Lecture 8 hypertension - Pathology

1. Hypertension
Lecture 8
Problem Magnitude
 Hypertension (HTN) is the most common primary diagnosis in America.
 35 million office visits are as the primary diagnosis of HTN.
 50 million or more Americans have high BP.
 Worldwide prevalence estimates for HTN may be as much as 1 billion.
 7.1 million deaths per year may be attributable to hypertension.
Hypertension
 The purpose of the control of blood pressure is to keep blood flow constant to vital
organs such as the heart, brain, and kidneys.
 Without constant flow to these organs, death occurs within seconds, minutes, or days.
 Although a decrease in flow produces an immediate threat to life, the continuous
elevation of blood pressure that occurs with hypertension is a contributor to premature
death and disability due to its effect on the heart, blood vessels, and kidneys.
197

2. Control of Blood Pressure
 The arterial blood pressure reflects the rhythmic ejection of blood from the left
ventricle into the aorta.
 It rises as the left ventricle contracts and falls as it relaxes.
 In healthy adults, the highest pressure, called the systolic pressure, ideally is less than
120 mm Hg,
 and the lowest pressure, called the diastolic pressure, is less than 80 mm Hg.
 The difference between the systolic and diastolic pressure (approximately 40 mm Hg)
is the pulse pressure.
 The mean arterial pressure (approximately 90 to 100 mm Hg), represents the average
pressure in the arterial system during ventricular contraction and relaxation (Cardiac
Cycle)
 Mean arterial pressure = diastolic pressure + pulse pressure/3.
198

3. MAP Clinical significance
 MAP is a useful concept because it can be used to calculate overall blood flow, and thus
delivery of nutrients to the various organs. It is a good indicator of perfusion pressure
(ΔP) seen by organs in the body
 Perfusion is the process of nutritive delivery of arterial blood to a capillary bed in the
tissue.
 Tests of adequate perfusion are a part of the patient assessment process performed by
medical or emergency personnel.
 The most common methods include evaluating skin color, temperature, condition and
capillary refill.
 It is believed that a MAP that is greater than 60 mmHg is enough to sustain the organs
of the average person.
 If the MAP falls significantly below this number for an appreciable time, the end organ
will not get enough blood flow, and will become ischemic.
Determinants of Blood Pressure
 The systolic and diastolic components of blood pressure are determined by the cardiac
output and the peripheral vascular resistance.
 Cardiac output is the volume of blood pumped by the heart per minute (mL
blood/min).
 The stroke volume is the volume of blood, in milliliters (mL), pumped out of the heart
with each beat.
 The heart rate is simply the number of heart beats per minute.
 Increasing either stroke volume or heart rate increases cardiac output.
 Cardiac output of an adult male ranges from 4.5 to 8 L/minute.
 Cardiac Output in mL/min = Stroke volume (mL/beat) X Heart rate (beats/min)
 An average person has a resting heart rate of 70 beats/minute and a resting stroke
volume of 70 mL/beat.
 The cardiac output for this person at rest is:
 Cardiac Output = 70 (mL/beat) X 70 (beats/min) = 4900 mL/minute.
 The total volume of blood in the circulatory system of an average person is about 5
liters (5000 mL).
 According to our calculations, the entire volume of blood within the circulatory system is
pumped by the heart each minute (at rest).
199

4.  During vigorous exercise, the cardiac output can increase up to 7 fold (35
liters/minute).
Definition
 A systolic blood pressure ( SBP) >139 mmHg and/or
 A diastolic (DBP) >89 mmHg.
 Based on the average of two or more properly measured, seated BP readings.
 On each of two or more office visits.
The progression of essential hypertension is as follows:
1) Prehypertension in persons aged 10-30 years (by increased cardiac output)
2) Early hypertension in persons aged 20-40 years (in which increased peripheral
resistance is prominent)
3) Established hypertension in persons aged 30-50 years
4) Complicated hypertension in persons aged 40-60 years
200

5. Classification of Hypertension
 Primary (Essential) Hypertension
 No identifiable cause of hypertension, it is most often the result of complex
interactions between multiple genetic and environmental factors.
 The onset is usually between ages 25 and 55 years; it is uncommon before age 20
years.
 Secondary Hypertension
 Those previously well controlled who become refractory to treatment.
201

6. Cardiac output and peripheral resistance
 Maintenance of a normal blood pressure is dependent on the balance between the
cardiac output and peripheral vascular resistance.
 The hemodynamic hallmark of established essential hypertension is elevated
peripheral vascular resistance.
 An increase in cardiac output is occasionally noted early but is not a persistent
finding.
 Peripheral resistance is determined not by large arteries or the capillaries but by
small arterioles, the walls of which contain smooth muscle cells.
 Prolonged smooth muscle constriction is thought to induce structural changes with
thickening of the arteriolar vessel walls possibly mediated by angiotensin, leading to
an irreversible rise in peripheral resistance.
202

