PATOFISIOLOGI PENYAKIT KARDIOVASKULERPugud SamodroBag Ilmu Penyakit Dalam FKIK Unsoed / RSUD Prof Margono Soekarjo Purwokerto

Patofisiologi Penyakit KardiovaskulerPenyakit Jantung KoronerHipertensiAritmia

Penyakit Jantung Koroner

Definisi Kelainan jantung yg disebabkan oleh kelainan arteri koronaria

Etiologi Proses atherosklerosis pada arteria koronaria

Pendahuluan Keseimbangan kebutuhan dan suplai O2 miokardFaktor penentu kebutuhan O2 - frekuensi denyut jantung - daya kontraksi - massa otot - tegangan dinding ventrikelTegangan dinding ventrikel : - tek intraventrikuler - radius ventrikel - tebal ventrikel

Pendahuluan Kebutuhan O2 : - takikardia - peningkatan daya kontraksi jantung - hipertensi - hipertrofi - dilatasi ventrikelRangsangan dilatasi koroner : hipoksia jaringan lokal

Pendahuluan Iskemia keadaan kekurangan O2 yg bersifat sementara & reversibelIskemia lama nekrosis (infark)Ventrikel kiri paling rentan : - kebutuhan O2 - aliran darah koroner bersifat fasik

PatogenesisAterosklerosis koroner

Timbunan lipid & jar fibrosa

Lumen koroner sempit

Resistensi aliran darah

Ketidakseimbangan suplai & kebutuhan O2

Iskemia (infark)

Kolesterol & trigliserida jangka lama Endapan pada pembuluh darahPembuluh darah menjadi kaku / kerasAliran darah tersumbatOtak: strokeJantung : penyakit jantung koronerPembuluh darah perifer : PAD

Patologi

Atherosclerosis Timeline

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.

FoamCells

FattyStreak

IntermediateLesion

Atheroma

FibrousPlaque

ComplicatedLesion/Rupture

From FirstDecade

From ThirdDecade

From FourthDecade

Historical Model of Atherogenesis

Threshold

Decades

Years-Months

Months-Days

Plaque

Intima

Media

Lumen

Stable angina Stable plaques with narrowing Simple diagnostic (ECG, angiography) Rare MI Easy to treat

Antischkow N. Beitr Path Anat Allg Path 1913;56:379404.

New Paradigm

Threshold

Decades

Years-Months

Months-Days

Intima

Media

Plaque

Thrombus

Lumen

Unstable anginaUnstable plaque no narrowingDifficult to diagnose (IVUS, MRI)Frequent MI with sudden deathEasy to prevent

Pathogenesis of Atherosclerotic Plaques

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to sticky surface of endothelial cells

Migrate through arterial wall to subendothelial space

Lipid-rich foam cells

Endothelial damage

Macrophages take up oxidised LDL-C

Fatty streak and plaque

activated endothelium

CELLULAR ADHESION MOLECULES

induces cell proliferation and a prothrombic state

attracts monocytes and T lymphocytes which adhere to endothelial cells

Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T1926.

The Activated Endothelium

Libby P. Circulation 1995;91:28442850.

The Synthesis and Breakdown of Atheromatous Plaques

Libby P. Circulation 1995;91:28442850.

The Vulnerable Atherosclerotic Plaque

SMC smooth muscle cellHDL-DR transplantation antigen indicating activation of SMCs

Global Burden of Cardiovascular Disease

In 2002:CVD contributed to approximately a third of all global deaths (17 million) 80% of burden is in low and middle-income countries

By 2020:CHD and stroke will become the leading cause of death and disability worldwideMortality from CVD will increase to 20 million

Clinical care of CVD is costly and prolonged

International Cardiovascular Disease Statistics 2005; AHA.

LDL-C achieved mg/dL (mmol/L)

WOSCOPS Placebo

AFCAPS - Placebo

ASCOT - Placebo

AFCAPS - Rx

WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Placebo

LIPID - Rx

4S - Placebo

CARE - Rx

LIPID - Placebo

CARE - Placebo

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Event rate (%)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPRA pravastatinATV - atorvastatin

200(5.2)

PROVE-IT - PRA

PROVE-IT ATV

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279LaRosa JC et al. N Engl J Med 2005;352:1425-1435

TNT ATV10

TNT ATV80

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials Lower is Better

PLAC-1

PLAC-1

LCAS-1

REGRESS

CCAIT

CCAIT

MARS

MAAS

MARS

REGRESS

MAAS

LCAS

2.180

2.6 100

3.1 120

3.6140

4.1160

4.7180

0

0.01

0.02

0.03

0.04

0.05

0.06

Treatment

Placebo

?

LDL-C Levels Correlate with Angiographic Progression

MLD decrease (mm/y)

LDL-C (mmol/L, mg/dL)

LDL-C=low-density lipoprotein cholesterol; MLD=minimum lumen diameter r2=0.71; p=0.0005

Adapted from Ballantyne CM et al. Curr Opin Lipidol 1997; 8: 354361

Imaging Techniques Used to Assess Atherosclerosis

Invasive techniquesIntravascular ultrasound (IVUS)Coronary angiography

Non-invasive techniquesMagnetic resonance imaging (MRI)Computed tomography (CT)Ultrasound (B-mode)

Magnetic Resonance Image (MRI) of a Stenotic Carotid Artery Bifurcation

left carotid artery bifurcation with an atherosclerotic plaque with a necrotic core

relatively normal artery

Chu B et al. Stroke 2004;8:24442448.

Computed Tomography (CT)Showing Atherosclerotic Artery

B-mode Ultrasound

Reproduced with permission from Kastelein, JJP et al. Am Heart J 2005;149:234239.

