Cardiovascular Hypertension training

CVS Medical Training
Ahmed Radwan

2
Contents
• Introduction
• The Cardiovascular System
• What Is Blood Pressure?
• Primary Systems in Blood Pressure Regulation
• Hypertension and its Complications

3
INTRODUCTION
• This module will provide the background you need to understand the role
of MS Pharma CVS Portfolio in controlling Cardiovascular risk and thus
minimizing the risks of cardiovascular disease.
• Left uncontrolled risks is a substantial contributor to the development of
cardiovascular disease and its associated manifestations, such as Myocardial
Infarction, Angina, Cerebrovascular accident (Stroke) and Congestive heart
failure.

The principal component of cardiovascular system
2. Blood Vessel
1. Heart
3. Blood

Layers of heart:
-Heart lies a protective sac of tissue
called Pericardium
1. Epicardium.
2. Myocardium.
3. Endocardium.
-Septum is separates between
the right & left halves.
Heart
Basic Anatomy Of The Heart

Chambers of the heart:
• 2 chambers on the right side.
• 2 chambers on the left side.
Heart valves:
• The atrioventricular valves
(tricuspid,mitral)
• The semilunar valves
(pulmonic, aortic)
Heart
Basic Anatomy Of The Heart

SA node:
Heart’s pacemaker coz. It maintains heartbeat.
sends electrical impulses causing atria to contact.
AV node:
Network of muscles in heart wall.
Conducts impulses from atria to ventricles.
Bundle of HIS:
Conducting muscle fibers within the septum.
the impulses travel into left and right bundle branches.
4-Purkinje fibers:
Tiny fibers transmit impulses directly to muscles of ventricle
Heart
Function of the Heart Cardiac Conduction

Cardiac Output:
• Amount of blood pumped with each contraction of left ventricle in a minute.
CO = HR X SV
HEART RATE:
• No. of times the ventricles contract each min.
• Normal heartbeat 72/min.
Stroke volume (SV):
• is the amount of blood pumped with each contraction of the ventricle in one contraction.
• SV = EDV − ESV
Ejection fraction (EF)
• is the fraction of blood pumped out of a ventricle with each heartbeat.
• indicator of ventricular function It reflects the vigor of the heart’s pumping action
• Normal EF is approximately 65%
Heart
Function of the Heart

Artery Blood vessel carrying
oxygenated blood away from the
heart to body tissues
Arteriole Small artery that branches
into capillaries; the major resistance
vessel of the arterial system
Capillaries The smallest blood
vessels that connect arterioles and
venules; the site of gas exchange in
the tissue
Venule Small vein that leads from
capillaries to larger veins
Vein Blood vessel carrying
Deoxygenated blood
from body tissues
back to the heart
Aorta One of two major arteries
from the heart; exits from left
ventricle and carries blood to the
systemic circulation
Blood Vessels
Structure and function of Blood vessel

Blood Vessels
Structure and function of Blood vessel

Is an important vascular regulatory organ and the largest organ in body.
The healthy endothelium maintains CV homeostasis.
Injury of endothelium promote oxidation of LDL >>>>>>> Atherosclerosis.
Blood Vessels
Endothelium

Role of the Healthy Endothelium in Cardiovascular Homeostasis:
► Vasoconstriction/Vasodilatation
► Growth promotion/Growth inhibition
► Promotes fibrinolysis
► Inhibits thrombosis
► Mediates inflammatory mechanisms
► Inhibits platelet aggregation
► Influence lipid oxidation
► Regulates vascular permeability
Blood Vessels
Endothelium

Vasoconstrictors Released by the Endothelium
Endothelin
Angiotensin II
Thromboxane A2
Blood Vessels
Endothelium-derived Vasoconstrictors

The endothelium releases a number of factors that promote vasodilatation.
Vasodilators send a message to the smooth muscle cells of the artery wall to relax, inducing
vasodilatation.
Vasodilators Released by the Endothelium
• Nitric oxide
• Prostacyclin
• Bradykinin
• Endothelium-derived hyperpolarizing factor
Blood Vessels
Endothelium-derived vasodilators

