tran van huy tac dung cua khotailieu y hoc

TÁC DỤNG CỦA ỨC CHẾ MEN CHUYỂN
TRONG BẢO VỆ TIM, NGOÀI HẠ HUYẾT ÁP
ACEIs Effect On Cardioprotection,
Beyond Blood Pressure Lowering
PGS TS TRẦN VĂN HUY FACC FESC
Phó Chủ Tịch Phân Hội Tăng Huyết Áp Việt Nam
Chủ Tịch Hội Tim Mạch Khánh Hòa,
Giảng viên Thỉnh Giảng ĐHYD Huế, ĐH Tây Nguyên
Trưởng Khoa Tim Mạch Bệnh Viện Tỉnh Khánh Hòa


Mục tiêu tiếp cận chọn lựa thuốc tối ưu:
• Giảm tối đa nguy cơ về bệnh suất và tử suất:
– Hiệu qủa:
• Giảm tử vong chung,
• Giảm tử vong tim mạch và bệnh thận
• Giảm các biến cố tim mạch và can thiệp
• Bảo vệ các cơ quan đích
• Cải thiện và tăng cường chất lượng cuộc sống
– An toàn: Không tăng tỷ lệ ung thư, ít tác dụng phụ…
– Kinh tế & Hiệu qủa: Lợi ích chi phí giá / hiệu qủa
– Tuân thủ điều trị


CV and renal continuum:
RAAS as a mediator of pathophysiology
Atherothrombosis
& progressive CVD

Tissue injury (MI, stroke,
renal insufficiency, PAD)

Early tissue dysfunction

Oxidative & mechanical stress
inflammation

Pathological
remodeling

RAAS

Target organ damage

Vasoconstriction/Na/H2O
retention (High BP)

Risk factors

ESRD = end-stage renal disease

End-organ failure
(CHF, ESRD)

Death

Adapted from Dzau V et al. Circulation. 2006;114:2850-70.


Ang II is central to the development of
atherosclerosis

Oxidative stress

Inflammation

NAD(P)H oxidase activity

Vascular permeability

Reactive oxygen species

Leucocyte infiltration

LDL peroxidation, LOX-1
Nitric oxide

Vasoconstriction
PAI-1 activation
Platelet aggregation

Endothelial dysfunction

Signaling pathways (NFB)

Ang II

Inflammatory mediators
VSMC proliferation
Matrix deposition
MMP activation

Tissue remodeling
Adapted from Schmieder R et al. Lancet. 2007;369:1208-19.


RAAS modulation: ACEI and ARB pathways
Substance P

Bradykinin/NO

ANGIOTENSIN I

Vasodilation
Tissue protection

Chymase
tPA
Cathepsin

ACEI
Inactive fragments

ANGIOTENSIN II

“Angiotensin II
escape”

ARB
AT1 RECEPTOR

AT2 RECEPTOR

Vasoconstriction
Na/H2O retention
Sympathetic activation
Cell growth
Mediates apoptosis

Vasodilation
Natriuresis
Tissue regeneration
Anti-proliferation

NO = nitric oxide

Adapted from Dzau V. J Hypertens. 2005;23(suppl I):S9-17.


ACEIs giảm mức angiotensin II mô và tuần hoàn
và gia tăng mức bradykinin
• Giảm angiotensin II dẫn đến giảm: • Tăng bradykinin dẫn đến tăng
–
–
–
–
–
–
–

Rối loạn chức năng nội mạc
Thoái biến matrix ngoại bào

Bám bạch cầu đơn nhân
Sản phẩm Oxy gốc tự do
PAI-1 và thrombogenesis
Tăng sinh nội mạc
Co mạch

–
–
–
–
–
–
–

Hoạt động chống oxy hóa
Hoạt động chống tái cấu trúc
Phóng thích eNOS
Chống bám bạch cầu đơn nhân
Bảo tồn chức năng nội mạc
t-PA và fibrinolysis
Gỉan mạch

Roberto Ferrari European Heart Journal Supplements (2008) 10 (Supplement G), G13–G20


What is BPLTTC?
BPLTTC is a WHO/ISH joint
research project characterized

by a prospective systematic

overview (meta-analysis) of
all the major ongoing studies of
blood pressure lowering drugs
from a neutral viewpoint.
BPLTTC is recognized as
the most reliable evidence.

26 studies

146.848 participants

AASK
ABCD (H)
ABCD (N)
ALLHAT
ANBP2
CAMELOT
CAPPP
CHARM added
CHARM alternate
CHARM
preserved
DIAB-HYCAR
EUROPA
HOPE

IDNT
JMIC-B
LIFE
PART-2

PEACE
PROGRESS
RENAAL
SCAT
SCOPE
STOP-2
UKPDS-HDS
Val-HEFT
VALUE

BPLTTC J Hypertens 2007, 25:951-958


CORONARY HEART DISEASE: ACE-I and ARB
Meta-regression-CHD
Beyond BP lowering effect !
2.0

Odds Ratio

IDNT
(CA arm)

UKPDS

SCOPEPEACE

LIFE

PROGRESS

1.0

IDNT
(plac arm)

PART2

VALUE

ALLHAT
(D arm)

CAPPP

DIAB-HYCAR

ALLHAT
STOP-2 (CA arm)
(CA arm)
RENAAL
ANBP2

EUROPA

STOP-2
(D/BB arm)
JMIC-B

SCAT

0.5

ACE-I vs. ARB: p=0.01
ABCD (H)

0.25
-8

-6

-4

-2

0

2

4

Difference in achieved SBP reduction (mmHg)

ACE-I trials
ARB trials
BPLTTC J Hypertension 2007; 25, 951-8


BPLTTC Conclusions
 Reduction in CHD with ACE inhibitors

is about 9% greater than expected
 No similar independent effect
observed with ARBs