The IVUS Coronary Imaging Technique

Rotating transducer

Normal coronary anatomy

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

GALAXY ProgrammeTM Studies

AURORACORONAJUPITER

ASTEROIDCOSMOSMETEORORION

CENTAURUS COMETS DISCOVERY ECLIPSEEXPLORERLUNARMERCURY IMERCURY IIORBITALPLUTOPOLARISPULSARSTELLAR

GALAXY ProgrammeTM studies with rosuvastatin, investigating:

Atherogenic lipid profile+/- inflammatory markers

Atherosclerosis

Reduction in CV morbidity & mortality

Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200

GALAXY atherosclerosis studies

1. Hatsukami TS et al. Atherosclerosis Supplements 2001; 2 (2): 47-8, Abs P42. Chu B et al. Atherosclerosis Supplements 2003; 4 (2): 253, Abs 3P-0871 3. Chu B et al. Atherosclerosis Supplements 2003; 4 (2): 253, Abs 3P-0872 4. Crouse III JR et al. Cardiovascular Drugs and Therapy 2004;18:23138 5. Nissen S. Atherosclerosis Supplements 2003; 4 (2): 27, Abs 1P-0037

STUDYOVERVIEW

A 24-month, randomised, double-blind study to assess the progression of carotid artery atheroma using MRI and ultrasound in hypercholesterolaemic subjects with asymptomatic carotid disease following treatment with CRESTOR 5mg or 40mg1-3

A 24-month, randomised, double-blind, placebo-controlled study to evaluate CRESTOR 40mg on the progression of carotid atherosclerosis by measuring intima media thickness (IMT) in low risk, asymptomatic, hypercholesterolaemic subjects with sub-clinical evidence of atherosclerosis4

A 24-month, open-label, non-comparative study using IVUS and QCA to evaluate the effect of CRESTOR 40mg on the regression of coronary artery atheroma in patients with coronary artery disease who require coronary angiography5

rosuvastatin low dose 5 mg (n=21)

rosuvastatin high dose 40/80 mg (n=22)*

Lipids

Week:

6

8

104

1

0

12

20

28

40

52

2

2

4

78

65

91

Carotid ultrasound

Safety

MRI

Inflammatory markers

Dietary run in / eligibility

1Hatsukami TS, et al. Atheroscler Suppl 2001;2:47 2Chu B, et al. Stroke 2004;35:2444-2448

*In the ORION protocol, the original intention was that all subjects in the high-dose group received rosuvastatin 40 mg for 4 wks and were then up-titrated to rosuvastatin 80 mg. Back titration to 40 mg occurred for subjects who achieved LDL-C levels

Reductions in LDL-C and % LRNC*with Low- and High-dose Rosuvastatin

LDL-C

% LRNC

Mean change from baseline (%)

**P

ASTEROID

A Study To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden

Nissen SE: Presented at ACC 55th Annual Scientific Session, March 11-14, Atlanta, USA; Late Breaking Clinical Trials II

The IVUS Technique Can Detect Angiographically Silent Atheroma

Nissen SE, Yock P. Circulation 2001; 103: 604616

Angiogram

IVUS

Little evidence of disease

Atheroma

No evidence of disease

Prior Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50

60

70

80

90

100

110

120

MedianChangeIn PercentAtheroma Volume(%)

Mean LDL-C (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

UnexploredRegion

?

Nissen SE: Presented at ACC 55th, March 11-14, Atlanta, USA; Late Breaking Clinical Trials II

ASTEROID: Hypothesis and Objective

Objective:To evaluate whether 24 months treatment with rosuvastatin 40 mg will result in regression in coronary atherosclerosis as measured by IVUS.

Primary hypothesis:Very intensive lipid lowering will reduced coronary atheroma burden using two separate IVUS efficacy parameter.

Null hypothesis:Treatment will result in either progression or no change in disease burden.

Nissen SE: Presented at ACC 55th Annual Scientific Session, March 11-14, Atlanta, USA; Late Breaking Clinical Trials II

Rosuvastatin 40 mg (n=349 evaluated serial IVUS examinations)

PatientsCAD, undergoing coronary angiographyTarget coronary artery: 50% reduction in lumen diameter of 40 mm segmentNo cholesterol entry criteria18 years

Visit:Week:

Lipids

Lipids Tolerability

IVUS Lipids Tolerability

Lipids Tolerability

Tolerability

Tolerability

Tolerability

16

20

313

426

539

652

765

878

991

10104

Eligibility assessment

CAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound

ASTEROID study design

IVUS Lipids

Endpoint analysis: Change in median percentage atheroma volume

*p

*p

Number (%) of patients showing regression measured by each IVUS parameter

Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.

Example of regression of atherosclerosis with rosuvastatin in ASTEROID, measured by IVUS

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

Summary

Atherosclerosis known as chronic, progressive disease characterized by continuous plaque within arterial wallThree method invasive and non invasive are available to asses the atheromatus plaques within the vessel : MRI, B-Mode Utrasound and IVUSORION study show that dangerous Lipid Rich Necrotic Core of Atherosclerosis can be reduce by Rosuvastatin therapyASTEROID showed for the first time that regression of atherosclerosis can be achieved significantly with intensive statin therapy using rosuvastatin 40mgRegression in ASTROID Study of atherosclerosis was associated with a substantial reduction of LDL-C (-53%) combined with a significant increase in HDL-C (15%).Rosuvastatin 40mg was well tolerated with a safety profile consistent with the existing extensive safety database

*

Originally it was thought that atherogenesis was a relatively simple process and revolved around the formation of atheromatous plaques within the intimal wall leading to eventual blockage of the artery. The gradual increase in size of the plaque was thought to encroach into the lumen of the artery, eventually causing a reduction in lumen size. The resulting reduction in blood flow was then thought to cause stable angina pectoris and rarely, myocardial infarction.1

Reference1. Antischkow N. Beitr Path Anat Allg Path 1913;56:379404.