The most important vasodilator known and proliferation of smooth muscle >>>>>
prevent hypertrophy &hyperplasia.
Have antithrombotic effect and inhibits >>>>> the development Atherosclerosis.
Stimulating production of nitric oxide, so vasodilatation.
Another vasodilator but less potent than NO.
Blood Vessels
Endothelium-derived vasodilators

Blood Pressure = CO x PVR
Is the force exerted by
circulating blood on the walls
of blood vessels.
BLood pressuRE

Defining blood pressure
Hypertension prevalence

The therapeutic control of arterial hypertension is still a global
challenge
According to the World Health Organization (WHO) almost 600 million people
worldwide suffer from this disease
Ref. world health organization / international society of hypertension: guidelines for the management of
hypertension (1999). Journal of hypertension 1999; 17 (1): 151-183

0
5
10
15
20
infectious
disease
CVD cancer Other
Ref peter A Meredith, Henry L Elliott, William B white ; hypertension & related
Disorders 2003 Elsevier, Moby Rapid reference
Cardiovascular disease is the second leading cause of mortality worldwide

100
50
25
12.5
87.5
Ref. world health organization / international society of hypertension: guidelines for the management of hypertension
(1999). Journal of hypertension 1999; 17 (1): 151-183
WHO worldwide blood pressure control %

Hypertension can be sub-classified into seven categories:
Essential hypertension
Secondary hypertension
Isolated systolic hypertension
Pseudo hypertension
White coat hypertension
Accelerated hypertension
Malignant hypertension
Blood Pressure Subclassification

Essential hypertension
• is the most common form of elevated blood pressure and may be defined as an elevation
of arterial BP
• usually defined as persistent Hypertension which can be attributed to a definable
Underlying disorder

White coat hypertension
Some patients exhibit elevated blood pressure when measurements are made in the clinic or
office environment. In contrast, when blood pressure is assessed a way from the clinical
environment, usually by ambulatory recording, pressure is considered to fall within normal range

Pseudo hypertension
When BP measured by cuff is falsely elevated compared to reference standard because of
hardened calcific arterial walls
• Pathophysiology
• arterial calcification as opposed to atherosclerosis/collagen deposition*
• Associations
• Age
• Hypertension
• Atherosclerosis
• Scleroderma
• Prevalence
• 1.7% and 2.5% but poorly studied*
* Zuschke et al, Pseudohypertension, Southern Medical Journal 1995, 88:1185-90

Isolated Systolic Hypertension (ISH)
• Isolated Systolic blood pressure continuous to rise with age because loss of elasticity in the large
Capacitance arteries
• ISH is largely associated with westernized or industrialized populations and is not observed in more
primitive societies
Pulse Pressure
• The difference between SBP and DBP is the pulse pressure.
• It increases slowly from age 50 to 59 and more rapidly thereafter, as SBP increases and DBP
decreases.
• In the elderly, pulse pressure is an independent predictor of cardiovascular disease.
• In the SHEP study, pulse pressure predicted stroke and total mortality more strongly than did SBP
or DBP.

Accelerated hypertension
• is the terminology applied in severe hypertension with Blood pressure around 200/120
mmHg and above, when Significant target organ damage is present, usually in
Association with advancing renal insufficiency and Fundoscopic hemorrhages, but in
the absence of Papilloedema or a medical emergency
Malignant hypertension
may be defined as severe hypertension in association With one or more of the
following:
• Papilloedema
• Pulmonary oedema

Circadian Rhythm
Blood pressure fluctuates according to a predictable pattern during the day. Blood pressure
is usually lower at night, but in the early morning hours, it rises along with pulse rate.
Circadian Rhythm

Primary System in Blood Pressure
Regulation

The autonomic nervous system itself is divided into two components:
The sympathetic nervous system:
▪ Thereby increasing total peripheral resistance.
▪ It also markedly increases the activity of the heart, both increasing
▪ The heart rate and enhancing the strength of pumping.
The parasympathetic nervous system:
▪ Conversely, stimulation of the parasympathetic (vagus) nerves which reduce heart rate and
slightly decrease heart muscle contractility, thereby reducing CO and blood pressure.
Primary System in Blood Pressure Regulation
Vasomotor center