7. Mechanisms of Hypertension
The pathogenesis of essential hypertension is multifactorial and highly complex
203

8. Causes of Hypertension
 Primary– 90-95% of cases – also termed “essential” or “idiopathic”
 Secondary – about 5% of cases
 Renal parenchymal 2-3%
 Renovascular disease 1-2%
 Endocrine disease 0.3-1%
o Pheochromocytoma
o Cushings syndrome
o Conn’s syndrome (Primary Hyperaldosteronism)
o Acromegaly and hypothyroidism
 Vascular
o Coarctation of the aorta
o Nonspecific aortoarteritis
 Iatrogenic 0.50%
o hypertension associated with pregnancy,
o Hormonal / oral contraceptive
o Hypercalcemia (may be caused by renal insufficiency, calcium-mediated
vasoconstriction, or both).
o Medications (NSAIDs)
Other Patterns of Hypertension
 White coat or office hypertension may account for as many as 20% of elevated blood
pressures and is associated with an increased cardiovascular risk.
 Isolated systolic hypertension (ISH), defined as a systolic blood pressure >160 mm Hg
and a diastolic blood pressure >90 mm Hg, is a far greater risk factor for the
development of cardiovascular disease than is the diastolic blood pressure.
 The systolic blood pressure increases in a linear fashion throughout life, whereas, the
diastolic blood pressure increases until 50 years of age and falls thereafter.
 This phenomenon is thought to reflect a gradual decrease in arterial compliance
(elasticity) over time (due to remodeling and calcification of the vessel wall).
204

9.  The decrease in compliance with age and menopause. causes an increase in blood
pressure during systole and a decrease during diastole (because of loss of the elastic
recoil which augments pressure during diastole).
 Because a decrease in compliance in the vessel is related to vascular remodeling and
calcification, ISH is a de facto clinical marker of injury in the vessel wall.
Secondary Hypertension
1) Renovascular disease (Renal artery stenosis)
 Renal artery disease can cause of narrowing of the vessel lumen (stenosis). This
stenosis reduces the pressure at the afferent arteriole in the kidney. Reduced arteriolar
pressure and reduced renal perfusion stimulate Renin release by the kidney.
 This increases circulating angiotensin II (AII) and aldosterone. These hormones
increase blood volume by enhancing renal reabsorption of sodium and water.
 Increased AII causes systemic vasoconstriction and enhances sympathetic activity.
 Chronic elevation of AII promotes cardiac and vascular hypertrophy.
 The net effect of these renal mechanisms is an increase in blood volume that
augments cardiac output by the Frank-Starling mechanism.
 Therefore, hypertension caused by renal artery stenosis results from both an increase
in systemic vascular resistance and an increase in cardiac output.
2) Chronic renal disease
 Diabetic nephropathy or Glomerulonephritis can damage nephrons in the kidney.
 When this occurs, the kidney cannot excrete normal amounts of sodium which leads
to sodium and water retention, increased blood volume, and increased cardiac output
by the Frank-Starling mechanism. Renal disease may also result in increased release
of renin leading to a renin-dependent form of hypertension.
 The elevation in arterial pressure secondary to renal disease can be viewed as an
attempt by the kidney to increase renal perfusion and restore glomerular filtration.
3) Secondary Hypertension (Endocrine)
 Pheochromocytoma is a rare (2 to 8 cases per 1 million persons per year)
 adrenaline-producing tumor that arises from the Adrenal medulla. High levels of
Catecholamines (Norepinephrine). <0.2% of cases of hypertension; all ages ,mainly
30-50 years.
 Headaches, Palpitations, Diaphoresis, Severe hypertension
 Cushing's syndrome is a collection of symptoms that develop due to very high levels
of cortisol hormone.
 Conn syndrome (Primary aldosteronism): HTN, Low K, caused by aldosterone-
producing adenoma (80% of cases) usually unilateral and solitary.
205

10. 4) Vascular Hypertension: Coarctation of the aorta
 It is a congenital condition whereby the aorta narrows in the area where the ductus
arteriosus (ligamentum arteriosum after regression) inserts.
 The word “coarctation” means narrowing.
206

