peny. kardiovaskuler

PENYAKIT KARDIOVASKULER

Suhendiwijaya, Sp.JP., FIHA., FAsCC

SMF. Kardiovaskuler

RSUD Gunung Jati

THE CARDIOVASCULAR CONTINUUMTHE CARDIOVASCULAR CONTINUUM

Acute CoronarySyndrome

Arrhythmia &loss of muscle

Remodelling

Ventriculardilatation

Congestiveheart failure

Death

Coronarythrombosis

Myocardialischaemia

CAD

AtherosclerosisLVH

Sudden Death

Risk factors

Normal Artery

FoamCells

FattyStreak

IntermediateLesion Atheroma

FibrousPlaque

ComplicatedLesion/Rupture

Endothelial dysfunction

Smooth muscleand collagen

From first decade From third decade From fourth decade

Growth mainly by lipid accumulationThrombosis,haematoma

Adapted from Stary HC et al. Circulation 1995;92:1355-1374.

Atherosclerosis Timeline

Faktor Risiko

• Faktor Risiko Utama

1. Merokok

2. Hipertensi

3. Hiperkolesterol

• Faktor Risiko Sekunder

1. Hipertrigliserid 6. Umur

2. Diabetes Mellitus 7. Stress

3. Obesitas 8. Kurang aktifitas

4. Jenis Kelamin 9. Homosistein

5. Genetik 10. Inflamasi

x1.6 x4

x3

x6

x16x4.5 x9

Hypertension(SBP 195mmHg)

Serum cholesterol level(8.5mmol/l, 330mg/dl)

Smoking

(Adapted from Poulter et al., 1993)

Levels of Risk Associated with Smoking,Hypertension and Hypercholesterolaemia

Atherosclerosis

• A disease of the intima

• Atheromas, atheromatous / fibrofattyplaques, fibrous plaques

• Narrowing / occlusion; weakness ofwall

ATHEROSCLEROSIS :Pathology, Pathogenesis, Complications, Natural History

Endothelial cell Monocyte Macrophage Foam cell Smooth muscle cell

Internal elasticlamina

Vessel lumen

1. Endothelialpermeability

4. SMCmigration2. Monocyte

adhesion andtransmigration

Increased stiffness

3. Macrophagetransformationinto foam cells

The major cellular events in theprogression of atherosclerosis

http://www.robbinspathology.com/content/lightbox.cfm?action=add&ImgID=F011007&ImgBody=graphics/S01871-011-f007.jpg&ID=iBox

Major components of plaque

• Cells (SMC, macrophages and other WBC)

• ECM (collagen, elastin, and PGs)

• Lipid = Cholesterol (Intra/extracellular)

• (Often calcification)

Two major processes in plaque formation

• Intimal thickening (SMC proliferation andECM synthesis)

• Lipid accumulation

Response to injury hypothesis

* Injury to the endothelium

(dysfunctional endothelium)

* Chronic imflammatory response

* Migration of SMC from media to intima

* Proliferation of SMC in intima

• Excess production of ECM

• Enhanced lipid accumulation

Response to injury hypothesis (I)

1. Chronic EC injury (subtle?)

– EC dysfunction

– Increased permeability

– Leukocyte adhesion (via VCAM-1)

– Thrombotic potential

Response to injury hypothesis (II)

2. Accumulation of LDL (cholesterol)

3. Oxidation of lesional LDL

4. Adhesion & migration of bloodmonocytes; transformation intomacrophages and foam cells

5. Adhesion of platelets

6. Release of factors from platelets,macrophages and ECs

Response to injury hypothesis (III)

7. Migration of SMC from media to intima

8. Proliferation of SMC

9. ECM production by SMC

10.Enhanced lipid accumulation

- Intracellular (SMC and macrophages)

- Extracellular

Response to Injury

Endothelial Dysfunction

Initiation of Fatty Streak

Fatty Streak

Fibro - fatty Atheroma

Consequences ofAtherosclerosis

Altered Vessel Function

• Vessel change– Plaque narrows

lumen

– Wall weakened

– Thrombosis

– Breaking loose ofplaque

– Loss of elasticity

• Consequence

– Ischemia, turbulence

– Aneurysms, vesselrupture

– Narrowing, ischemia,embolization

– Athero-embolization

– Increase systolic bloodpressure

Consequences of plaque formation

Generalized

– Narrowing/Occlusion

– Rupture

– Emboli

– Leading to specific problems:

• Myocardial and cerebral infarcts

• Aortic aneurysms

• Peripheral vascular disease

Fig. 11.7

Printed from: Robbins & Cotran Pathologic Basis of Disease (on 11 April 2005) © 2005 Elsevier