Primary System in Blood Pressure Regulation
The Autonomic Nervous System

Baroreceptors (or baroceptors):
• In the human body detect the pressure of blood flowing
through them and can send messages to the central
nervous system to increase or decrease total
peripheral resistance and cardiac output.
• Baroreceptors can be divided into two categories:
a. high pressure arterial Baroreceptors
b. low pressure Baroreceptors (also
c. known as cardiopulmonary receptors).
Nervous System in Blood Pressure Regulation
Baroreceptors

Nervous System in Blood Pressure Regulation
Chemoreceptor

The kidneys maintain homeostasis by regulating the balance between excretion
and intake of water and electrolytes.
The kidneys perform their excretory function by constantly filtering large
quantities of blood and removing substances at varying rates, depending on the
needs of the body.
The Kidneys in Blood Pressure Regulation
Role of Kidneys in Homeostasis

Glomerular filtration rate:
• The rate of excretion of substances from the kidneys.
• regulate the fluid volume.
• The major function of this AuToReGuLaTiOn in the kidneys is to maintain
a relatively constant GFR and allow control of renal excretion of water and
solutes.
GFR and Auto regulation

The long-term regulation of BP (dominant role):
The primary mechanism by which the kidneys influence long term control of blood
pressure is by regulating the fluid volume of the body.
• Pressure diuresis.
• Pressure natriuresis
The short-term regulation of BP:
via the production of vasoactive substances or substances such as Renin
The role of kidneys in Blood Pressure

If blood pressure does become elevated and remains persistently elevated, the
kidneys are adversely affected. (hypertensive nephrosclerosis)
Hypertension + diabetes
is a particularly damaging combination for the kidneys. An early sign of kidney
damage related to hypertension and/or diabetes is microalbuminuria, Proteinuria, or
the presence of excess protein in urine, indicates the presence of renal damage or
disease.
The role of kidneys in Blood Pressure

51
Angiotensinogen
(syn. By liver)
AI AII
Renin
arteries
kidneys
adrenal glands
vasoconstriction
Na+ Na+
Cough,
Angioedema
Aldosterone
Bradykinin Inactive
Fragments
ARBs
The Renin-Angiotensin-Aldosterone System


AT1
• Vasoconstriction
• ↑ Cell growth (Vascular and myocardial
hypertrophy)
• Increase Na and water reabsorption
• Increase intraglomerular pressure
• Positive Inotropic & chronotropic effect
• Arrhythmogenic effect
AT2
• Potent vasodilatation
• Increase renal blood flow
• Increase sodium and
water excretion
• Inh. Of cell growth.
AT3
• unknown.
AT4
• act as a renal
vasodilator &
stimulates
plasminogen
activator
inhibitor-1.

The circulating RAAS exerts acute (short-term) control of BP.
The local RAAS exerts long-term effects on BP.
The long-term effects of the tissue RAAS may contribute to path physiological condition.
Blood vessels
• vascular hypertrophy which
makes Hypertension.
• Thrombus which makes
Atherosclerosis.
Heart
• increase force of contraction
make heart failure.
• Ventricular hypertrophy
makes Arrhythmias.
• Vasoconstriction of coronary
make Angina + MI.
Kidney
• Intraglomerular hypertension
make Proteinuria.
• Glomerular hypertrophy
makes Nephropathy.
Circulating RAAS &Tissue RAAS

Hypertension and its Complications

Types of hypertension
Primary hypertension
Role of regulatory system
Sympathetic nervous system
The RAAS
Angiotensin II receptors

Hypertension and its Complications
TARGET ORGAN

PVR
In lumen due to wall thickness
or vasoconstriction
Change structure
Vascular Hypertrophy
( in the size of vascular smooth
muscle)
Pressure-related consequences of hypertension
Vascular hypertrophy and remodeling