*

More recently, atherogenesis has been revealed as a complex process and is preceded and accompanied by inflammation. The endothelium responds to damage by inducing a protective response, eventually leading to the formation of the atherosclerotic plaque. Over time, the plaque may grow or reduce in size, and may or may not encroach into the lumen of the artery. The clinical outcome often depends on the stability of the plaque.1 The less stable the plaque, the more susceptible it is to erosion or rupture. Both erosion and rupture can lead to thrombus formation on the site of the plaque and vessel occlusion, culminating in unstable angina or myocardial infarction.1 Treatment with statins, in addition to dietary and lifestyle changes, may result in regression of atherosclerotic plaques.

Reference1. Ross R. Nature 1993:362:801809.

*

The primary event in atherosclerosis is thought to be damage caused to the endothelium of arterial walls, resulting in endothelial dysfunction. This damage may be caused by a variety of factors; haemodynamic forces (shear stress caused by e.g. hypertension), a number of vasoactive substances, mediators (cytokines) from blood cells, cigarette smoke, atherogenic diet, elevated glucose levels and oxidised LDL-C.1 Initially, damage causes the endothelial cells to express cellular adhesion molecules such as cytokines (interleukin-1, IL-1; tumour necrosis factor alpha, TNF-alpha), chemokines (monocyte chemoattractant factor 1, MCP-1; IL-8) and growth factors (platelet-derived growth factor, PDGF; basic fibroblast growth factor, bFGF).1 This sticky surface encourages inflammatory cells such as monocytes and T lymphocytes to attach to the endothelial surface. Once attached they migrate through the intact endothelium into the subendothelial space. Many of the monocytes differentiate into macrophages and take up oxidised LDL, which is more atherogenic than native LDL; these macrophages then become foam cells.1 Oxidised LDL promotes death of endothelial cells and an inflammatory response resulting in impairment of normal function of the endothelium. In addition, it modifies the response to angiotensin II, resulting in vasodilatory impairment, and induces a prothrombic state by affecting platelets and coagulation factors.Thus, the endothelium responds to damage by inducing a protective response which will eventually lead to the formation of fibrofatty and fibrous lesions, the atherosclerotic plaque, preceded and accompanied by inflammation.2This schematic linear diagram represents part of a network of complex processes that include various disease (and protecting) mechanisms that occur simultaneously.

References 1. Koenig W. Eur Heart J Supplements 1999:1:T1926.2. Ross R. Nature 1993;362:801809.

*

Endothelial injury, or exposure to atherogenic stimuli, triggers endothelial cell inflammatory responses leading to recruitment of leukocytes and release of cellular adhesion molecules; cytokines, including tumour necrosis factor- (TNF-), interleukin-1 (IL-1) and interferon gamma (IFN- ), chemokines, including monocyte chemoattractant factor 1 (MCP-1) and interleukin-8 (IL-8), and growth factors, including platelet derived growth factor (PDGF) and fibroblast growth factor (FGF).1The cytokines, in addition to amplifying the immune response, alter endothelial cell function towards a prothrombotic state, characterised by increased production of platelet activator inhibitor-1 (PAI-1), tissue factor expression (TFE) and activation of the extrinsic coagulation pathway), and release of PDGF.

Reference1. Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T1926.

*

The atheromatous plaque is comprised of a dense fibrous extracellular matrix that accounts for the strength of the cap. Matrix metabolism and formation depends on the balance of synthesis and breakdown products in the fibrous cap, especially at the shoulder regions. Vascular smooth muscle cells synthesise extracellular matrix protein, collagen and elastin. In the unstable fibrous cap, activated T lymphocytes provide signals via interferon gamma, (IFN-), which lead eventually to decreased collagen formation. The macrophage, activated by IFN-, in addition to interleukin-1 (IL-1), tumour necrosis factor- (TNF-), monocyte chemoattractant factor 1 (MCP-1) and macrophage colony stimulating factor (M-CSF), leads to increased production of collagenases, gelatinases, stromelysin, and other proteases and peptidases that break down and limit the formation of collagen in the fibrous cap.1

Reference Libby P. Circulation 1995;91:28442850.

Adapted from Circulation 1995;91:2844-42850, with permission from Lippincott Williams & Wilkins.

*

Vulnerable plaques are characterised by thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation. In contrast, the stable plaque has a relatively thick fibrous cap protecting the lipid core from the contact with blood.

Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi. The size of the plaque does not appear to predict whether a plaque is prone to rupture, indeed clinical data suggest that stable plaques more often show luminal narrowing detectable by angiography than do vulnerable plaques. At sites of lesion disruption, smooth muscle cells (SMCs) are often activated, as detected by their expression of the transplantation antigen HLA-DR.

Rupture usually occurs at sites of thinning (particularly at the shoulder area of the plaque) and is associated with regions where there are relatively few SMCs but abundant macrophages and T cells. Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen.1

Reference1. Libby P. Circulation 1995;91:28442850.

Adapted from Circulation 1995;91:2844-42850, with permission from Lippincott Williams & Wilkins.

