Hypertension Mediated Organ Damage : How We Prevent It?The Role Of RAAS In Cardiovascular Continuum.Changes in Arterial Diameter in Patients with Arteriosclerosis or Atherosclerosis.Not All Angiotensin-Converting Enzyme Inhibitors Are Equal.Question : ACEIs vs. ARBsIs One Class Better For Cardiovascular Diseases?BP Variability .Central BP . Vascular Age & Arterial Stiffness.Achieving BP Goals.

1. Magdy El-Masry
Prof. of Cardiology
Tanta University
Hypertension Mediated Organ Damage : How We Prevent It?

3. Lower your number
Lower your risk
Benefits of Lowering Blood Pressure

4. Benefits Beyond BP Lowering ? :
ACEIs vs. ARBs
Treat the patient, not the number?
More Than Just
Numbers
If you could treat the
patient, not just the
numbers
That would be
great

5. BP reduction
Cardio - protection
Vasculo - protection
Nephro - protection
RAAS inhibitors : Evolution of benefits
Heart / Blood Vessels /Brain / Kidney → HMOD
Beneficial effects of BP lowering therapy in hypertension :
(HMOD regression and cardiovascular risk reduction with antihypertensive treatment)

6. Historical Perspective
The history of the discovery of the renin-angiotensin system began in 1898 with
the studies made by Tigerstedt and Bergman, who reported the pressor effect of
renal extracts; they named the renal substance renin based on its origin.
The RAAS has
been discovered
for more than a
century

8. Physiological and detrimental roles of RAAS molecules
in cardiac, vascular tissues and kidneys.
Aldosterone and Ang II are the principal RAAS molecules involved in cardiovascular and renal system changes during
hypertension. Both molecules are also involved in the physiological control of blood pressure (blue text), directly
impacting cardiomyocytes, kidney epithelial cells, and vascular smooth muscle cells. During hypertension, excesses of
these molecules have also been linked with cardiovascular and kidney tissue hypertrophy and fibrosis (red text)

9. The term ‘cardiovascular continuum’ was first coined by
Dzau and Braunwald in 1991 to describe a new paradigm for
cardiovascular diseases

10. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary
artery disease: a workshop consensus statement. Am Heart J 1991;121:1244–1263.

11. The cardiovascular (CV) [upper curve] and renovascular (lower curve) disease continuum.
 CV risk factors such as arterial hypertension, dyslipidaemia, diabetes mellitus and smoking
facilitate the generation of atherosclerotic lesions, leading to coronary artery disease,
symptomatic ischaemia and, via plaque rupture and acute coronary thrombosis, to acute
coronary syndromes and myocardial infarction (MI). Persistent cardiac structural damage
reduces contractility and is the basis of left ventricular dilatation and remodelling, which
leads to chronic congestive heart failure and, ultimately, premature death.
 Renal endothelial dysfunction may be followed by microalbuminuria, macroproteinuria,
nephrotic syndrome and, finally, end-stage renal disease
The Role Of RAAS In Cardiovascular Continuum

12. Changes in Arterial Diameter in Patients with Arteriosclerosis or Atherosclerosis.
Individuals with arteriosclerosis are affected by changes in the thickness of the blood vessel wall owing to smooth muscle proliferation, which
alters the size of the lumen and stiffness of the artery, and leads to impaired blood circulation. Atherosclerosis is characterized by arterial
stenosis, with presence of plaques that restrict blood flow through the lumen.

13. LVH indicates left ventricular hypertrophy; IMT, intima-media thickness;
PP, pulse pressure; BP, blood pressure.
Cycle of microvascular
damage in hypertension.
Is Microcirculation
a Culprit or Victim of
Hypertension?
Indeed, there may be a
cyclical process of damage
and hypertension that is self-
perpetuating; however, the
majority of available
evidence points to the
microcirculation being
altered in response to
sustained elevation in
pressure after the
onset of essential
hypertension
MAP = 1/3 (SBP – DBP) + DBP

15. *1 in combination with a potassium-sparing diuretic, as indicated
*2 symptomatic treatment for angina pectoris
Recommendations for drug treatment of arterial hypertension with additional indications
for first-line treatment because of further underlying diseases.

16. Medications aimed at inhibiting the RAAS
have been used extensively for preventing
cardiovascular and renal outcomes in
patients with diabetes.