AHA Classification of atherosclerosis



Summary of Atherosclerotic Process

• Multifactorial process (risk factors)

• Initiated by endothelial dysfunction

• Up regulation of endothelial and leukocyte adhesionmolecules

• Macrophage diapedesis

• LDL transcytosis

• LDL oxidation

• Foam cells

• Recruitment and proliferation of smooth muscle cells(synthesis of connective tissue proteins)

• Formation and organization of arterial thrombi

Atherosclerotic Process

Coronary Artery Disease

Coronary Artery Disease

Atherosclerotic Coronary Artery Disease

Ischemic Heart Disease (IHD)

Myocardial Ischemia

• Results when there is an imbalance betweenmyocardial oxygen supply and demand

• Resulting from coronary artery narrowing orobstruction

• Most occurs because of atheroscleroticplaque with in one or more coronary arteries

• Limits normal rise in coronary blood flow inresponse to increase in myocardial oxygendemand

Dr. Afzal Haq Asif 38

39

Ischemic Heart Disease

• Angina Pectoris, stable, classical, exertional angina,Ischemia causing Pain at exertion

• Variant Angina, prinzmetal, vasospastic Angina

• Acute Coronary Syndrome :

– Unstable Angina

– Non ST Elevation MI (Non STEMI)

– ST Elevation (STEMI)

Angina

• When ischemia results it is frequentlyaccompanied by chest discomfort :Angina Pectoris

• In the majority of patients with angina,development of myocardial ischemiaresults from a combination of fixed andvasospastic stenosis

41

Classes of Angina(Canadian Cardiovascular Society = CCS)

Class INormal physical activity (e.g., climbing stairs or walking) does not cause anginal

symptoms; angina occurs primarily with strenuous, extended, or rapid physical

activity or recreation

Class IIAngina poses a slight limitation on ordinary activity and typically occurs with the

following types of activities : Quickly walking or climbing stairs

Uphill walking

Walking/stair climbing after meals

Windy or cold weather

Emotional stress

Within the first few hours after waking

Walking more than two blocks or climbing more than one flight of stairs at a normalpace (under normal conditions)

Class IIIAnginal symptoms impose marked limitation on physical activity; angina occurs

upon walking one to two blocks or climbing one flight of stairs at a normal pace

(under normal conditions

Class IVSymptoms of angina may be present at rest; physical activity cannot be carried out

without discomfort

Angina Pectoris

• Angina Pectoris : uncomfortable sensationin the chest or neighboring anatomicstructures produced by myocardialischemia

Silent Ischemia

• Asymptomatic episodes of myocardialischemia

• Detected by electrocardiogram andlaboratory studies

44

Pathophysiology

Inadequate coronary perfusion.

Caused by increased myocardial oxygen

requirements, created during increased activity or

stress,

Leading to a supply-demand mismatch and

resulting in ischemia.

Progression of ATHEROSCLEROSIS in the

coronary arteries can lead to plaque deposition

external to the lumen,

Intruding into the lumen, causing obstruction, and,

therefore, angina

45

Pathophysiology : Risk Factors

• Positive family history, First Degree relatives with onset before 50.

• Age

• Male gender

• Lipid abnormalities LDL / HDL >5

• Hypertension

• Sedentary lifestyle

• Smoking , after 1 year of quitting, risk decreases to 50%

• Metabolic Syndrome: When any three or more of the following pre

1. Abdominal obesity

2. Triglycerides : > 150 mg/dL,

3. HDL < 40 mg/dL

4. Fasting glucose > 110 mg/dL

5. Hypertension

• Hyperuricemia

• Markers of Inflammation :

CRP , Interleukin-6 , CD-40 ligend Myeloperoxidase, Placental growthfactor

46

Pathophysiology

• Fatty streak (Subendothelial lipid andmacrophage accumulation)

• Migration of smooth muscle cells

• Abnormal endothelial function

• Formation of fibrous cap

• Calcification

• Narrowing of lumen

• Unstable plaque ruptureThrombosisocclusion

47

• Diagnostic Criteria– Symptoms ------- anamnesis– ECG, scan showing ischemia– Angiographic evidence.

• Clinical Findings– Precipitating & relieving factors– Characteristics of pain– Location, radiation– Duration– Effect of nitroglycerine– Risk factors– Signs– Differential diagnosis

Angina Pectoris

49

Angina Evaluation

• Lab. tests

• ECG

• ETT (treadmill test)

• Radionuclide studies ------- perfusionscan

• Echocardiogram

• Stress - Echo

• MRI / MSCT

• Coronary Angiography

Treadmill test

Echocardiogram

Coronary Angiography

Management Angina Pectoris

The short term goals :• Prevent complications – myocardial infarction, and

to prolong life

The long term goals :• to prevent CHD events such as MI, arrhythmias, and

heart failure

• to extend the patient's life.

