HYPERTENSION: DEFINITION,CLASSIFICATION ANDPATHOPHYSIOLOGIC MECHANISMS

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

DEFINITION OF HYPERTENSION

General Considerations

· Both systolic and diastolic blood pressure criteria are used.

· Depends upon the level of pressure at which risks of blood pressure elevation are significantly increased.

· Individuals whose resting values of diastolic blood pressure remain persistently at or
above 90 mmHg and/or systolic blood pressure at or above 140 mmHg after repeated measurements are at increased risk of cardiovascular morbidity and mortality
(strokes, heart failure, myocardial infarction…).

· Blood pressure is extremely variable, raised blood pressure values should be confirmed
by repeated measurements over several weeks
(see section on sources of blood pressure variability, chapter 3).

· Patients with mild or borderline elevation of blood pressure need repeated confirmatory measurements over 3 to 12 months before labeling the patient as being hypertensive.

· Shorter observation periods (days or weeks) are required in patients with marked blood pressure elevations or in patients with complications (chapter 7, table).

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

CLASSIFICATION AND CATEGORIZATION OF HYPERTENSIVE PATIENTS

Purpose of Classification

Guide to Prognosis

Patients with organ damage (e.g., left ventricular hypertrophy, coronary atherosclerosis,
fundus retinal changes) or with other cardiovascular risk factors
(e.g., diabetes mellitus, hypercholesterolemia, cigarette smoking) have a worse prognosis.

Guide to Decision for Initiating Treatment

Classifying patients as having severe hypertension, or having organ damage or presence
of risk factor is an indication to start drug therapy at a shorter period of observation and
at lower initial blood pressure levels.

Guide to Type of Treatment

Etiology, mechanisms responsible for/or contributing to hypertension
(pathophysiologic mechanisms), severity of blood pressure, type and extent of organ
damage, associated disease conditions may influence the choice of treatment.

Basis and Types of Classification

1. Severity of hypertension as judged by:
a. Blood pressure level.
b. Optic fundus changes.

2. Etiology.

3. Target organ damage.

4. Pathophysiologic mechanisms.

5. Hemodynamic mechanisms.

6. Presence of other cardiovascular risk factors. Hypertension: Definition, Classification
and Pathophysiologic Mechanizms

Definitions and Classification of Blood Pressure Levels (mmHg)

Hypertension diagnosis is based on the average of two or more readings taken at each
of two or more visits after initial screening.

Classification By Optic Fundus Changes

Retinal vessels and optic fundus should be examined in a systematic way. Changes in
optic fundus reflect the following:

1. Severity of hypertension.

2. Duration of hypertension.

3. Persistence of hypertension.

4. Course of hypertension: accelerated or malignant.

5. Other concomitant disease, e.g., diabetes mellitus.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Grading of Optic Fundus Changes: (Keith–Wagner–Barker)

Grade 0 Normal

Grade 1 Minimal disease: spasm, silver wire appearance, tortiousity, and constrictions.

Grade 2 Grade 1 + evidence of arteriolar sclerosis: heightened light reflex, arteriovenous
nicking (indentation and constriction of the vein at site of arteriovenous crossing).

Grade 3 Hemorrhages and exudates in addition to the above. When present, hypertension
is classified as accelerated.

Grade 4 Papilledema (edema of the optic disc). This is a sign pathognomonic of malignant
hypertension.

Classification by Etiology

Primary or Essential

· Occurs among 95-99% of all hypertensive patients.

· Has no identifiable cause.

· Hereditary factors and salt intake contribute to its development.

· Can be controlled but not cured.

Secondary

· Has identifiable cause, which may be correctable, e.g., primary aldosteronism, pheochromocytoma, renal artery stenosis, coarctation of the aorta and oral contraceptives
or other identifiable causes, which are uncorrectable such as chronic renal disease.

· Some conditions such as severe emotions, drugs, exogenous substances, (chapter 3)
can produce transient and sometimes severe elevations of blood pressure in a healthy subject. Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Causes of Secondary Hypertension

1. Renal Disease

a. Renal parenchymal – responsible for 3 to 4% of cases of hypertension, it includes
renal trauma, congenital hypoplastic or atrophic kidney, polycystic disease, acute
glomerulonephritis, collagen disease and vasculitis, chronic renal failure, renal tumors,
pyelonephritis, hydronephrosis, analgesic nephropathy, etc.

b. Renovascular – renal artery stenosis responsible for 0.5 -1.0% of hypertension cases.
It is due to atheroma in 90%, fibromuscular dysplasia in 10% and rarely due to embolism
, and compression.