18. Serum potassium levels
Renal function ( Cr Cl )
Blood pressure
ACEIs & ARBs monitoring requirements
 Care should be taken in patients on diuretic therapy
(monitor for hypotension )

19. Not All
ACEIs
Are
Equal

20. Perindopril, in the EUROPA study, and ramipril, in HOPE trial,
are the only ACE inhibitors that have data showing their
therapeutic association with the prevention of CV events and
lower CV mortality rates in patients with or at high risk for
CAD, who have normal LV function
Not All Angiotensin-Converting Enzyme Inhibitors Are Equal
Patients With or at High Risk of CAD
EUROPA study
HOPE studyRamipril
Perindopril

21. “Ever since the HOPE study, published in 2000,
ACEIs have become a sacred cow and nobody
dared to say anything against them”
The Heart Outcomes
Prevention Evaluation
(HOPE) study
The trial confirmed beyond
a doubt the cardiac and
renal protective benefit of
ACE inhibition and
extended the patient base
in whom ACE inhibition has
been proven effective.

22. Question : ACEIs vs. ARBs
Is One Class Better For Cardiovascular Diseases?
Benefits Beyond BP Lowering ?
Breaking a Scientific Taboo

23. Efficacy
Side effects
ACEIs = ARBs
ARBs < ACEIs

26. The Problem With ACE Inhibitors
Between 5% and 20% of patients treated with ACE inhibitors experience
a dry persistent cough that requires termination of therapy
“ACE cough” results from the concurrent
blockade of bradykinin breakdown

27. The effects of angiotensin II inhibition and improvement in bradykinin availability
↓Angiotensin II ↑Bradykinin
↓Vasoconstriction ↑Vasodilatation
↓Adhesion of monocytes ↑Antiadhesion of monocytes
↓SMC growth , proliferation , and
migration
↑Increased eNOS expression
↓Increased PAI-1 and thrombogenesis ↑Increased t-PA and fibinolysis
↓Matrix degradation ↑Antiremodeling effect
↓Oxygen free radical production ↑Antioxidant effect
↓Endothelial dysfunction ↑Preserved endothelial function
The decrease in angiotensin II levels prevents a number of
deleterious cardiovascular effects, while the increase in
bradykinin has cardioprotective consequences
ACE Inhibition : Vasculo - protection

28. Most guidelines for the management of patients
with cardiovascular disease recommend angiotensin-
converting enzyme (ACE) inhibitors as first-choice
therapy, whereas angiotensin receptor blockers (ARBs)
are merely considered an alternative for ACE inhibitor–
intolerant patients.

29. OFFICE BLOOD PRESSURE

30. Revolutionizing Hypertensive Care : Beyond The Office Horizon
Certain factors independently increase CV risk , beyond clinical BP
Central BP
BP Variability
Vascular Age &
Arterial Stiffness

31. Central
BP
Why is central BP important?

32. Central Blood Pressure
The term 'central blood pressure' usually refers to the
pressure in the aorta near the heart.

33. Brachial BP
Central BP

34. Changes in contour and magnitude as the
BP wave moves distally.
Central Peripheral

35. Central Blood Pressure Measurement
Any Added Value?

36. Persistent Systolic Hypertension (brachial ) on a Single Agent
Clinical Question: Increase Dose or Add Other Medication?.
The central pressure readings provided support for not altering current management.
Guiding Hypertension Management Using Central Blood Pressure

37. Central aortic pressure
Some studies and meta-analyses have shown that in hypertensive
patients, central BP predicts CV events and that there is a differential
effect of antihypertensive drugs on central compared with brachial BP.

38. Comparative effect of anti-hypertensive drugs and
nitrates on central systolic pressure
European Heart Journal, Volume 35, Issue 26, 7 July 2014, Pages 1719–1725

39. Vascular Age & Arterial Stiffness
Why is vascular age important?
A person whose vascular age is older than his or her chronological age may be
at increased risk of developing cardiovascular disease later in life.

40. You're as old as your arteries , which doesn't always equal the
number of candles on your birthday cake.
How old are your arteries?
Two currently available tools estimate artery "age" using
pulse wave velocity and carotid intima-media thickness.

41. The effects of early vascular aging may best be managed by early intervention.
The graph above shows early vascular ageing along the red arrow, compared to normal
vascular ageing along the blue arrow. Early vascular ageing may lead to premature
cardiovascular complications.
Early intervention can help to delay these events.

42. Components of healthy
vascular aging.
 Higher blood pressure and
stiffening of the large
elastic arteries are
associated with unhealthy
vascular aging.
 With a shifting profile
toward healthy vascular
aging, blood pressure is
lowered to a
nonhypertensive range,
and arterial stiffness is
also reduced.