*

According to WHO estimates in 2002, 17 million people around the globe die of cardiovascular disease (CVD) each year, contributing to nearly one-third of global deaths.1,2Today, people of all ages are at risk, including children, and 80 percent of the burden of CVD is in low- and middle-income countries. By 2020 heart disease and stroke will become the leading cause of both death and disability worldwide, with the number of fatalities projected to increase to more than 20 million a year and to more than 24 million a year by 2030.1,2

Not only is CVD costly in terms of clinical care but it affects individuals in their peak mid-life years, disrupting the future of families dependent on them and undermining the economic basis of countries by reducing the productivity of the work-force.

References1. American Heart Association. International Cardiovascular Disease Statistics 2005. (www.americanheart.org/presenter.jhtml?identifier=3001008).2. The World Health Organization. Atlas of Heart Disease and Stroke 2005. (www.who.int/cardiovascular_diseases/resources/atlas/en/).

*

A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available.

ReferencesBallantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:722.Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279.LaRosa J, Grundy S, Waters D, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-1435.

Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc.

*

MARS (Monitored Atherosclerosis Regression Study)

Objective: To assess the effects of lipid-lowering therapy with lovastatin on coronary angiographic findings in patients with coronary artery disease and to compare the findings with those of two lipid-lowering angiographic trials using similar end points.

Design: Randomized, double-blind, placebo-controlled, multicenter coronary angiographic trial.

Setting: Community- and university-based cardiac catheterization laboratories.

Participants: A total of 270 patients, 37 to 67 years old, with total cholesterol ranging from 4.92 to 7.64 mmol/L (190 to 295 mg/dL) and angiographically defined coronary artery disease.

Intervention: A cholesterol-lowering diet and either lovastatin, 80 mg/day, or placebo.

Outcome: Per-patient change in percent diameter stenosis as determined by quantitative coronary angiography (primary end point). Global change score, based on the consensus of blinded expert readers regarding angiographic change (secondary endpoint).

Results: Lovastatin lowered total cholesterol level by 32%, low-density lipoprotein cholesterol by 38%, and the apolipoprotein B by 26% and raised the high-density lipoprotein cholesterol by 8.5% (P < 0.001). Average percent diameter stenosis increased 2.2% in placebo recipients and 1.6% in lovastatin recipients (P > 0.20). For lesions 50% or greater, average percent diameter stenosis increased 0.9% in placebo recipients and decreased 4.1% in lovastatin recipients (P = 0.005). The mean global change score was +0.9 (indicating progression) in the placebo group and +0.4 in the lovastatin group (P = 0.002); 13 placebo recipients and 28 lovastatin recipients had global change scores indicating regression (P < 0.02).

Conclusion: Treatment with lovastatin plus diet slows the rate of progression and increases the frequency of regression in coronary artery lesions (by global change score), especially in more severe lesions (by quantitative angiography). This is the third lipid-lowering trial to show a benefit using the global change score, an end point predictive of clinical coronary events. Differences between two of these trials, using quantitative coronary angiographic end points, may have theoretical bearing on the mechanisms by which lipid-lowering therapy operates at the level of the arterial wall.

*

Invasive techniquesIntravascular ultrasound (IVUS)The IVUS technique, developed in the 1990s, involves the sending and receiving of ultrasound waves which are emitted from a catheter introduced into an artery. The catheter rotates at about 1800 revolutions per minute producing a detailed picture of the lumen and wall, including the atheromatous plaques, at those sites visualised by the catheter. This technique may be used to examine arterial wall thickness (intima-media thickness or IMT). Assessments of IMT have proved to be an extremely reliable surrogate marker for examining the progression of atherosclerosis and for assessing cardiovascular risk.Coronary angiographyCoronary angiography, introduced in 1958, uses X-rays to examine the blood vessels or chambers of the heart. A catheter is inserted into a blood vessel and the tip is positioned either in the heart or in the coronary arteries supplying the heart. A contrast medium or dye is injected into the artery which is then visible by X-ray. The X-ray images obtained are called coronary angiograms and enable visualisation of the lumen of the overall coronary bed.

Non-invasive techniquesMagnetic resonance imaging (MRI)MRI produces extremely detailed pictures of body tissues and organs without the need for X-rays. Electromagnetic energy released when exposing a patient to radio waves in a strong magnetic field is measured and analysed by a computer, which then forms a two- or three-dimensional image. MRI provides detailed images of blood vessels without using any contrast material, although a special form of contrast may be given to make the images even clearer.Computed tomography (CT)A traditional CT scan is an X-ray procedure that combines many X-ray images with the aid of a computer to generate cross-sectional views of the body. Cardiac CT uses the advanced CT technology with intravenous contrast dye. X-ray computed tomography provides cross-sectional images of the chest, including the heart and coronary blood vessels. Ultrasound (B-mode)High resolution B-mode ultrasound (also referred to as quantitative carotid B-mode ultrasound), uses high frequency sound waves and their echoes to create an image. The B-mode ultrasound makes it possible to non-invasively characterise arterial wall function in the carotid and brachial arteries by measuring IMT and wall stiffness.

*

Magnetic Resonance Imaging (MRI) produces extremely detailed pictures of body tissues and organs without the need for X-rays. Electromagnetic energy released when exposing a patient to radio waves in a strong magnetic field is measured and analysed by a computer, which then forms a two- or three-dimensional image. MRA provides detailed images of blood vessels without using any contrast material, although a special form of contrast may be given to make the images even clearer. Limitations to this method include the complex equipment required and the difficulty in obtaining precise images because of the continuous motion of the heart.This slide shows an MRI image relatively normal artery with little or no signs of atherosclerosis and the left carotid artery bifurcation with an atherosclerotic plaque with a necrotic core.1

Reference1. Chu B et al. Stroke 2004;8:24442448.

