Bambang Irawan SpPD [K], SpJP [K],

FIHA, FASCC, FINASIM

Internist
Cardiovascular Consultant
Cardiologist

[SpPD]
[KKV]
[SpJP]

1981
1996
2004

Fellow of Indonsian Heart Association[FIHA]

2004

Cardiologist Consultant

[K]

2005

Professor in Cardiology

[ Prof ]

2006

Fellow of Asean College Cardiology[FASCC]

2008

Fellow of Ind Society of Internal Medicine

2009

NEUROHUMORAL ACTIVATION
& THERAPEUTIC APPROACH
IN HEART FAILURE
BAMBANG IRAWAN MD FIHA FASCC FINASIM

Professor in Cardiology and Vascular Medicine

Departement of Cardiology, Faculty of Medicine,
Gadjah Mada University Yogyakarta

PREVENTING & THERAPEUTIC IN HEART

FAILURE
HEART FAILURE IS A COMMON DISEASE

HEART FAILURE IS DISEASE WITH A HIGH

MORBIDITY & MORTALITY

ASSOCIATED WITH HIGH COST BOTH THE PATIENTS

& HEALTH-CARE SYSTEMS

65 YEARS AGO, BEFORE ANTIHYPERTENSION DRUG,

HEART FAILURE WAS THE MOST COMMON
COMPLICATIONS OF HYPERTENSION

FRAMINGHAM [1971] DEMONSTRATED THAT

HYPERTENSION WAS THE MAJOR FACTOR IN
CAUSED OF HEART FAILURE

MAJOR RISK FACTOR FOR THE

DEVELOPMENT OF HEART FAILURE

HYPERTENSION
MYOCARDIAL INFARCTION

ANGINA PECTORIS
DIABETES
LEFT VENTRICULAR HYPERTROPHY
VALVULAR DISEASE

HEART FAILURE & DIABETES

HEART FAILURE 2X COMMON IN DIABETIC MAN & 5X

IN DIABETIC WOMEN
12% TYPE 2 DIABETICS BECOME HEART FAILURE
EACH YEAR 3.3% TYPE 2 DIABETICS BECOME
HEART FAILURE

Bell Diabetes Care 2003

Amato et al Diabetes Metab 1997

CAUSE of HEART FAILURE

MYOCARDIAL DISEASE: MYOCARDIAL INFARCTION,
MYOCARDITIS, TOXIN [ALCOHOL]
ELEVETED PRELOAD: MITRAL REGURGITATION,
AORTIC REGURGITATION, INTRA-CARDIAC SHUNT

ELEVATED AFTERLOAD: AORTIC STENOSIS

HYPERTENSION, AORTIC COARTATION
OTHERS

MORTALITY IN PATIENTS WITH HEART

FAILURE IN FRAMINGHAM STUDY

MORTALITY FROM
DIAGNOSE OF HF

MEN

WOMEN

2 YEARS

37%

33%

6 YEARS

82%

67%

Kannel (1991)

HEART FAILURE
SYMPTOM OF HERAT FAILURE [breathlessness at
rest or exercise, fatigue, tiredness]
SIGN OF HEART FAILURE
[tachycardia,tachypnea,pulmonary rales,pleural
effusion,raised jugular venous pressure,peripheral
oedema,hepatomegaly]
STRUCTURAL ABNORMALITY [cardiomegaly, 3rd heart
sound, cardiac murmurs]

NEW YORK HEART ASSOCIATION [NYHA]

CLASS I : ORDINARY ACTIVITY DOES NOT CAUSE FATIGUE
PALPITATION DYSPNEA OR ANGINAL PAIN
CLASS II: COMFORTABLE AT REST BUT ORDINARY ACTIVITY
CAUSE COMPLAIN
CLASS III: COMFORTABLE AT REST, LESS THAN ORDINARY
ACTIVITY CAUSE COMPLAIN
CLASS IV: INABILITY TO PERFORM ANY ACTIVITY WITHOUT
COMPLAIN

PROGRESSION HYPERTENSION HEART FAILURE

Obesity
Diabetes

LVH

Diastolic
dysfunction

Hypertension
Smoking
Dyslipidaemia
Diabetes

Normal
LV structure
and function

HF
MI

LV
remodelling
Time: decades

Death

Systolic
dysfunction

Subclinical LV
dysfunction

Overt heart
failure
Time: months

NEUROHUMORAL ACTIVATION IN
PROGRESSION OF HEART
FAILURE

ACUTE RESPONSE
SNS ACTIVATION [AFTERLOAD]
NEUROHUMORAL PATHWAY [PRELOAD]

CHRONIC REMODELLING
SYSTEMIC & LOCAL CYTOKINE OR GROWTH FACTOR
FAMILIES
HYPERTROPHY WITH CHAMBER DILATATION
[ECCENTRIC]
HYPERTROPHY NOT ASSOCIATED MYOCYTE
STRETCHING [CONCENTRIC]