11. Patent ductus arteriosus
 In the developing fetus, the mother provides oxygen and the baby's lungs are filled with
fluid.
 Blood flow bypasses the lungs through a blood vessel that connects the pulmonary artery
(1) with the aorta (2). This blood vessel is called the ductus arteriosus (3).
 When the lungs inflate at birth, blood flows through the pulmonary vessels and the ductus
arteriosus occludes.
 When it remains open after birth it is called a patent ductus arteriosus. In most babies
it remains open for a short period of time after birth but 90% will be closed by 8 weeks of
age. Most of the rest will close during the first year of life.
 In about 1 of every 5500 births this duct fails to close properly and remains patent.
 The presence of this duct allows for the backflow of aortic blood into the pulmonary
artery. The turbulent blood flow can be detected on auscultation as a murmur.
 If not corrected, the continued pulmonary congestion places an excess workload on the
heart that can result in heart failure years later.
 Surgical correction of patent ductus arteriosus is relatively simple and essentially
involves ligation of the ductus arteriosus.
207

12. Physiological mechanisms involved in development of essential hypertension
1) Cardiac output } discussed before
2) Peripheral resistance } discussed before
3) Renin-angiotensin-aldosterone system
4) Autonomic nervous system
5) Other factors:(will be discussed by Endothelial dysfunction)
A. Bradykinin
B. Endothelin
C. EDRF (endothelial derived relaxing factor) or
D. Nitric Oxide
E. ANP (atrial natriuretic peptide)
F. Ouabain
208

13. 3) Renin-Angiotensin-Aldosterone system (RAAS) Summary
Renin-angiotensin system (Detailed Figure)
209

14.  The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system
(RAAS) is a hormone system that regulates blood pressure and water (fluid) balance.
 When blood volume is low, the kidneys secrete an enzyme called renin.
 Renin stimulates the production of angiotensin.
 Angiotensin causes blood vessels to constrict resulting in increased blood pressure.
 Angiotensin also stimulates the secretion of the hormone aldosterone from the
adrenal cortex.
 Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium
and water.
 This increases the volume of fluid in the body, which also increases blood pressure.
 If the renin-angiotensin-aldosterone system is too active, blood pressure will be too
high.
 The system can be activated when there is a loss of blood volume or a drop in blood
pressure (such as in hemorrhage).
 If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa
decreases, then the juxtaglomerular cells release the enzyme renin.
 Inhibitors of angiotensin-converting enzyme (ACE inhibitors) are often used to
reduce the formation of the more potent angiotensin II. Captopril is an example of an
ACE inhibitor.
 Alternatively, angiotensin receptor blockers (ARBs) can be used to prevent
angiotensin II from acting on angiotensin receptors.
 Direct renin inhibitors are aliskiren
4) Autonomic nervous system
 Sympathetic nervous system (which is a part of autonomic nervous system)
stimulation can cause both arteriolar constriction and arteriolar dilatation.
 Thus it has an important role in maintaining a normal blood pressure.
 It is also important in the mediation of short term changes in blood pressure in
response to stress and physical exercise.
 Autonomic nervous system: A part of the nervous system that regulates key
involuntary functions of the body, including the activity of the heart muscle; the
smooth muscles, including the muscles of the intestinal tract; and the glands
(breathing, the heartbeat, and digestive processes)
210

15. 5) Endothelium
 The endothelium is the inner lining of the arterial wall that comes in direct contact
with the blood.
 It is composed of a single layer of simple squamous lining cells and polygonal in
shape.
 A healthy endothelial protects against atherosclerosis.
 Nitrite oxide causes the blood vessels to dilate in order to increase blood flow.
Abnormal endothelial function causes a reduction in the secretion of nitric oxide.
Lack of nitrite oxide causes the blood vessels to constrict instead.
Endothelial Function
 The healthy endothelium is optimally placed and is able to respond to physical and
chemical signals by production of a wide range of factors that regulate vascular tone,
cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel
wall inflammation.
 A healthy endothelium maintains a balance between all these different forces. It is
normal to have a certain level of constriction, of inflammation, but it should be in
balance with all the other functions.
 Endothelial dysfunction defined as an imbalance between vasodilating and
vasoconstricting substances produced by (or acting on) the endothelium. It may be
the result of an injury from high blood glucose, high blood pressure, high cholesterol,
smoking, or those cytokines and substances released from visceral fat.
211