44. Systole
Aortic Stiffening and Early Wave Reflection
Diastole
Systole
Young compliant arteries : Normal PW velocity (8 m/sec)
Elderly stiff arteries : Increased PW velocity (12 m/sec)
(1) Ventricular-Vascular coupling
(2)  coronary blood flow
(1) Ventricular-vascular mismatch
(2) The reflected wave increases or “augments” central SBP during late systole:

45. For the determination of aortic PWV it is
necessary to define when the arterial
blood is injected into the aorta what is
the starting point of the arterial pulse
wave. It corresponds with the opening of
the aortic valve what is characterised by
the B-point in the ICG wave form. To
detect the arrival of the pulse wave in the
femoral artery a cuff is placed on the
upper leg which has a constant pressure
of about 80 mmHg close to the diastolic
blood pressure. This cuff allows to
measure a pressure pulse wave in which
the slope rise onset is defined (F-point).
The time delay between the B-point in
the ICG (opening of the aortic valve) and
the F-point in the pressure pulse wave
defines the propagation time (PT) of the
arterial pulse wave in the aorta. For the
calculation of the aortic pulse wave
velocity it is necessary to measure the
distance (d) between the middle of the
thigh cuff and the Jugulum to
approximate the length of the aorta.
Pulse Wave Velocity
Measurement principle

46.  All antihypertensive drugs, by reducing BP, reduce
arterial stiffness, as the reduction in BP unloads the stiff
components of the arterial wall, leading to a passive
decrease in PWV.
 Pharmacodynamic RCTs and meta-analyses suggest that
ACE inhibitors and ARBs may reduce PWV beyond the
effect of BP lowering on a long-term basis.
Arteriosclerosis and increased arterial stiffness
 The aortic pulse wave velocity (PWV) is the most
widely validated and universally accepted measure of
arterial stiffness.
 It is known that aortic PWV increases with age and
blood pressure.
 The higher the PWV the higher the arterial stiffness.

47. yo-yo BP

49. Different types of BPV, their determinants, and prognostic relevance for CV and renal
outcomes. AHT, antihypertensive treatment; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MA,
microalbuminuria; MI, myocardial infarction; SOD, subclinical organ damage. *Assessed in laboratory conditions. †Cardiac, vascular, and
renal SOD. ‡BPV on a beat-by-beat basis has not been routinely measured in population studies.

52. Total hypertensive population
50% are aware of having
hypertension
50% are diagnosed
50% are treated
50% are controlled
Is the ‘Rule of Halves’ in Hypertension Still Valid?

53. Achieving BP
Goals
Medications
Adherence
Combination
Therapy
Optimizing hypertension treatment

54. ESC/ESH vs. ACC/AHA guideline

55. USA ACC/AHA 2017Europe ESH/ESC 2018

56. Achievement Of BP Goals : Six Steps
Review
measurement of
blood pressure
Drug compliance
(Adherence)
Lifestyle factors
Substances
interfering with
efficacy of drugs
Optimize
drug
therapy
Rule out
secondary
hypertension

57. Drugs for Hypertension
The A,B,C,D drug classes
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Beta-blockers
Calcium channel blockers
Diuretics
Treatment of HTN : First‐line drugs
In the absence of any compelling condition, any of the following three classes of
agents can be used as a first‐line therapy:
 Thiazide diuretic
 ACE‐I or ARB
 CCB

58. Core drug treatment strategy for uncomplicated hypertension
The core algorithm is also appropriate for most patients with
HMOD, cerebrovascular disease, diabetes, or PAD.

59. Drug Combinations

60. Patients suitable to receive a two-drug combination with either RAS
blocker/calcium channel blocker (CCB) or RAS blocker/thiazide diuretic.
DC
A
Dual Antihypertensive Therapy

61. • Perindopril + Amlodipine
• Benazepril+ Amlodipine
ACEIs +
CCB – DHP
• Valsartan + Amlodipine
• Olmesartan + Amlodipine
ARBs +
CCB – DHP
+ hydrochlorothiazide
Diuretic
RAAS Blocker CCB

62. C C A

63. Fixed-dose Combinations
Monotherapy and Separate Agents
RAS
Blocker
Diuretic
CCB

64. Advantages of fixed-dose combinations versus
monotherapy and separate agents
A promising choice in hypertension
treatment : Fixed-dose combinations