*

A traditional computed tomography (CT) scan is an X-ray procedure that combines many X-ray images with the aid of a computer to generate cross-sectional views of the body. Cardiac CT uses the advanced CT technology with intravenous contrast dye. CT provides cross-sectional images of the chest, including the heart and coronary blood vessels. The complex equipment required and the difficulty in obtaining precise images because of the continuous motion of the heart are also limitations to this method.

This slide is a CT scan of an artery showing the presence of atherosclerosis.

Photograph M175/302 (CVS 20): Zephyr/Science Photo Library.

*

High resolution B-mode (brightness mode) ultrasound (also referred to as quantitative carotid B-mode ultrasound), uses high frequency sound waves and their echoes to create an image. The B-mode ultrasound makes it possible to non-invasively characterise arterial wall function in the carotid and brachial arteries by measuring IMT and wall stiffness. B-mode ultrasound has been used extensively in epidemiologic studies to quantify associations of risk factors with extracranial carotid atherosclerosis and atherosclerosis progression as well as associations of atherosclerosis (and atherosclerosis progression) with coronary events.

This slide shows an ultrasound of the common carotid artery depicting visualisation of the far wall IMT. The white arrow points to the intima-lumen interface and the grey arrow points to the intima-media interface, demarcating the intima-media thickness.

Reproduced with permission from Kastelein, JJP, Sager PT, de Groot E et al. Am Heart J 2005;149:234239.

*

Studies to investigate the effect of rosuvastatin on the atherogenic lipid profile:- CENTAURUS Efficacy of rosuvastatin 20mg and atorvastatin 80mg in subjects with acute coronary syndrome (lipids/ApoB/ApoA-I ratio and inflammatory markers) COMETS Efficacy of rosuvastatin 1020mg and atorvastatin 1020mg and placebo in subjects with metabolic syndrome (lipids/inflammatory markers)DISCOVERY Efficacy of rosuvastatin, atorvastatin and other statins in subjects with primary hypercholesterolaemia (lipids/LDL-C goals) ECLIPSE - Efficacy of rosuvastatin 1040mg and atorvastatin 2080mg in subjects with hypercholesterolaemia EXPLORER - Efficacy of rosuvastatin 40mg alone and in combination with ezetimibe 10mg subjects with hypercholesterolaemia LUNAR Efficacy of rosuvastatin 20mg or 40mg and atorvastatin 80mg in patients with acute coronary syndrome (lipids/inflammatory markers).MERCURY I Efficacy of rosuvastatin 10mg & 20mg following a switch from atorvastatin 10mg or 20mg, simvastatin 20 mg or pravastatin 40mg (lipids/ European LDL-C goals) MERCURY II Efficacy of rosuvastatin 10 mg & 20 mg) following a switch from atorvastatin 10 mg or 20 mg, simvastatin 20 mg or pravastatin 40mg (lipids/NCEP ATP III LDL-C goals) ORBITAL Efficacy of rosuvastatin based compliance initiatives linked to achievement of LDL-C goals PLUTO Efficacy and safety of rosuvastatin in paediatric subjects with heterozygous familial hypercholesterolaemia (planned)POLARIS - Efficacy of rosuvastatin 40mg and atorvastatin 80mg in high-risk subjects with hypercholesterolaemia PULSAR - Efficacy of rosuvastatin 10mg and atorvastatin 20mg in subjects with hypercholesterolaemia STELLAR Efficacy of rosuvastatin, atorvastatin, simvastatin across doses and pravastatin (lipids/LDL-C goals)

*COMETS & LUNAR also assess the effects of rosuvastatin on inflammatory markers Studies to investigate the effect of rosuvastatin on atherosclerosis:- ASTEROID Effect of rosuvastatin 40mg on the regression of coronary artery atheroma in patients with CAD using intravascular ultrasound (IVUS)COSMOS Effect of rosuvastatin on progression of plaque volume in Japanese subjects with hypercholesterolaemia and CHD (IVUS)METEOR Effect of rosuvastatin 40mg on progression of carotid atherosclerosis by measuring intima media thickness (IMT) ORION - Effect of low and high dose rosuvastatin on progression of carotid artery atheroma using magnetic resonance imaging (MRI)Studies to investigate the effect of rosuvastatin on cardiovascular morbidity and mortality - AURORA, CORONA ,JUPITER together with GISSI-HF, an independent study are described on the next slide As the GALAXY Programme is constantly evolving, new studies will be included as the statin environment changes, research needs dictate and the clinical development of rosuvastatin continues.

*

ORION = Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic resonance Imaging ObservatioNMETEOR = Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin ASTEROID = A Study To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived Coronary Atheroma Burden

*

Additional Information:ORION is a randomized, double-blind, parallel-group study to assess the effect of rosuvastatin on progression of carotid artery atheroma in moderately hypercholesterolemic patients with asymptomatic carotid stenosis. Approximately 200 individuals from 2 centers in the US were screened and, after an initial enrollment period, 43 patients were randomised to receive either low-dose rosuvastatin (5 mg) or high dose rosuvastatin (40 / 80 mg*) once daily for 24 months.

*

*

Background Study:

Although statins have shown consistent morbidity and mortality benefit, nearly all clinical trials have been placebo controlled. Accordingly, there are virtually no data available comparing relative benefits of drugs in this class.Angiographic trials suggest that statin slow the progression of atherosclerosis, but do not completely halt disease progression nor induce regression.

*

This slide shows an example where an atheroma, evident by IVUS, remains undetected by angiography as a result of coronary remodelling. On the left, the angiogram is completely normal. However, two sites in the anterior descending coronary artery, indicated by arrows, show a varying extent of atherosclerosis by IVUS. The more distal site (top right) has little disease, but the more proximal site (bottom right) has a large crescentic atheroma. The lumen size at both sites is similar because of remodelling, resulting in a false-negative angiogram.

ReferenceNissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001; 103: 604616.

*

Primary objectives:to assess the nominal change (end of treatment minus baseline) in PAV in the entire 3080 mm segment of the coronary artery assessed.to quantify the change in TAV in the most severely diseased 10 mm segment of the coronary artery

Secondary objectives are to evaluate:whether long-term treatment with rosuvastatin 40 mg results in regression of coronary artery atheroma burden, as assessed by TAV in the complete imaged section, as measured by IVUSpercentage change from baseline in lipid and lipoprotein levels after 104 weeks of rosuvastatin therapythe safety of rosuvastatin 40 mg throughout the duration of the study.

ReferenceNissen S. Design and methodology of A Study To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden: the ASTEROID study. Poster presented at International Symposium on Atherosclerosis, 28 September2 October 2003, Kyoto, Japan.

AbbreviationsCAD=coronary artery disease; TAV=total atheroma volume; PAV=percentage atheroma volume; IVUS=intravascular ultrasound

*

ASTEROID is an open-label, multicentre study evaluating the effect of rosuvastatin 40 mg treatment on atherosclerotic disease as measured by IVUS in CAD patients undergoing coronary angiography. The study included 507 patients who had a baseline IVUS examination from 53 centres worldwide. 349 patients had evaluable serial IVUS examinations.The target coronary artery must have 50% reduction in lumen diameter throughout a segment of at least 40 mm in length. This vessel may be designated the target vessel if it is accessible to the IVUS catheter and if it has not undergone prior PCI or CABG, has not sustained a MI, is not currently a candidate for intervention or a likely candidate for intervention over the next 104 weeks, and is not a bypass graft. The same vessel will be reassessed by IVUS after 104 weeks of treatment with rosuvastatin 40 mg. There are two primary endpoints:- (1) the nominal change (end of treatment minus baseline) in Percent Atheroma Volume (PAV) in the entire 3080 mm segment of the coronary artery assessed.(2) the change in Total Atheroma Volume (TAV) in the most severely diseased 10 mm segment of the coronary artery The secondary endpoints were the change in TAV within the entire segment (determined by IVUS) and the percentage change in lipid and lipoprotein levels from baseline.

ReferenceNissen, SE, Nicholls S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA2006;295 (13):1556-1565.

AbbreviationsCAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound; CABG=coronary artery bypass graft; TAV=total atheroma volume; PAV=percent atheroma volume; MLD=minimum lumen diameter

Rosuvastatin 40 mg was used in the ASTEROID study. The 40 mg dose is the highest registered dose of rosuvastatin. Rosuvastatin should be used according to the prescribing information, which contains recommendations for initiating and titrating therapy according to the individual patient profile. In most countries, the usual recommended starting dose of rosuvastatin is 5 or 10 mg.Please consult local prescribing information for guidance on use of CRESTOR

*

All three efficacy parameters using IVUS showed statistically significant regression. Percent Atheroma Volume and Normalised Total Atheroma Volume relate to the total artery segment assessed, and represent more rigorous tests of regression than Atheroma Volume assessed in the most diseased 10mm subsegment.

Because the data was not normally distributed, statistical significance of the difference from baseline was determined using the appropriate non-parametric test (Wilcoxon signed rank test). The p value reflects this analysis of the median values. A bonferonni correction applied to account for multiple comparisons and significance level was set at 0.025

ReferenceNissen, SE, Nicholls S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA2006;295 (13):1556-1565.

*

All three efficacy parameters using IVUS showed statistically significant regression. Percent Atheroma Volume and Normalised Total Atheroma Volume relate to the total artery segment assessed, and represent more rigorous tests of regression than Atheroma Volume assessed in the most diseased 10mm subsegment.

Because the data was not normally distributed, statistical significance of the difference from baseline was determined using the appropriate non-parametric test (Wilcoxon signed rank test). The p value reflects this analysis of the median values. A bonferonni correction applied to account for multiple comparisons and significance level was set at 0.025

ReferenceNissen, SE, Nicholls S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA2006;295 (13):1556-1565.

*

The percentage of patients showing regression measured by each IVUS parameter is presented above. 64 to 78% of patients showed regression depending on the IVUS parameter measured. This means that, with respect to Atheroma Volume in the most most diseased subsegment and Normalised Total Atheroma Volume, 4 out of 5 patients showed regression.

ReferenceNissen, SE, Nicholls S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA2006;295 (13):1556-1565.

*

This slide shows an example of regression of atherosclerosis in a patient in the ASTEROID study. The left images show the IVUS results at baseline, while the right images show the IVUS results following 24 months treatment with rosuvastatin 40mg. The images at the bottom are the same cross-sections as those at the top with the lumen area and atheroma area superimposed to better see the reduction in atheroma volume that occurred in this patient.

Baseline Follow-up Lumen Area 8.42 10.32 EEM Area 19.05 17.31 Plaque Area 10.63 6.99

Development of Atherosclerotic PlaquesNormalFatty streakFoam cellsLipid-rich plaqueLipid coreFibrous capThrombusRoss R. Nature. 1993;362:801-809.