16. 212

17. Endothelial Vasoactive Substances
Vascular endothelial cells play a key role in cardiovascular regulation by producing a
number of potent local Vasoactive Substances:
 Bradykinin is a potent endothelium-dependent vasodilator, leading to a drop in blood
pressure.
o It also causes contraction of non-vascular smooth muscle in the bronchus and
gut, increases vascular permeability.
o Bradykinin also causes natriuresis (excretion of sodium in the urine),
contributing to the drop in blood pressure.
o Bradykinin is also thought to be the cause of the dry cough in some patients
on angiotensin-converting enzyme (ACE) inhibitor drugs.
o It is thought that bradykinin is converted to inactive metabolites by ACE,
therefore inhibition of this enzyme leads to increased levels of bradykinin,
which causes a dry cough via bronchoconstriction.
 Endothelin is a powerful, vascular, endothelial vasoconstrictor, which may produce
a salt sensitive rise in blood pressure. It also activates local rennin angiotensin
systems.
 Endothelial derived relaxant factor (EDRF) or Nitric Oxide (NO), is produced by
arterial and venous endothelium and diffuses through the vessel wall into the smooth
muscle causing vasodilatation
 Atrial natriuretic peptide is a hormone secreted from the atria of the heart in
response to increased blood volume.
o Its effect is to increase sodium and water excretion from the kidney as a sort of
natural diuretic.
o A defect in this system may cause fluid retention and hypertension.
o Sodium transport across vascular smooth muscle cell walls is also thought to
influence blood pressure via its interrelation with calcium transport.
 Ouabain may be a naturally occurring steroid›like substance which is thought to
interfere with cell sodium and calcium transport, giving rise to vasoconstriction.
213

18. Endothelium-Derived Contracting Factors (EDCFs) include endothelin-1, angiotensin II,
thromboxane A2 (TxA2), prostaglandin H2, and reactive oxygen species (ROS).
HTN Risk Factors
 Although the cause or causes of essential hypertension are largely unknown, several
constitutional factors have been implicated as contributing to its development.
 These risk factors include family history of hypertension, race, diabetes mellitus, and
age-related increases in blood pressure.
 Hypertension not only is more prevalent in African Americans than whites, it is more
severe, tends to occur earlier, and often is not treated early enough or aggressively
enough. Blacks also tend to develop greater cardiovascular and renal damage at any level
of pressure.
 Diabetes mellitus and hypertension are closely interrelated disorders that share similar
genetic and life-style factors.
 Lifestyle Factors: These lifestyle factors include high sodium intake, excessive calorie
intake and obesity, physical inactivity, and excessive alcohol consumption.
 Oral contraceptive drugs also may increase blood pressure in predisposed women.
214

19.  Although stress can raise blood pressure acutely, there is less evidence linking it to
chronic elevations in blood pressure.
 Dietary fats and cholesterol are independent risk factors for cardiovascular disease, but
there is no evidence that they raise blood pressure.
 Smoking, although not identified as a primary risk factor in hypertension, is an
independent risk factor in coronary heart disease and should be avoided.
Manifestations of Hypertension
 Essential hypertension is typically an asymptomatic disorder.
 When symptoms do occur they are usually related to the long- term effects of
hypertension on other organ systems of the body including the kidneys, heart, eyes, and
blood vessels.
 Diastolic blood pressure is the best predictor of cardiovascular disease in young people.
 Systolic blood pressure is the dominant predictor of risk of cardiovascular disease in
older people
215

20. Hypotension
 Hypotension is an abnormally low blood pressure.
 One common form of hypotension is orthostatic hypotension (also called postural
hypotension) that occurs upon standing.
 Orthostatic hypotension is a systolic blood pressure decrease of at least 20 mm Hg or a
diastolic blood pressure decrease of at least 10 mm Hg within three minutes of standing.
 In healthy persons, muscle contraction increases venous return of blood to the heart
through one-way valves that prevent blood from pooling in dependent parts of the body.
 The autonomic nervous system responds to changes in position by constricting veins and
arteries and increasing heart rate and cardiac contractility.
 When these mechanisms are faulty or if the patient is hypovolemic, orthostatic
hypotension may occur.
 More common in: Elderly pts with systolic HTN , DM, Pts on diuretics, vasodilators, or
some psychotropic drugs
 In persons with orthostatic hypotension, gravitational opposition to venous return causes
a decrease in blood pressure and threatens cerebral ischemia.
Causes of Orthostatic Hypotension
1) Aging — Associated with reduced baroreceptor responses, decreased cardiac output and
reduced vascular responsiveness
2) Decreased blood or fluid volume — Caused by dehydration, diarrhea, diuretic use
3) Autonomic nervous defects — An inability to initiate vasoconstriction and increased
heart rate reflexes
4) Prolonged bed rest — Associated with reduced plasma volume, decreased vascular tone
5) Drug-induced — Examples: antihypertensive drugs, calcium channel blockers,
vasodilators
6) Idiopathic — Cause is not known
Orthostatic hypotension
 Manifestations
 Dizziness (syncopy)
 Decreased cardiac output
 Reduced brain blood flow
216

21.  Pooling of blood in the extremities
 Falls and injuries, particularly in elderly individuals
 Treatment
 Maintain fluid volume.
 If patient is lying down, have the patient first sit for several minutes to allow blood
pressure to equilibrate, then have patient stand slowly.
 Provide elastic support garments and stockings that may help prevent pooling of blood in
the lower extremities.
--------------------------------
217