Goals to reduce Anginal Symptoms

Management Angina Pectoris

Control of aggravating factors : risk factorsmodification

Medical / pharmacolgic treatment – drugs

Coronary intervention as angioplasty andcoronary stent implatation

Coronary artery bypass grafting (CABG)

Goals to reduce Anginal Symptoms

59

Risk Factor Modification

• Primary prevention through the modification of risk factors shouldsignificantly reduce the prevalence of IHD.

• Secondary intervention is effective in reducing subsequent morbidity andmortality.

• Risk factors for IHD

– Unalterable risk factors

• gender, age, family history or genetic composition, environmentalinfluences, and, to some extent, diabetes mellitus.

– Alterable risk factors

• Smoking, hypertension, hyperlipidemia, obesity, sedentarylifestyle, hyperuricemia,

• Psychosocial factors such as stress and type A behavior patterns,

• Drugs : progestins, corticosteroids, and cyclosporine).

• Thiazide diuretics and Beta blockers (nonselective without intrinsicsympathomimetic activity) may elevate both cholesterol andtriglycerides by 10% to 20%, but no objective evidence exists fromprospective well-controlled studies to support avoiding these drugs

Pharmacologic Therapy

• Therapy is aimed in restoring balancebetween myocardial oxygen supply anddemand

• Useful Agents: nitrates, beta-blockers andcalcium channel blockers, Plateletinhibiting agents and Lipid lowering agent

Nitrates

• Reduce myocardial oxygen demand

• Relax vascular smooth muscle

• Reduces venous return to heart

• Arteriolar dilators decrease resistanceagainst- which left ventricle contracts andreduces wall tension and oxygen demand

Nitrates : cont

• Dilate coronary arteries with augmentationof coronary blood flow

• Side effects: generalized warmth, transientthrobbing headache, or lightheadedness,hypotension

• ER if no relief after X2 nitro's: unstableangina or MI

Problems with Nitrates

• Drug tolerance

• Continued administration of drug willdecrease effectiveness

• Prevented by allowing 8 – 10 hours nitratefree interval each day.

• Elderly / inactive patients: long acting nitratesfor chronic antianginal therapy isrecommended

• Physical active patients : additional drugs arerequired

Beta Blockers

• Prevent effort induced angina

• Decrease mortality after myocardialinfarction

• Reduce Myocardial oxygen demand byslowing heart rate, force of ventricularcontraction and decrease blood pressure

Beta adrenergic receptors

1 2

vasoconstriction

heart rate

contractility

coronary vasoconstriction

bronchodilatation

vasodilatation

Beta-adrenergic blocking drugs

Nonselective Selective -blockingactivity

ISA – ISA –ISA + ISA +

Nadolol

Propanolol

Timolol

Sotalol

Alprenolol

Oxprenolol

Pindolol

Penbutolol

Atenolol

Bisoprolol

Esmolol

Metoprolol

Acebotolol

Celoprolol

Bucindolol

Carvedilol

Labetolol

Beta -1

• Block myocardial receptors with less effecton bronchial and vascular smooth muscle-patients with asthma, intermittentclaudication

Beta - Agonist blockers

• With partial B-agonist activity:

• Intrinsic sympathomimetic activity (ISA)have mild direct stimulation of the betareceptor while blocking receptor againstcirculating catecholamines

• Agents with ISA are less desirable inpatients with angina because higher heartrates during their use may exacerbateangina

• not reduce mortality after AMI

Contraindications

• Symptomatic CHF, history ofbronchospasm, bradycardia or AV block,peripheral vascular disease with s/s ofclaudication

Side Effects

• Bronchospasm (RAD), CHF, depression,sexual dysfunction, AV block, exacerbationof claudication, potential masking ofhypoglycemia in IDDM patients

Abrupt Cessation

• Tachycardia, angina or MI

• Inhibit vasodilatory beta 2 receptors

• Should be avoided in patients withpredominant coronary artery vasospasm

Beta-Blockers: Long Term effects

• Serum lipids: decrease of HDL cholesteroland increased triglycerides

• Effects do not occur with beta-blockerswith B-agonist activity or alpha-blockingproperties

Calcium Channel Blockers

• Anti-anginal agents prevent angina• Helpful: episodes of coronary vasospasm• Decreases myocardial oxygen

requirements and increase myocardialoxygen supply

• Potent arterial vasodilators: decreasesystemic vascular resistance, bloodpressure, left ventricular wall stress withdecrease myocardial oxygen consumption