Vascular hypertrophy and remodeling

64
Atherosclerosis
HyperTioN
LVH
SHF
DHF
Heart
Failure
DEATH
Cardiovascular continuum*
*Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.
Myocardial
Infraction

65
Cardiovascular continuum*
*Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

OXIDATION
INGESTED ! CHOLESTROL-
RICH OXIDIZED LDL
DIE
LARGE LIPID CORE
COVERED BY A THIN
FIBROUS .
rupture
Adhere to site
of trauma
Atherosclerosis

Left ventricular Hypertrophy(LVH)

Left ventricular Hypertrophy (LVH)

69
Weber M.A. et al., Rev Cardiovasc Med 2004
Correlation with CV events
The circadian pattern of BP

Severe ischemia more than 20 min, commonly known as a heart attack.
If more than 30 min. damage to myocardial tissue can result.
Symptoms:
Burning, aching or pressure in ! Center of ! Chest .
Also pain or aching in the jaw or neck.
Myocardial Infraction
Angina:
chest discomfort association with myocardial ischemia.
Symptoms are tightness or fullness which may radiated to Neck, shoulder
or left arm.
Classified to:
Stable angina.
Unstable angina.

Diastolic & Systolic heart failure

HF is the inability of the Heart, specifically the Left ventricle to pump blood
into the Circulation.
CHF(congestive heart failure):
When heart is pump blood into ! Aorta as fast as ! Venous system.
Returns blood from ! Lung, the pressure Backs up into ! lung & other
tissues causing SWELLING or EDEMA.
Heart Failure

❑ Shortness of breath (dyspnea).
❑ Angina, Fatigue and fluid buildup (Edema).
❑ NYHA (the New York Heart Association):
Heart Failure; Assessment of HF status

Ischemia can alter ! Electrical function of ! heart, leading to an irregular
heartbeat.
Arrhythmias themselves may not be life threating, but they can precipitate
major cardiovascular events, as stroke and sudden cardiac death.
Arrhythmias

Ischemic stroke occurs when blood supply to ! Brain becomes blocked by atherosclerotic
plaque or blood clot which travels to ! Brain from another organ such as carotid artery.
Transient ischemic attack (TIA):
also called MINISTROKE.
caused by transient constriction of a small brain vessels or small clot.
Hemorrhagic strokes
caused by rupture of an artery in ! Brain.
risk of stroke in ISH 2-4 > HT ptn.
Atherosclerotic consequences of hypertension
Stroke (occlusion)

HTN can damage the glomeruli of ! Kidneys ▬▬▬► can be permeable to
proteins in ! Urine ▬▬► leads to Micro_& Macroalbuminuria (PROTEINURIA)
Atherosclerosis may occur in ! Artery renal arteries causing vessels obstruction
,ischemia & death of renal tissue ▬▬►chronic renal failure.
HTN & Atherosclerosis may lose their ability to remove waste products from the
blood, causing UREMIA.
Damage of kidneys

AT 2
AT1
Afferent
Efferent
Ag II
ACE inh
Normal
ARBs
PROTEINURIA
Microalbuminuria, Macroalbuminuria
Intraglomerular
pressure
vasoconstriction
Vasodilatation
Vasodilatation
PROTEINURIA

Increase BP causing hemorrhage, exudates & edema in ! Eyes.
Retinal ischemia ▬▬▬▬►thicken of wall.
Damage to the Eyes

Diagnosis and Management of Hypertension

83
Few patients under control?

The problem
Underdiagnosis and undertreatment of hypertension

85
13.0%
9.3%
5.7%
7.7%
5.0%
11.6%
26.8%
0%
5%
10%
15%
20%
25%
30%
USA Canada England Finland Germany Spain Italy
Control
in
%
Wolf-Maier K et al, Hypertension 2014;43:10-17
The problem
Control Rates

Turkey 24%
UAE 19%
Tunisia 13%
2
3
Egypt
Algeria
8%
6%
4
5
1
0 10 20 30 40(%)
Erem C et al. Prevalence of prehypertension and hypertension and associated risk factors among Turkish adults:
Trabzon Hypertension Study. J Public Health (Oxf). 2008 Sep 30.
The problem
Control Rates

The problem
26.1% of Saudi Population Hypertensive in 2001

The problem
24% of Saudi Population Hypertensive in 2007
0
10
20
30
40
50
60
70
80
SBP < 130 DBP < 80 SBP<130 & DBP<80
32%
74%
24%
Al Nozha et al, S Med J, 2007.

