 B- Modifiable risk factors:
 1- Dyslipidemia,
 2- Hypertension
 3- Cigarette smoking,
 4- Diabetes and insulin resistance,
 5- Obesity,
 6- Sedentary life-style,
 7- Atherogenic diet, 49

 8-Low high density lipoprotein (HDL) <40 mg/dl

CHD—Risk Factors
 C- Novel risk factors:
 1- Markers of inflammation and thrombosis,
 2- Hyperhomocysteinemia,
 3- Infection.

50
Progression of CHD Damage to
endothelium and
invasion of
macrophages

Smooth muscle
migration

Cholesterol
accumulates
around
macrophage and
muscle cells
Collagen and
elastic fibers
form a matrix
around the
cholesterol,
macrophages
and muscle 51
cells
CHD—Complications

 Myocardial infarction (MI)

 Unstable angina

 Dysrhythmias

 Sudden cardiac arrest

 Heart failure
Rationale for treatment of myocardial ischemia:

 Treatment of myocardial ischemia and the resulting angina

can involve two strategies:

 1. Increase coronary blood flow by dilating coronary

arteries.

 2. Reduce cardiac workload by reducing heart rate and/or

force of contraction
 The treatment regimen may include :
1. nonpharmacologic treatment
2. pharmacologic therapies.

Nonpharmacologic treatment

• Pacing of physical activity.

• Avoidance of stress (emotional, physiologic, cold).
• Reduction of risk factors for ischemic heart
disease, (hyperlipidemia, obesity, hypertension,
diabetes, smoking, etc.)
 Pharmacologic treatment

Organic Nitrates

Mechanism of action:

• Dilate coronary arteries and increase myocardial blood flow.

• Dilate peripheral arteries and reduce afterload.

• Dilate peripheral veins and reduce preload.

Examples

 Amyl nitrate, nitroglycerine, isosorbide dinitrite

 Route of administration : Inhalation, sublingual, oral, transdermal,

intravenous
 β-Adrenergic blockers

Mechanism of action:

 Block myocardial β-adrenergic receptors.

 Reduce heart rate and cardiac output (reduced myocardial workload

and oxygen demand).

Examples of β-Adrenergic Receptor Antagonists :

 May be selective β1 (atenolol), or

 nonselective β1 and β2 blockers (propranolol)

Major adverse effects :

 include bradycardia, reduced cardiac output, pacemaker

 depression and bronchoconstriction with nonspecific drugs

 Calcium channel blockers

Mechanism of action:
• Block calcium channels in vascular smooth muscle.
• Dilate coronary arteries and increase myocardial blood flow.
• Dilate peripheral arteries and reduce afterload.

• Examples: Dihydropyridines (nifedipine), verapamil, diltiazem

• Dihydropyridines have greater specificity for relaxing vascular smooth

muscle
• Verapmail and diltiazem have greater effects on cardiac pacemaker tissues

• Major adverse effects include headache, hypotension, reflex tachycardia;

risk of
• heart block of cardiac failure particularly with verapamil or diltiazem

• Also used for hypertension and arrhythmia

Afterload :The force that the contracting heart must generate to eject blood.
Affected by peripheral vascular resistance and arterial pressure.
 Aspirin

• Prevent platelet aggregation.

• Use for prophylaxis of blood clots particularly

in unstable angina.
Myocardial Infarction
Acute Coronary Syndromes
 When metabolic demand for
oxygen exceeds supply, the
myocardium becomes ischemic,
which leads to a dysfunction in
cardiac pumping and
predisposes to abnormal heart
rhythms.
 If the ischemic episode is severe
or prolonged, irreversible
damage to myocardial cells may
result in MI.
 Acute Coronary Syndromes

Unstable Angina Myocardial Infarction


 the occlusion is partial or the
clot is dissolved before the
death of myocardial tissue
the occlusion is complete and the thrombus
persists long enough for the development of
irreversible damage to myocardial cells, resulting
in necrosis

Both are characterized by chest pain that may be more severe and
lasts longer than the patient’s typical angina and may occur in
individuals whose disease was previously asymptomatic.
Myocardial Infarction