• Secondary agents in management ofstable angina

• Are prescribed only after beta blockersand nitrate therapy has been considered

• Potential to adversely decrease leftventricular contractility

• Used cautiously in patients with leftventricular dysfunction

Class :

A. Dihydropyridin : Nifedipine, amlodipine,felodipine, clevidipine, Lacidipine,Lercanidipine, Nicardipine, etc

B. Non-dihydropyridin

- Phenylalkylamin : verapamil

- Benzothiazepine : diltiazem

C. Nonselective : fendiline, mibefradile,befridile, fluspirilene


Nifedipine and other dihydropyridinecalcium channel blockers

• Fall in blood pressure, trigger increaseheart rate

• Undesirable effect associated withincreased frequency of myocardialinfarction and mortality

Amlodipine and Felodipine

• Are newer CCB

• Decrease (-) inotropic effects

• Amlodipine is tolerated in patients withadvanced heart failure without causingincrease mortality when added with aceinhibitor, diuretic, and digoxin

Non-dihydropyridine

a. Phenylalkilamine (Verapamil)- reduce myocardial oxygen demand and

reserve coronary vasospasm- have minimal vasodilatory effects- causing negative inotropic

b. Benzothiazepine (Diltiazem)- intermediate class between

phenylalkilamine and DHP- reduce arterial pressure without producing

reflex cardiac stimulating


CCB HRAV Node

ConductionMyocardial

contractilityArteriolar

vasodilation

Verapamil

Diltiazem

DHPs 0/ 0 0/

Anti Plattelet Agent

The aim of therapy is to prevent thrombus formation byinhibiting platelet aggregation. Antiplatelet therapy has been shown to reduce the odds

of serious vascular events. Four main classes of antiplatelet drug:

1. Cyclooxygenase inhibitors (e.g. aspirin)2. Thienopyridine derivatives (e.g. clopidogrel and

ticlopidine)3. Phosphodiesterase inhibitors (e.g. cilostazol,

dipyridamole)4. Glycoprotein IIb/IIIa receptor blockers (e.g.

abciximab)

No Jenis Anti-Agregasi Platelet Mekanisme Kerja Contoh

1 Penghambat Thromboxan A2 Menghambat ensimsiklo-oksigenase padajalur pembentukanmediator inflamasisehingga tidakterbentuk thromboxanA2

Asam AsetilSalisilat/Acytyl SalicylicAcid (ASA)

2 Penghambat reuptake adenosin Menghambat re-uptake adenosin yangdilepaskan pada saatterjadi luka

Dipyridamol

3 Glycoprotein (GP) llb/llla Blocker Menghambat ikatanfibrinogen dan faktorvon Willebrand padareseptor GP llb/llla

Parenteral: Abciximab,Eptifibatide, Tirofiban

4 Antagonis reseptor ADP Menghambat ikatanADP denganreseptornya di platelet

Clopidogrel,

Ticlopidine

5 Penghambat Phosphodiesterase lll Menghambat ensimPDE lll, sehingga tidakterbentuk ADP

Cilostazol

Anti Agregasi Platelet

Lipid Lowering Agent

ATP III: New Features of Guidelines —Updated Lipid/Lipoprotein Classifications

• Optimal LDL-C level: identified as <100mg/dL

• Categorical low HDL-C: raised to <40 mg/dL to moreaccurately define patients at increased risk

• TG classification cutpoints: lowered to focus moreattention on moderate elevations

– normal: <150 mg/dL

– borderline high: 150–199 mg/dL

– high: 200–499 mg/dL

– very high: 500 mg/dL

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

ATP III: LDL-C, HDL-C, TC Classification


High 240

Borderline high200 – 239

Desirable< 200

TC (mg/dL)

High 60

Low< 40

HDL-C (mg/dL)

Very high 190

High160 – 189

Borderline high130 – 159

Above, near optimal100 – 129

Optimal< 100

LDL-C (mg/dL)

ATP III : Risk Categories, LDL-C Goals

<1600 – 1 risk factor*

<130 2 risk factors(10 - year risk 20%)

<100CHD and CHD risk equivalents(10-year risk >20%)

LDL-C Goal (mg/dL)Risk Category

*Almost all people with 0–1 risk factor have a 10-year risk <10%;thus, Framingham risk calculations are not necessary.


ATP III: LDL-C Treatment Cutpoints forTherapy

*Therapeutic lifestyle changes†Some authorities use LDL-C–lowering drugs if TLC does notachieve LDL-C <100 mg/dL; others use drugs to modify HDL-Cand TG.

