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

FIHA, FASCC, FINASIM

Internist [SpPD] 1981

Cardiovascular Consultant [KKV] 1996

Cardiologist [SpJP] 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 2003Amato 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 MEN WOMEN

DIAGNOSE OF HF

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,pleuraleffusion,raised jugular venous pressure,peripheraloedema,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

NormalLV structure and function

Hypertension HF

Overt heart failure

SmokingDyslipidaemiaDiabetes

ObesityDiabetes

LV remodelling

LVH

MISystolic

dysfunction

Diastolicdysfunction

Subclinical LV dysfunction

Time: decades Time: months

Death

PROGRESSION HYPERTENSION – HEART FAILURE

.

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

Blood vessel

KIDNEY Adrenal cortex

LIVER

Endothelial cells

Angiotensinogen

Angiotensin I

ACE

Angiotensin II

Aldosteron

Renin

Kidney Kidney

Intraglomerular

hypertension

Tissue RAS

Long-term effects

Circulating RAS

Short-term effects

Sodium/water reabsorption

via aldosterone secretion

Vasoconstriction

HeartHeart

t

Positive chronotropic

effects/

arrhythmogenic

effects

Angiotensin II

Myocardial

hypertrophy

Vascular

hypertrophy

Circulating and tissue RAS influence on the cardiovascular system

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;52:11–34

Vascular inflammation

Progression and clinical complications of atherosclerosis

Angiotensin II

Vascular ROS production

Endothelial dysfunction(Reduced NO availability)

LDL oxidation

Pro-inflammatory

gene expression

(eg. VCAM-1 and MCP-1)

(Landmesser & Drexler, 2003)

Angiotensin II

Direct vasoconstriction

Sympathetic activationEndothelial

dysfunctionCell growth Na reabsorption

aldosterone

Vasoconstriction Inflammation

cytokine

Superoxide

Cardiac and

vascular

remodelling

Volume

ATHEROSCLEROSIS

BLOOD PRESSURE

(SKK/2000)

Pleiotropic Cardiovascular Effects of Angiotensin II

Pleiotropic effects of ACEI

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.

Fibrinolysis

Platelet aggregation

Mononuclear cell migration

Collagen matrix formation

Endothelial function

Oxidative stress Inflammation

Plaque stability

Arterial compliance

NO

MMP activity

VSMC proliferation

Cholesterol depositionin membrane

MMP = matrix metalloproteinase

AHTN

agents

BP-

lowering

agents

Both

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

Cytosolic

Ca ++

Arrhythmias

Inotropy

Myocardial O2

expenditure

Myocardial cell

death

Heart

+

+

Vasoconstriction

Afterload

Myocardial O2

expenditure

Myocardial cell

death

Circulation

_

+

Heart failure

Cardiac output

Neurohormonal stimulation

Renin – Angiotensin

Sympathetic - adrenergic

Modified after Dzau & Braunwald Am Heart J 1991

Risk factors• Hyperlipidemia• Hypertension• Diabetes• Smoking

Atherosclerosis

CAD

Myocardialischemia Neurohormonal

activation

Loss of muscle Sudden

death

Remodeling

Ventriculardilation

Heart Failure

Coronary thrombosis

Myocardial infarction

Arrhythmias

Stroke

Renal failure

LV Hypertrophy

CHAIN LEADING TO HEART FAILURE

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