 MI results when prolonged or total disruption of blood

flow to the myocardium causes cellular death by
necrosis or apoptosis.
 An MI may occur at any age, but the frequency rises with
advancing age.
 Females younger than 45 years have a sixfold lesser risk of
MI than men of the same age. After menopause, the rate of
MI in women approaches that of their male counterparts
and becomes essentially equal by age 80.
MI-Pathophysiology
 The initiating event in most MIs is a sudden change in the
structure of the plaque. Platelets passing by the surface of the
ruptured plaque adhere to it, initiate the formation of a platelet
plug, and activate the clotting cascade. The resultant thrombus
grows until it occludes the vessel and triggers the MI because
of prolonged ischemia.
 Acute occlusion causes a range of cellular events, depending
on the availability and adequacy of collateral blood flow, the
relative workload, and the length of time that flow is
interrupted.
MI-Complications

 Arrhythmias (the most common complication of acute

MI)
 Cardiogenic shock
 Pericarditis
 Rupture of heart structures
 Aneurysm formation
 Thromboembolism
 Thrombolytic Agents Used Clinically

a. Streptokinase : Derived from β -hemolytic streptococcus

bacteria; involved in the activation of plasmin

b. Anistreplase (APSAC) : Complex of human lys-plasminogen and

streptokinase; Administered as a prodrug

c. Alteplase (TPA): Recombinant tissue plasminogen activator

d. Urokinase : Endogenous human enzyme that converts

plasminogen to active plasmin

e. Routes of administration : Intravenous. for all of the above

f. Major unwanted effects : Internal bleeding, gastrointestinal

bleeding, stroke, allergic reactions
 Pain Management in Myocardial Infarction

a. Sublingual nitroglycerin : Potent vasodilator of coronary

arteries, also dilates peripheral arteries and veins to
reduce preload and afterload on the heart
b. Morphine sulfate : Powerful opioid analgesic that also
provides a degree of sedation and vasodilatation;
although the opioid analgesics have little effect on the
myocardium, they are powerful respiratory depressants
 Aspirin

• Inhibits the cyclo-oxygenase pathway for the

synthesis of prostaglandins, prostacyclins and

thromboxanes.

• Inhibits aggregation of platelets and is effective in

reducing myocardial infarction, stroke and

mortality in high-risk patients.

HEART FAILURE
Heart Failure

 Heart failure is a disorder in which the heart pumps blood

inadequately, leading to reduced blood flow, back-up
(congestion) of blood in the veins and lungs, and other changes
that may further weaken the heart.
 Heart failure (HF) is defined as the pathophysiologic condition
in which the heart is unable to generate an adequate cardiac
output such that inadequate perfusion of tissues or increased
diastolic filling pressure of the left ventricle, or both, occurs;
consequently, pulmonary capillary pressures are increased.
Heart Failure- Risk factors

 Ischemic heart disease and hypertension are the most

important predisposing risk factors with 75% of HF cases
occurring in individuals with hypertension.

 Other risk factors include age, smoking, obesity, diabetes, renal

failure, valvular heart disease, cardiomyopathies, myocarditis,
congenital heart disease, and excessive alcohol use.
Heart Failure- Etiology

 Increased demands on heart cause failure

 Depends on ventricle most adversely affected
 Ex: Hypertension increases diastolic bp
Requires L ventricle to contract more forcibly to
open aortic valve
 Ex: Pulmonary disease
Damages lung caps, increases pulm resistance
Increase work load to R vent
80
Heart Failure- Etiology

 Causes of failure on the affected side:

Infarction that impairs pumping ability or efficiency of
the conduction system
Valve defects
Congenital heart defects
Coronary artery disease
Heart Failure- Classification

 1- congestive heart failure (left heart failure),

 2- right heart failure,
 3- high-output failure

82
Left-sided Heart Failure

 Left-sided heart failure occurs when the heart loses its

ability to pump blood.

 It often happens in people with high blood pressure and

certain heart conditions.

 It can result from systolic heart failure or diastolic heart

failure.
84
 LEFT
HEART
FAILURE-
SIGN &
SYMPTOMS
Right-sided Heart Failure

 Right heart failure (RHF) is a clinical syndrome in which

symptoms and signs are caused by dysfunction of the right
heart structures (predominantly the right ventricle [RV], but
also the tricuspid valve apparatus and right atrium) or impaired
vena cava flow, resulting in impaired ability of the right heart
to perfuse the lungs at normal central venous pressures.
93
 COR PULMONALE-
PATHOPHYSIOLOGY
 RIGHT
HEART
FAILURE-
SIGN &
SYMPTOMS
High Output Heart Failure

 High-output failure is the inability of the heart to

adequately supply the body with blood-borne
nutrients, despite adequate blood volume and normal
or elevated myocardial contractility.