THE RENIN ANGIOTENSIN ALDOSTERON SYSTEM

LIVER
Endothelial cells

Blood
vessel

Angiotensinogen

Angiotensin II
Aldosteron

Angiotensin I
Renin

KIDNEY

ACE

Adrenal cortex

Circulating and tissue RAS influence on the

cardiovascular system
Kidney

Circulating RAS

Kidney

Tissue RAS
Long-term effects

Short-term effects

Intraglomerular
hypertension

Sodium/water reabsorption
via aldosterone secretion

Angiotensin II
Vascular
hypertrophy

Vasoconstriction

Heart

Positive chronotropic
effects/
arrhythmogenic
effects

Myocardial
hypertrophy

Heart
t

Dzau VJ. Arch Intern Med. 1993;153

LVH & THE RAAS

CIRCULATING LEVELS OF ANGIOTENSIN II &

ALDOSTERONE ARE DIRECTLY TO LVM
ANGIOTENSIN II
INCREASES BP
PROMOTESS MYOCYTE GROWTH
INDUCES HYPERTROPHY OF SMOOTH MUSCLE
CELLS
ALDOSTERON : INCREASES FIBROBLAST
COLLAGEN CONTENT & STIMULATES MYOCARDIAL
FIBROSIS
Kim, Iwao. Pharmacol Rev 2000;52:1134

Angiotensin II
Vascular ROS production
Endothelial dysfunction
(Reduced NO availability)

LDL oxidation

Pro-inflammatory
gene expression
(eg. VCAM-1 and MCP-1)

Vascular inflammation
Progression and clinical complications of atherosclerosis
(Landmesser & Drexler, 2003)

Pleiotropic Cardiovascular Effects of Angiotensin II

Angiotensin II

Direct vasoconstriction
Sympathetic activation

Vasoconstriction

Endothelial
dysfunction

Cell growth

Inflammation
cytokine
Superoxide

Cardiac and
vascular
remodelling

Na reabsorption
aldosterone

Volume

ATHEROSCLEROSIS
BLOOD PRESSURE
(SKK/2000)

Pleiotropic effects of ACEI

Fibrinolysis
Mononuclear
cell migration

NO
MMP activity

Collagen matrix
formation
Endothelial function

BPAHTN
lowering
agents
agents

Plaque stability

Cholesterol
deposition
in membrane

Arterial
compliance

Both
Oxidative stress

Platelet aggregation

MMP = matrix metalloproteinase

Inflammation

VSMC proliferation

Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-A8.

Wassman S and Nickenig G. Eur Heart J Suppl. 2004;6(suppl H):H3-H9.
Mason RP et al. Arterioscler Thromb Vasc Biol. 2003;23:2155-63.

ACE inhibition: BP-lowering mechanisms

A II synthesis
Bradykinin, prostacyclin, NO production

Endothelin synthesis
Parasympathetic tone
Central and peripheral sympathetic tone
Natriuresis/diuresis

HEART FAILURE AND NEUROHORMONAL

STIMULATION
Myocardial cell
death

+
Heart failure

Myocardial cell
death

Myocardial O2

Myocardial O2
expenditure

expenditure

Cardiac output
_

Afterload

Inotropy

Neurohormonal stimulation

Renin Angiotensin
Vasoconstriction

Sympathetic - adrenergic

Cytosolic
++

Ca

Arrhythmias
Circulation

Heart

CHAIN LEADING TO HEART FAILURE

Myocardial
infarction

Coronary
thrombosis

Myocardial
ischemia
CAD

Arrhythmias

Neurohormonal
activation

Sudden
death

Remodeling
Stroke

Atherosclerosis

Ventricular
dilation

Renal failure
Risk factors
Hyperlipidemia
Hypertension
Diabetes
Smoking

Loss of
muscle

LV Hypertrophy

Heart Failure

Modified after Dzau & Braunwald Am Heart J 1991

SUMMARY
ANGIOTENSIN II ARE RISK FOR NOT JUST HYPERTENSION
BUT ATHEROGENESIS WITH RUPTUR PLAQUE,
REMODELLING WITH THE RISK OF STROKE, HEART FAILURE
EVEN RENAL FAILURE

ANGIOTENSIN II RECEPTOR BLOCKER, ACE I & ANTI

RENNIN ACT NOT JUST TO COMBAT HYPERTENSION BUT
MORE IMPORTANT IS TO PROTEC TARGET ORGAN

RECOMENDATION: THESE KIND OF DRUGS MUST INCLUDE IN

THE TREATMENT OF ALL HYPERTENSION, HEART FAILURE,
RENAL FAILURE & STROKE