Brain Attacks PADPrimary Prevention Secondary Prevention The Promotion and Education National Health ProgramHearth attack

Faktor-faktor risiko

Dislipidemia Peningkatan kolesterol dan atau trigliserida serum diatas normalLipid plasma : kolesterol trigliserida fosfolipid asam lemak bebasBerasal dari eksogen & endogenPunya makna klinis kolesterol & trigliserida

DislipidemiaLipid terikat protein : lipoproteinLipoprotein dibagi : a. ultra sentrifugasi : 1. Kilomikron 2. Very low density lipoprotein ( VLDL) 3. Intermediate density lipoproten (IDL) 4. Low density lipoprotein (LDL) 5. High density lipoprotein (HDL) b. elektroforesis : 1. Beta lipoprotein (LDL) 2. pre-beta lipoprotein (VLDL) 3. Alfa lipoprotein (HDL) 4. Broad beta (beta VLDL atau IDL)Kolesterol : LDLTrigliserida : kilomikron & VLDL

DislipidemiaMRFIT : kolesterol > 180 mg/dl > 240 mg/dlLDL : faktor risiko aterosklerosisHDL : faktor protektifHDL aterogenikHiperlipidemia primer sekunder

DislipidemiaDislipidemia primer - kelainan genetik - gaya hidup salah (banyak makan , kurang gerak, merokok dll)Dislipidemia sekunder - disebabkan penyakit mis: DM, gangguan tiroid, peny. Hepar, peny. Ginjal - reversible - disebabkan obat (beta bloker, diuretik)

DislipidemiaKlasifikasi klinis Dislipidemia HiperkolesterolemiaHipertrigliseridemiaDislipidemia campuran

Diagnosis :Pemeriksaan lipid darah Penderita puasa 12-14 jam

DislipidemiaTRIAD LIPID : 1. LDL 2. TG 3. HDL faktor risiko PJK

Penatalaksanaan :DietOlah ragaObat-obatan

DislipidemiaObat hipolipidemik :Menurunkan kolesterolResin pengikat asam empedu kolestipol, kolestiraminPenghambat enzim HMG co-A reduktase (statin) simvastatin, pravastatin, lovastatin, fluvastatinAsam nikotinat atau niasinD- tiroksinprobukol

Dislipidemia2. Menurunkan kadar trigliserida Golongan asam fibrat gemfibrozil, bezafibrat, fenofibratb. Asam nikotinat

3. Pengobatan Dislipidemia campuran Gol.asam fibrat ( + gol. Resin )

Hipertensi Peningkatan tek darah sistolik dan atau diastolik yang tidak normalHipertensi : tek sistolik > 140 mmHg tek diastolik > 90 mmHgHipertensi primer / esensial / idiopatik sekunderHipertensi primer - genetik - ekskresi na & air - kepekaan baroreseptor - respon vaskuler - sekresi renin

JNC VI (1997)JNC 7 (2003)JNC 7 Re-Classification of SBP/DBPJNC VI. Arch Intern Med. 1997;157:2413-2446. JNC 7. JAMA. 2003; 289(19):2560-2572.Hypertension

Optimal< 120 and 160 or > 100Stage 3> 180 or > 110

Blood Pressure Classification JNC 7NORMAL BP = 120/80 mmHG

Normal 100

BP ClassificationSBP mmHgDBP mmHg

HipertensiTekanan darah sistemik

Resistensi

Beban jantung

Hipertrofi ventrikel kiri

Dilatasi jantung

Payah jantung

HipertensiAterosklerosis : angina / infark miokardKematian :payah jantung & infark miokard strokePenilaian pembuluh retina berguna utk - perkembangan penyakit - respon terapi

*AngiotensinogenAngiotensin IAngiotensin IIReninACEBradykininPeptide

Angiotensin IIAngiotensin IIDeathGlomerular filtration rateProteinuria/albuminuriaGlomerulosclerosisAldosterone releaseRenal failureLVHFibrosisRemodellingApoptosisVasoconstrictionVascular hypertrophyEndothelial dysfunctionAtherosclerosisStrokeHypertensionThrombosisArrhythmiaHeart failureMIAT1 receptorVascular remodellingDirect and indirect effects in target-organ damage

Faktor-faktor lainMerokok : - jumlah rokok yg dihisap - pengaruh nikotinDiabetes melitus : - kelainan metabolisme lemak - degenerasi vaskulerObesitas : - beban jantung - kebutuhan O2

Faktor-faktor lainKurang gerak & tipe kepribadianKepribadian tipe A : - persaingan kuat - ambisius - agresif - merasa dikejar waktu

Patofisiologi iskemiaKebutuhan O2

Iskemia miokard (hipoksia)

Metab aerob anaerob energi

Asam laktat asidosis

pH sel kontraksi ventrikel kiri

Angina pektorisNyeri dada yg menyertai iskemia miokard

Infark miokardIskemia yg lebih dari 30-45 menit akan sebabkan kerusakan ireversibelBagian yg infark berhenti kontraksi

Komplikasi iskemia & infark Gagal jantung kongestifSyok kardiogenikDisfungsi otot papilarisDefek septum ventrikelRuptur jantungAneurisma ventrikelTromboembolismeAritmia Perikarditis

Pengobatan

A . R . I . T . M . I .A

A R I T M I Aadalah :suatu kelainan dalam hal kecepatan, irama, tempat asal atau gangguan konduksi yang menyebabkan perubahan dalam urutan normal aktivasi atrium dan ventrikel

Patofisiologi AritmiaI. Aritmia Karena Gangguan Pembentukan Impulsa.Automatisitas Normal Berubahbisa terjadi pada SA, AV dan His Purkinyeb.Pembentukan Impuls Abnormal yang dpt dibagi 2 :1. Automatisitas abnormal terjadinya depolarisasi diastolik spontan pada nilai mV yang lebih (+).