ACEIs have “Beyond BP lowering effect” to reduce CHD
risk, therefore, should be “ a first line drug” for high
risk patients with hypertension.
BPLTTC J Hypertens 2007, 25:951-958



Yếu tố nội mô của động mạch
BK/NO
Improve endothelial function
Increase in coronary blood flow etc

PAI-1
Thrombogenicity
（t-PA suppression）
Cell proliferation
Extracellular matrix aggregation
Vascular smooth muscle migration

Normal Vessel
Early atherosclerosis
Unstable Plaque
Rupture
MMP (Matrix Metallo Proteinase)
Enhance rupture （Degradation of extracellular matrix）
Remodeling after MI

BK/NO: Bradykinin/Nitric Oxide
PAÍ1: Plasminogen, Activity


Quá trình tiêu sợi huyết


Vai trò tPA/PAI-1 trên sự hình thành huyết
khối
Endothelial Cells

tPA

ｔPA/PAI-1 complex

tPA

PAI-1
Disruption

×

Plasminogen

Plasmin

×
Lipid rich plaque
ｔPA：Tissue Plasminogen Activator

15
PAI-1：Plasminogen Activator Inhibitor-1


ACEIs và t-PA/PAI-1
Kininogen

Angiotensinogen

Bradykinin

AngiotensinⅠ

ACE
Inactive peptide

AngiotensinⅡ

PAI-1

PAI-1

tPA
t-PA

Ang IVIV
Ang

Angiotensin IV receptor

×:ACE-I

AT1-receptor
（Angiotensin type I
receptor)

Various organ damage


ARB và t-PA/PAI-1
Kininogen

Angiotensinogen

Bradykinin

Angiotensin I

ACE
Inactive
placebo

PAI-1
PAI-1

tPA

Angiotensin II
Ang IV
Ang

IV

Angiotensin IV receptor

×：ARB

×

AT1-receptor

（Angiotensin type I
receptor)

Various organ damage



FIRINOLYSIS AND INSULIN SENSITIVITY IN
IMIDAPRIL AND CANDESARTAN (FISIC)
AIM
To compare the effects of the ACE-I Imidapril and of
the ARB Candesartan on fibrinolytic balance and
insulin sensitivity in normal weight mild to moderate
hypertensive patients with at least another
cardiovascular risk factor

19
Fogari R, et al. Hypertension Research 2011; 34, 509-515

EFFECT OF IMIDAPRIL AND CANDESARTAN
ON BLOOD PRESSURE
SBP (mmHg)

150
140

p<0.001

p<0.001

130
120
110
100

Candesartan

DBP (mmHg)

Imidapril
100
90

p<0.001

p<0.001

80

70
60
50

Candesartan

Imidapril
Baseline

/

Treatment
Fogari R, et al. Hypertension Research 2011; 34, 509-515


EFFECT OF IMIDAPRIL AND CANDESARTAN ON
PLASMA t-PA ACTIVITY AFTER 12 WEEK TREATMENT
t-PA
IU/ml
0,6

p<0.05
0,5

ns

0,4

0,3

0,2

Candesartan

Imidapril
Baseline

/

Treatment

Fogari R, et al. Hypertension Research 2011; 34, 509-515


EFFECT OF IMIDAPRIL AND CANDESARTAN ON PLASMA
PAI-1 ANTIGEN AFTER 12 WEEK TREATMENT

PAI-1
ng/ml

p<0.01
p<0.05

p<0.05

25

20

15

10

5

Candesartan

Imidapril

Baseline

/

Treatment

Fogari R, et al. Hypertension Research 2011; 34, 509-515


Is there any relation between angiotensin
II and change of plasma PAI-1 ??? FISIC II
• Background
－While fibrinolysis and insulin sensitivity were evaluated in FISIC
study, relation between PAI-1 and Ang II was not evaluated.
Therefore, it was observed in the study “role of angiotensin II in
plasma PAI-1 changes induced by imidapril or candesartan in
hypertensive patients with metabolic syndrome”

• Aim

－To evaluate the relationship between plasma PAI-1 and

Ang II changes during treatment with (ACE-I) Imidapril and
(ARB) candesartan

Fogari et al., Hypertension Research 34, 1321-6, 2011


Change in Plasma Ang II Level
35

25

Delta Ag II (pg/ml)

** +

** +

Imidapril
Candesartan

*°
15

*

5

-5

-15

*
-25

Week 2

*

*

Week 4

Week 8

*
Week 12

*
Week 16

•p< 0.05; ** p< 0.01 vs baseline
•; ° p< 0.05; + p< 0.01 vs imidapril
Fogari et al., Hypertension Research 34, 1321-6, 2011


Change in Plasma PAI-1 Level
Imidapril
Candesartan

Delta PAI-1 (ng/ml)

10

*+

°

5

*+

0

-5

*
-10

*

*
**

Week 2

Week 4

**
Week 8

Week 12

**
Week 16

-15
* p< 0.05; ** p< 0.01 vs baseline
° p< 0.05; + p< 0.01 vs imidapril
Fogari et al., Hypertension Research 34, 1321-6, 2011


Bảo Vệ Tim


HOPE, EUROPA, PEACE: Reduction in all-cause
mortality
Events (%)
ACEI

Placebo

HOPE

10.4

12.2

EUROPA

6.1

6.9

PEACE

7.2

8.1

Total

7.8

8.9

Favors
ACEI

Favors
placebo

0.86 (0.79 - 0.94)
P<0.0004

(N = 29,805)

0.6

1.0
Odds ratio (95% CI)

1.4

Dagenais GR et al. Lancet. 2006;368:581-8.