2. Endocrine Disease (0.1- 0.3 %)
a. Primary aldosteronism.
b. Thyroid diseases.
c. Cushing syndrome.
d................................................................................. Pheochromocytoma.
e. Acromegaly.
f. Hyperparathyroidism.

3. Pregnancy Induced Hypertension.

4. Neurologic Disorders
Sleep apnea, brain tumors, increased intra-cranial tension, cerebrovascular accidents,
head trauma, quadriplegia, carotid sinus denervation (surgical complication) and brain
stem encephalitis.

5. Surgery
Open heart and coronary artery bypass.

6. Coarctation of the Aorta.

7. Exogenous Substances or Drugs. (Chapter 3)

8. Others.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms 

Classification By Target Organ Damage [TOD]

Staging of hypertension based upon the presence and extent of damage to organs,
which are likely to suffer from high blood pressure as heart, kidney, brain, retina, aorta
and blood vessels.

Presence of TOD carries a bad prognosis and is an indication for early and aggressive
control of blood pressure.

WHO GRADING (old)

Stage I: No manifestation of TOD.

Stage II: At least one of the following manifestations of TOD:
Heart: Left ventricular hypertrophy.

Optic Fundi: Generalized and focal narrowing of retinal arteries.

Kidney: Microalbuminuria, proteinuria and/or slight elevation of plasma creatinine concentration (1.2 – 2.0 mg/dl).

Vessels: Ultrasound or radiological evidence of atherosclerotic plaques
(aorta, carotid, iliac or femoral arteries).

Stage III: Both symptoms and signs have appeared as a result of TOD. Heart:
Angina pectoris.

Myocardial infarction.

Heart failure.

Brain: Stroke.

Transient ischemic attacks.

Hypertensive encephalopathy.

Vascular dementia.

Optic Fundi: Retinal hemorrhages and exudates.

Papilledema.

Kidney: Plasma creatinine concentration more than 2.0 mg/dl.

Renal failure.

Vessels: Dissecting aortic aneurysm.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Symptomatic arterial - occlusive disease. Classification by the Presence of other Cardiovascular Risk Factors

Risk factors other than hypertension are more prevalent among hypertensives than normotensives.

* Data from Egyptian NHP surveys (Ibrahim et al, 2001).

The presence of associated risk factors carry a bad prognosis and it is more than additive
but rather multiplicative, i.e. minor degrees of several risk factors may interact to have a severe impact on the risk for the individual.

Hypertensive patients can be classified into three groups based on the presence and type
of concomitant risk factors:

1. No risk factors present: isolated hypertension is uncommon present in less than 30%
of hypertensive patients.

Part of the metabolic hypertension syndrome (syndrome X):
a. Hypertension.
b. Upper body obesity.
c. Impaired glucose tolerance (insulin resistance).
d. Increased plasma triglycerides.
e. Decreased plasma HDL–Cholesterol. 3. Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Associated with other risk factors:
a. Cigarette smoking.
b. Diabetes mellitus.
c............................................................................. Hypercholesterolemia.
d. Positive family history of strokes and severe cardiovascular events at young age.
e. Sedentary life style.
f................... Abnormalities in blood coagulation: increased fibrinogen, 

increased platelet activity and increased plasminogen activator inhibitor activity.

Patients in groups 2 and 3 require early and aggressive treatment of hypertension even
in the presence of mild elevation of blood pressure together with correction of associated
risk factors.

Global Risk Stratification

The risk for cardiovascular disease in hypertensive patients is determined not only by the
level of blood pressure but also by the presence or absence of target organ damage or
other risk factors such as smoking, dyslipidemia, and diabetes.

1. Low Risk Group

- Men below 55 and women below 65 years of age with grade 1 hypertension and no
target organ damage and no other risk factors.

- The risk of a major cardiovascular event in this group in the next 10 years is less than 15%.

2. Medium Risk Group

- Patients with hypertension (grade 1-3) who have no target organ damage but have one or more of the cardiovascular risk factors but not diabetes mellitus.

- The risk of a major cardiovascular event over the next 10 years is about 15-20%. The risk
will be closer to 15% in those patients with Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Grade 1 (mild) hypertension and only one additional risk factor.
3. High Risk Group
- Patients with hypertension and target organ damage or diabetes or have three more risk
factors, or clinical cardiovascular disease. The risk of a major cardiovascular event in the
next 10 years is more than 20%.

Classification by Pathophysiologic Mechanism

Blood pressure is controlled by a number of regulatory body systems, which act to maintain
it in normal range in spite of changing environmental conditions, the most important of
these are:

1. The kidneys.

2. The endocrine, paracrine and autocrine hormonal systems.
3. The sympathetic nervous system.

The Renin–Angiotensin–Aldosterone System
The kidneys play an important role in blood pressure control through the activity of the renin–angiotensin–aldosterone system (RAS). The components of this system are:

Renin: a proteolytic enzyme secreted by the juxta-glomerular apparatus in the kidneys and
by possibly other tissues.