2. Aktivitas terpicu ( Triggered Activity ) pembentukan impuls pada fase repolarisasi yang sudah mencapai ambang.

II. Aritmia yang disebabkan oleh kelainan konduksi impuls :

Aritmia arus balik (Re-entrant arhytmia)

Obat-obat AntiaritmiaKelas I MK : penyekat kanal Na+ dan juga mempunyai efek anestetik lokal.I A : Kinidin, prokainamid dan disopiramid.I B : Lidokain, mexiletin, tokainid, fenitoin.I C : Flekainid, propafenon,moricizin.Efek thd ECG : prolonged QRS.IA : intermediate ; I B : fast ; IC : slow

2. Kelas II : Beta blokerex : Propranolol, asebutalol, esmololEfek thd ECG : prolonged PR3. Kelas III : Memperpanjang fase repolarisasi,dgn memblok ion Kex : Amiodaron, bretilium, sotalol, ibulitid.Efek thd ECG : prolonged QT4. Kelas IV : Pemblok Kanal Ca+ex : Verapamil dan diltiazemEfek thd ECG : prolonged PR.

Penatalaksanaan1. Obat yang efektif pada aritmia supraventrikular ( biasa tjd pd atrium or nodus AV )ex : adenosin i.v ; verapamil & digoksin2. Obat yang efektif pada aritmia ventrikularex: likodain i.v3. Obat yang efektif pada keduanyaex: amiodaron, sotalol, kinidin, disopiramid dan flekainid.

4. Aritmia yang berhubungan dengan kondisi stress diobati dgn beta bloker.

Penanganan lain :Implantasi Pacemaker

SINUS BRADIKARDIKeluhan1. Biasanya asymptomatic2. Nyeri dada3. Pusing sampai sinkopSigndenyut jantung 35-50 kali / menit.Terapi umum :1. Oksigen 2-3 l / menit.2. Obat :- Sulfas atropin 0,5 1 mg iv tiap 40 menit.- Isoprenalin sebagai alternatifD.Implan pacemaker.

**Morning blood pressure surge related cardiovascular riskBrainAgeingClock geneStressCold temperatureMechanical stressShear stressSpasmPlatelet aggregation

PAI-1

Coagulation Oxidative stressUbiquitin-proteasome systemInflammationSympathetic systemRenin-angiotensin systemHPA axisNitric oxides

Morning blood pressure surge HypertensionDiabetesHyperlipidaemiaAdipocytokineSmoking AlcoholSleep apnoeaEndothelial dysfunctionPlaque formationCardiovascular remodellingChronic risk factorsAtherosclerosisPlaque instabilityPlaque ruptureThrombosisCardiovascular eventsTriggerAcute risk factors*HPA=hypothalamic-pituitary-adrenal;PAI-1=plasminogen-activator inhibitor 1*With diurnal variation

*2.03**Convening of the JNC 7 committee was based on four reasons [Claude Lenfant, Director, NHLIB]Publication of many new hypertension observational studies or clinical trialsNeed for a new, clear and concise guideline that would be useful for cliniciansNeed to simplify the classification of blood pressureClear recognition that the JNC reports were not being used to their maximum benefitAlthough JNC 7 did not technically lower blood pressure goals, its simplification of them (for example the combination of stage 2 & 3 into stage 2, and the addition of the prehypertension category) and the directors reasons for the 7th version, bring light on the health risks of untreated hypertension for all patients, even those who were previously considered normal. Because the objective of identifying and treating high blood pressure (BP) is to reduce the risk of cardiovascular (CV) disease and associated morbidity and mortality, JNC 7 provides a classification of adult BP for the purpose of identifying high-risk individuals who are not at goal. The new classification includes the term prehypertension for those with BPs ranging from 120 to 139 mm Hg systolic blood pressure (SBP) and/or 80 to 89 mm Hg diastolic blood pressure (DBP). This new designation is intended to identify those individuals in whom early intervention by adoption of healthy lifestyles could reduce BP, decrease the rate of progression of BP to hypertensive levels with age, or prevent hypertension entirely. Another change in classification from JNC VI is the combining of stage 2 and stage 3 hypertension into a single stage 2 category. The objective of identifying and treating high blood pressure (BP) is to reduce the risk of cardiovascular (CV) disease and associated morbidity and mortality. It is therefore useful to provide a classification of adult BP for the purpose of identifying high-risk individuals and to provide guidelines for follow-up and treatment.Normal BP is now defined as 120/80 In JNC 7, a prehypertension category has been added and is defined as SBP 120-139 mm Hg or DBP 80-89 mm Hg. These patients are at increased risk for progressing to the hypertensive category; those in the 130/80 to 139/89 mm Hg range are at twice the risk to develop hypertensionStage 1 Hypertension is considered to be SBP 140-159 mm Hg or DBP 90-99 mm Hg Stages 2 and 3 from JNC VI are now combined.Stage 2 Hypertension is defined as SBP 160 or DBP 100When SBP and DBP fall into different categories, the higher category should be selected to classify the individuals BP status***Hypertension induces target-organ damage, leading to an increased risk of stroke, cardiovascular disease and renal failure.1 Antihypertensives, such as telmisartan (an ARB), can reduce the risk of these outcomes.In addition to its effects on blood pressure, angiotensin II also exerts a wide variety of deleterious effects on target organs that can hasten end-organ damage.2 These effects are mediated directly or via several signal transduction pathways that lead to cellular proliferation, increased oxidative stress and reduced nitric oxide.2Therefore, interventions that target the RAS can have benefits in addition to their effects on hypertension.

Whitworth JA. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11):19831992.Willenheimer R, et al. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J 1999;20:9971008.*Hospital Specialty_FINAL ATS***