190 mg/dL(160–189 mg/dL: LDL-C–lowering

drug optional)

160 mg/dL0–1 risk factor

10-year risk 10% – 20%: 130 mg/dL10-year risk 10%: 160 mg/dL

130 mg/dL2 risk factors

130 mg/dL(100–129 mg/dL: drug optional)†

100 mg/dLCHD and CHD riskequivalents

Consider Drug TherapyInitiate TLC*Risk Category


ATP III: The Metabolic Syndrome*

*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI.‡Some men develop metabolic risk factors when circumference is only marginallyincreased.


<40 mg/dL<50 mg/dL

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

110 mg/dLFasting glucose130/85 mm HgBlood pressure

HDL-C150 mg/dLTG

Abdominal obesity†

(Waist circumference‡)

Defining LevelRisk Factor


• Bile acid sequestrants

• Nicotinic acid derivates

• Fibrates

• Statins

• Others :

- selective cholesterol – absorption

inhibitor

- omega-3 fish oil


• Bile acid sequestrants

Drug Available Dosage Remarks

Cholestyramine 4 g/packet bulkpowd

4 g mixed in liqPO once-6x/dayMax dose :24 g / day

Adversereaction :GI effects

Colestipol 5 g/packet bulkpowd

5-30 g mixed inlig PO once dailyor in divided dose

1 g/tab 2-16 g PO oncedaily or in divideddose


• Fibrates

Drug Dosage Remarks

Bezafibrate 200 mg PO bid-tid Adverse reaction :• GI effects• myalgia,myopathy,rarelyrhabdomyolysis

Fenofibrate Regular release:100 mg, 300 mgMicronized :200 mgNanotechnology formula :145 mg POSuprabioavailable formula :160 mg PO

Gemfibrozil 600 mg POMax dose : 1500 mgExtended release : 900 mg


• Nicotinic acid derivates

Drug Dosage Remarks

Acipimox 250 mg POMax dose : 1250 mg

Adverse raection :• flushing, itching, rash, GI effects,headache

Nicotinic acid Regular :100 200 mg tidExtended release :Once daily atbedtimeWk 1 : 375 mgWk 2 : 500 mgWk 3 : 750 mgWk 4 – 7 : 1 g

Adverse raection :• flushing, itching, rash, GI effects,headache


• Statins

Drug Dosage Remarks

Simvastatin ID : 5 – 20 mg once dailyDR : 5 – 40 mgMD : 80 mg/day PO

Atorvastatin ID : 10 – 20 mg PO daily anytime

DR : 10 – 80 mg /dayMD : 80 mg

Fluvastatin ID : 20 – 40 mg PO once daily

Pravastatin ID : 10 – 20 mg PO daily at bedtime

DR : 10 – 40 mg

Rosuvastatin ID : 10 mg PO once daily


• Others

Drug Dosage Remarks

Ezetimibe 10 mg once daily Adverse reaction :• Headache,

abdominal pain,diarrhea

• when adminitered w/a statin : dizzines,fatique, arthralgia

Omega-3 fish oil 1 – 4 g/day PO in 2 divided dose

96

Revascularization

Indication :

1. Patients with unacceptable symptoms despite

maximum tolerable medical therapy

2. Patients with triple vessel disease with LVdysfunction

3. Patients with left main coronary artery stenosis

more than 50%, with or without symptoms

4. Patient of unstable angina, controlled on drugs

but exhibit ischemia on exercise testing

5. Post MI angina, or severe ischemia

97

Revascularization

• PCI / PTCA (Percutaneus CoronaryIntervention / coronary angioplasty)

• CABG

98

Secondary Prevention

1. Smoking cessation

2. Treatment of dyslipedemia

High LDL: Simvastatin, Atorvastatin, Low HDL: Niacin,Gemfibrozel, Fenofibrate

3. Treatment of HT

4. Antiplatelet Therapy : Aspirin 100-325 mg/day

5. Omega-3 fatty acids 1g/day

6. Physical exercise: Consult physician for secondary prevention

Minimum 30 min/week

30 min 3 times/week

30 min 5 times/week 50% decrease in risk of DM

THE CARDIOVASCULAR CONTINUUMTHE CARDIOVASCULAR CONTINUUM

Acute CoronarySyndrome

Arrhythmia &loss of muscle

Remodelling

Ventriculardilatation

Congestiveheart failure

Death

Coronarythrombosis

Myocardialischaemia

CAD

AtherosclerosisLVH

Sudden Death

Risk factors

peny. kardiovaskuler

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