 In high-output failure the heart increases its output but the

body’s metabolic needs are still not met.
COMPANSATORY
MECHANISMS
OF HEART
FAILURE
ACUTE RHEUMATIC FEVER &
RHEUMATIC HEART DISEASE
ACUTE RHEUMATIC FEVER

Autoimmune consequence of infection

with Group A streptococcal infection

Resultsin a generalised inflammatory

response affecting brains, joints, skin,
subcutaneous tissues and the heart.
104
ACUTE RHEUMATIC FEVER

 ARF is a delayed autoimmune response to Group A

streptococcal pharyngitis.

 Itis thought that 0.3-30% of untreated group A beta

haemolytic streptococcal infection progress to develop
acute rheumatic fever.

 ARF is thought to occur only after GAS infection of the

upper respiratory tract although this thinking has been
challenged by those working in tropical areas where skin
105

infections are rife.

ACUTE RHEUMATIC FEVER

 The clinical manifestation of the response and

its severity in an individual is determined by
host genetic susceptibility, the virulence of
the infecting pathogen and a conducive
environment.

 Currentlythe modified Duckett-Jones criteria

form the basis of the diagnosis of the condition.
Carapetis. Lancet 2005;366:155108
109
RHEUMATIC HEART DISEASE

Rheumatic Heart Disease is the

permanent heart valve damage
resulting from one or more attacks
of ARF.
It is thought that 40-60% of patients
with ARF will go on to developing
RHD.
RHEUMATIC HEART DISEASE

The commonest valves

affecting are the mitral and
aortic, in that order. However all
four valves can be affected.
RHEUMATIC HEART DISEASE

Sadly, RHD can go undetected

with the result that patients
present with debilitating heart
failure.
At this stage surgery is the only
possible treatment option.
RHEUMATIC HEART DISEASE

Patients living in poor countries

have limited or no access to
expensive heart surgery.
Prosthetic valves themselves are
costly and associated with a not
insignificant morbidity and mortality.
RHEUMATIC HEART DISEASE

 The main content of the activities focused around

early detection and treatment of sore throats and
streptococcal pharyngitis.

 Also, primary and secondary prevention of RF/RHD,

training of personnel, health education, dissemination
of information, community involvement and
epidemiological surveillance is important.
Primary Prevention of
Rheumatic Fever by Treating Streptococcal Pharyngitis

Antibiotic Administration Dose

Benzathine Single IM injection 1.2 MU > 30kg
benzyl penicillin 600 000 U < 30 kg
Phenoxymethyl PO for 10 days 250-500mg qds for 10 days
penicillin 125mg qds X 10 if <30 kg
(Pen VK)
Erythromycin PO for 10 days Use same dose as above.
ethylsuccinate

Oral penicillin is less efficacious than Penicillin IMI

Anaphylaxis is extremely unusual
 REFERENCES
1. Pathophysiology-The Biologic Basis for Disease in Adults and 11.
Children (2019) https://calgaryguide.ucalgary.ca/Left-Heart-Failure---Physical-Exam-Fi
ndings/
2. Karin C. VanMeter & Robert J. Hubert - Gould’s Pathophysiology
for the Health Professions-Saunders (2013) 12. https://www.cdc.gov/heartdisease/heart_attack.htm

3. Jacquelyn L Banasik – Pathophysiology. Saunders (2018) 13. Illustrated Textbook of Paediatrics, 18, 323-346. Cardiac Disorders.

4. John_E_Hall_-
_Guyton_and_Hall_Textbook_of_Medical_Physiology_2016
5. Lippincott Illustrated Reviews. Physiology(2019)
6. https://calgaryguide.ucalgary.ca/Atherosclerosis---Pathogenesis/
7. https://calgaryguide.ucalgary.ca/Atherosclerosis---Complications/
8. https://calgaryguide.ucalgary.ca/?s=hypertension
https://calgaryguide.ucalgary.ca/Overview-of-Ischemic-Heart-Disease/
9. https://calgaryguide.ucalgary.ca/Right-Heart-Failure/
10. https://calgaryguide.ucalgary.ca/Left-Heart-Failure---Pathogenesis/