Poor Efficacy
Poor Compliance
REF; Chobanian AV, Bakris GL, Black HR, et al. the seventh report of the joint National Committee on prevention,
detection , report. JAMA 2003 May; 289 (19): 2560-722
The problem
Factors Related to the Result in Poor Control Rates

91
‘‘Drugs don’t work in patients who don’t take them’’
C. Everett Koop, MD
Osterberg and Blaschke. N Engl J Med 2005;353:487–97
The problem
The Importance of Medication Compliance

92
More Than 70% of Physicians Suspect Poor Compliance as the
Reason For Antihypertensive Treatment Failure
0
20
40
60
80
100
UK France Italy
Poor patient compliance
Products not effective
Side effects
Ménard and Chatellier. J Hum Hypertens 1995;9:S19–S23;
Andrade et al. Arq Bras Cardiol 2002;79:375–84
Doctors
citing
reason
(%)
*
* In patient surveys, side effects are a major reason for poor compliance
The problem
Factors Related to the Result in Poor Control Rates

Standard Diagnosis of Hypertension

1. The patient should be
relaxed and the arm
must be supported.
Ensure no tight clothing
constricts the arm.
2. The cuff must be level with
the heart. If arm circumference
exceeds 33 cm, a large
cuff must be used. Place
stethoscope diaphragm over
the brachial artery.
3. The column of mercury must
be vertical. Inflate to occlude the
pulse. Deflate at 2 to 3 mm/sec.
Measure systolic (first sound)
and diastolic (disappearance)
to nearest 2 mm Hg.
Evaluation of blood pressure
Office monitoring of blood pressure

Mercury
Aneroid
Electronic
Sphygmomanometer

Ambulatory
Sphygmomanometer; Ambulatory Blood Pressure Monitoring

The standard components of the evaluation of a patient with
suspected hypertension are the medical history, the physical
examination, laboratory tests, and other diagnostic procedures.
Initial workup for patients with hypertension
Office monitoring of blood pressure

Classification of blood pressure

Medical History

Laboratory Tests

Noninvasive Tests (Electrocardiography)
Rest stress

Noninvasive Tests (Doppler ultrasonography)

Normal Floracin
Invasive Tests (Angiography)

Principles of Antihypertensive Therapy

State the treatment goals for patients with hypertension
Goals of therapy

Tailoring treatment to fit the patient's global risk

Non-pharmacological Therapy

Pharmacological Therapy

JNC7 Recommendations for drug therapy
Stage I Hypertension
Stage II Hypertension
Initial combination drug therapy
More frequent follow up visit.
Treatment regimen may require 3 drugs with very high doses of
some agents.

50% of patient achieve the goal blood pressure with monotherapy.
Basic of combination therapy is to combine drugs from different
classes to take advantage of their complementary modes of
action.
Combination therapy

provides convenient dosing and makes it possible to use low doses of
both agent to
Maximum effect.
Minimizing the risk of adverse effect.
Improving patient compliance.
Fixed Combination therapy

Diuretics
Alpha1 blockers
Beta blockers
Alpha beta blockers
Calcium channel blockers
ACE inhibitors
ARBs
Major Classes of Antihypertensive Drugs

Overview of Antihypertensive Agents

Direct
vasodilators
Alpha
blockers
DRIs
Peripheral
sympatholytics
Ganglion blockers
Veratrum
alkaloids
Central alpha2
agonists
Non-DHP
CCBs
Beta blockers
Thiazide
diuretics
DHP CCBs
ARBs
ACE
inhibitors
Effectiveness
Tolerability
1940s 1950 1957 1960s 1970s 1980s 1990s 2007
DHP, dihydropyridine; CCB, calcium channel blocker; ARB, angiotensin II receptor blocker; DRI, direct renin inhibitors
Development of Antihypertensive Therapies