Angiotensinogen: the renin enzyme substrate is a globulin (tetradecapeptide) formed mainly
in the liver.

Angiotensin I: a peptide made of 10 amino acids (decapeptide) formed from Angiotensinogen
through the action of renin.

Angiotensin II (AII): a peptide made of 8 amino acids (octapeptide) formed from angiotensin
I through the action of a converting enzyme present in many tissues mainly the endothelium
of pulmonary vessels.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Angiotensin II has many actions: 1. Directly constricts blood vessels.

2. Stimulates the sympathetic nervous system.

3. Stimulates aldosterone (a sodium retaining hormone) production from the adrenal cortex.

4. Actions on central nervous system such as thirst and vasopressin stimulation.

5. Growth promoting actions in heart and vascular smooth muscles.

6. Increase oxidative stress, proinflammatory and proatherogenic effects.

Renin production is stimulated by:

1. Decrease in blood pressure.

2. Increase in sympathetic stimulation.

3. Reduction of sodium delivery to the juxta glomerular apparatus in the kidney.

4. Decrease in blood volume.

5. Hypokalemia.

6. Prostaglandin E2 and prostacyclin.

Role of Salt Excess:

The following is the sequence of events that follows when a normal individual increases his
salt and water intake:

· Expansion in blood volume and increase in venous return.

· Increase in cardiac output (CO) and blood flow to the tissues.

· Increase in blood pressure (Blood Pressure = CO × PR).

· Peripheral arterioles constrict as an auto regulatory mechanism to limit the excessive
flow and tissue perfusion.

· Further rise in blood pressure.

· Higher blood pressure increases sodium and water excretion through the kidneys.

· Over a period of few days the salt and water output in urine will equal salt and water intake. Hypertension: Definition, Classification and Pathophysiologic Mechanizms

· Blood volume and cardiac output will return to normal. Blood pressure will return to normal.

Furthermore, expansion of blood volume through excessive salt and water intake would suppress renin production, which diminishes Angiotensin II formation. Diminished A II generation increases renal blood flow through decrease of renal vasoconstriction and diminishes aldosterone production. Both actions increase sodium and water excretion via the kidney with subsequent reduction of blood volume and its return to its original size.

In some salt–sensitive hypertensive patients, the above sequence of events does not occur.
In these patients there is no increase in renal blood flow and no sodium diuresis in response to high salt diet with subsequent rise in blood pressure.

Sodium intake is a very important determinant of plasma renin activity. It is recommended
when measuring plasma renin to relate it to 24–hours urinary sodium excretion.

Based upon plasma renin activity patients with essential hypertension are classified into
three groups:

1. High renin: 15%

2. Low renin: 25%

3. Normal renin: 65%

Causes of High Plasma Renin Activity

With Hypertension

· Malignant hypertension.

· Renovascular hypertension.

· Renal parenchymal hypertension with renin over secretion.

· Essential hypertension: 15%.

· Pheochromocytoma, renin-secreting tumors. Hypertension: Definition, Classification
and Pathophysiologic Mechanizms

WITHOUT HYPERTENSION

· Edematous states: Congestive heart failure, nephrotic syndrome, and liver cirrhosis
with ascites.

· Hypokalemic state: Renal tubular acidosis, nephropathies.

· Sodium depletion: Diuretics, laxatives.

· Converting enzyme inhibitor therapy (High renin and A I, but low A II).

· Barttar’s syndrome: Metabolic alkalosis, hypokalemia, high plasma aldosterone,
and normal blood pressure. There is a defect in NaCl re-absorption in thick ascending
limb of Henle’s loop in the kidney.

· Psychogenic vomiting.

Causes Of Low Plasma Renin Activity (Volume Dependent Hypertension)

1. Hyperaldosteronism and mineralocorticoid excess.

2. Essential hypertension: 25%.

3. Renal insufficiency (some patients), bilateral nephrectomy and end stage renal disease.

4. Expansion of blood volume.

5. Excessive sodium intake.

6. Treatment with sympatholytics, excessive licorice intake.

7. Black race.

8. Old age.

9. Rare Syndromes:

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

· Liddle’s Syndrome

· Gordon’s Syndrome

The Sympathetic Nervous System

Increased sympathetic adrenergic activity can cause rapid and dramatic blood pressure changes but they are usually of short duration. Sympathetic adrenergic stimulation
increases blood pressure through:

1. b1–adrenergic receptors stimulation increases heart rate and cardiac output.