Major Classes of Antihypertensive Drugs and their sites of action

Homodynamic effects of Antihypertensive agents
Different, but complementary mechanism of action
=
=
Total
peripheral
resistance
β-blockers CCBs
Diuretics ARBs ACEIs
X
Stroke
volume
Heart rate X
Cardiac
output
Venous
pressure
BP
Arterial
pressure

compelling indication for first line therapy

Clinical effects of antihypertensive drugs
Diuretics

Beta Blockers MoA

Beta Blockers

Beta Blockers Classification

Beta Blockers Drug-Drug Interactions

Calcium Channel Blockers MoA

Calcium Channel Blockers Classification

Available ACE inhibitors

Angiotensin Receptor blockers
• Losartan potassium (Cozaar®)
• Valsartan (Diovan®)
• Candesartan cilexetil (Atacand®)
• Irbesartan (Aprovel®)
• Telmisartan (Micardis®)
• Eprosartan mesylate (Teveten®)
• Olmesartan Medoxomil (Olmetec®)

Angiotensin Receptor blockers

Angiotensin Receptor blockers MoA

Newer agent

142
Clinical trials & evidence-based medicine
Introduction
• Clinical trials are experiments done in clinical research. Such prospective biomedical or
behavioural research studies on human participants is designed to answer specific
questions about biomedical or behavioural interventions, including new treatments
(such as novel vaccines, drugs, dietary choices, dietary supplements, and medical
devices) and known interventions that warrant further study and comparison.
• Clinical trials generate data on safety and efficacy. They are conducted only after they
have received health authority/ethics committee approval in the country where
approval of the therapy is sought.

143
Introduction
• There is abundant evidence that links hypertension with increased risk of
cardiovascular disease.
• A large body of evidence also shows that lowering blood pressure reduces
the risk of these complications.

144
Classification

145
Phases of a clinical trial

146
Phases of a clinical trial

Primary vs Secondary trials

148
Clinical trial evaluation

149
Randomized
Participants are randomly (i.e., by chance) assigned to one of two or
more treatment arms of a clinical trial.
Minimizes the differences among groups by equally distributing
people with particular characteristics among all the trial arms.
Trial design

150
Trial design
Controlled
Studying a group of treated patients not in isolation but in comparison to other groups
of patients.
I.Placebo controlled
Compare the test group to placebo.
II.Double dummy
• Patients are given both placebo and active doses in during the study.
• Additional insurance against bias or placebo effect.
III.Active control.
The study would compare the 'test' treatment to standard-of-care therapy.

151
Blind vs Open label
I. Open label
• Both the researcher and the patient know the full details of the treatment.
• They do nothing to overcome the placebo effect or the bias.
• Sometimes they are unavoidable like surgery
II. Blind
• The researcher knows the details of the treatment, but the patient does not.
• They eliminate the placebo effect but not the bias.
• The researcher might give extra care to the placebo group
III. Double blind
• Neither the researcher nor the patient knows about the treatment.
• They eliminate both the bias and the placebo effect.

152
• Age
• Sex
• Type of disease
• Stage of disease(severity)
• Treatment history
Inclusion and exclusion criteria

153
CI
• Quantifies the uncertainty in measurement.
• They are used to indicate the reliability of an estimate.
• It is usually reported as a 95% CI
• It is the range of values within which we can be 95% sure that the true value for
the whole population lies.
Confidence interval

154
• Results are said to be statistically significant if it is unlikely to have occurred by
chance.
• A statistically significant difference" simply means there is statistical evidence that
there is a difference; it does not mean the difference is necessarily large.
Statistical Significance

155
• The smaller the p-value, the more significant the result is said to be.
• P value< 0.05 is usually accepted to be statistically significant.
P- Value

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