2. ±-adrenergic receptors stimulation increases peripheral arterial constriction.

Manifestations of increased sympathetic activity:

1. Tachycardia.

2. Hyperdynamic heart: forcible heart action, functional systolic murmur.

3. Excessive sweating: palms and feet.

4. Big arterial pulse pressure.

5. Increased plasma noradrenaline level.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms 

Hypertension associated with increased sympathetic activity

1. Young patients with hypertension.

2. Borderline and labile hypertension.

3. Obese hypertensives.

4. White coat (office) hypertension.

5. Severe blood volume depletion: diuretics.

6. Direct arterial vasodilators.

7. Pheochromocytoma.

8. Sympathomimetics.

9. Monoamine oxidase inhibitor therapy combined with tyramine rich foods.

Many patients in this category respond better to ²-adrenergic blockers and sympatholytics.

Salt Sensitivity

Hypertensive patients can be classified into:

· Salt sensitive.

· Salt resistant.

Salt sensitive individuals change their blood volume and arterial pressure according to
dietary salt intake.

Salt sensitivity is defined as “Reduction in blood pressure equal to or greater than 10% between a salt restricted diet (10 mEq/day) for one week and high salt diet (250 mEq/day)
for the following week”.

- Restriction of salt intake below 6 gm per day decreases blood pressure in many hypertensive patients.

- Salt sensitive individuals are likely to develop hypertension as a result of excess salt in diet.

- Possible mechanisms of salt sensitivity: see page 29.

- Salt sensitivity is present in 40% of patients with essential hypertension.

- There is a wide spectrum of salt sensitivity in the hypertensive population from none,
mild to severe.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Salt sensitivity is more common in the following groups: 1. Elderly.

2. Blacks.

3. Insulin dependant diabetes.

4. Secondary forms of hypertension: Mineralocorticoid hypertension, end stage renal
failure dialysis patients.

Diuretics and salt restriction can control hypertension in the previous groups.

Excess Body Fat (Obesity)

Hypertensive patients can be classified into:

1. Obese hypertensives.

2. Lean hypertensives.

Obesity is a known predisposing factor to hypertension. Possible mechanisms of hypertension in obesity:

1. High cardiac output secondary to a large blood volume and increased sympathetic activity.

2. High dietary salt intake.

3. Increased sympathetic activity secondary to hyperinsulinemia and increased caloric intake.

4. Hyperinsulinemia: Hyperinsulinemia (insulin resistance) is common in obese individuals. Insulin resistance means that for any given intake of carbohydrates, the blood insulin level rises higher than it should. Insulin can increase blood pressure through:
a. Increased sympathetic activity.
b. Sodium retention by direct action on renal tubules.
c. Vascular hypertrophy: growth-stimulating effects of insulin on

vascular smooth muscles can decrease blood vessels lumen diameter.

Hypertension: Definition, Classification and Pathophysiologic Mechanizms

Obesity is assessed by measuring body mass index (BMI), which is the

ratio of body weight in Kg/height in meters squared (Kg/m²).

· BMI > 30 Kg/m² indicates obesity.

· BMI 25 – 30 Kg/m² indicates overweight.

Body fat distribution (intra-abdominal visceral and abdominal wall) is more strongly related
to hypertension than BMI, assessed by measuring waist circumference and hip
circumference and obtaining waist/hip ratio. Increase of waist/hip ratio (> 0.85 in female)
and (> 0.95 in male) is an important cardiovascular risk factor and is a predictor of
strokes and ischemic heart disease.

Classification By Hemodynamic Profile

Blood Pressure = Cardiac output X peripheral arterial resistance.

Hypertensive patients can be classified according to the level of cardiac output into:

1. Normal.

2. Low.

3. High.

Increase in blood pressure in the majority of hypertensives is secondary to increase in
peripheral arterial resistance.

Cardiac output is normal in most hypertensives.

Low output is present in hypertension complicated by heart failure.

High cardiac output hypertension is present in some of the following conditions:

· Young hypertensives.

· Early and borderline hypertension.

· Obese.

· Renal Failure: Increased cardiac output secondary to anemia andhypervolemia.

· Treatment with direct arterial vasodilators

· Hyperthyroidism.

PR = Systemic peripheral resistance

Liddle’s Syndrome: Hypertension, hypokalemic alkalosis, muscle weakness, suppressed plasma aldosterone. Responds to triametrene therapy. Defect in Na – K exchange in renal tubule.

Gordon’s Syndrome: Hypokalemia, hypertension, distal renal tubular acidosis, retardation of development, elevated aldosterone. Responds to salt restriction and thiazide diuretics.