3Atherosclerosis is the leading cause of death and disability in the developed and developing worldClinical manifestations depend on the particular vascularbed affectedCoronary vasculature angina, MI, sudden deathCerebral TIA, strokePeripheral claudication, gangreneRenal hypertension
4Atherothrombotic disease is often a diffuse condition involving multiple vascular bedsMulti-territory atherothrombosis3-8% have symptomatic atherosclerosis in allthree territories23-32% have involvement in two territories
6EpidemiologyThe three major clinical manifestations of atherosclerotic CVD are:CHDCVAPVD
7Disease impact:In 1997, more than 5mn Americans had CVDCurrently one in five American has some form of CVDEach year 1mn deaths are due to CVD (42% of all deaths!)One-sixth of CVD deaths are in persons <65 yrs of ageAnnually1.5mn Americans have MI0.5mn die from CHD0.5mn have stroke0.15mn die from stroke
8Death rates from CHD has decreased by 40% since 1968 CVD still remains the leading cause of death in developednationsCHD & stroke are the 2nd and 3rd leading causes of mortalityeven in the developing regions
12Economic impact:Despite age adjusted decline in CVD mortality,there is paradoxic increase in economic burden due to:1) aging population causing actual number of CVDcases to remain stable2) technologic advances causing more aggressive andextensive treatment
15Concept of “risk factors” for CAD evolved from prospective epidemiological studies in US and Europe whichdemonstrated consistent association amongcharacteristics observed at one point of time inapparently healthy individuals and subsequentincidence of CAD in these patients.But, presence of a risk factor does not necessarily imply adirect causal relationship.
16ATP III classifies Risk factors for CVD into three categories: -Underlying-Major (traditional)-Emerging
17Underlying risk factors include: ObesityDisinclination to exerciseAtherogenic diet
18Major (traditional risk factors): -Age-Male gender-DyslipidemiaHigh LDL cholesterolLow HDL cholesterol-DM-HTN-Smoking-Family history of premature CAD in first degree relative
19Emerging risk factors: -Metabolic syndrome-Triglyceride-Lp(a)-Lp-PLA2-Fibrinogen-Homocysteine-Urine microalbuminuria/creatinine ratio-Hs CRP-Impaired fasting glucose ( mg/dl per ADA)-Markers of subclinical ASCVDABIExercise testingEBCT/MRICarotid IMT
20Dyslipidemia Better term than hyperlipidemia as it includes the risk of having low HDLSerum total cholesterol (TC) is a composite of:LDL cholesterol- directly related to CVDHDL cholesterol- inversely related to CVDVLDL cholesterol- related to CVD in patients withDM and low HDLBest single predictor for CVD risk is TC/HDL ratio.Ideal ratio is <3, intermediate 3-5, high risk >5This ratio is also the best predictor of treatment benefits
22HypertensionPotent risk factor for all CVD and dominant risk factor forstroke.Graded relationship between level of BP and outcomes.SBP rises with age, whereas DBP plateaus in the late middlelife and decreases somewhat then.Trials for isolated systolic hypertension have shown benefitsfor both stroke and CHD
23Systolic and diastolic hypertension increase the RR for CVD by 1.6 timesFor combined Systolic and diastolic HTN the RR is 2.0The risk for CVD is increased even in individuals with“high normal BP” (130-39/85-89 mm Hg)
24Smoking This habit increases the risk of vascular outcomes by 2 fold. Both, regular and filter cigarettes have same adverse effects.Low tar/low nicotine products have not been shown to reducethe riskUnlike other modifiable risk factors, cigarette smokingcan be eliminated entirelyBenefits of quitting smoking are dramatic. Risk inex-smokers falls to near non-smoking levels in2 yrs.
25ObesityIt contributes independently to CVD risk and also aggravates known CVD risk factors.Measures of obesity include:BMIWaist: hip ratio.
27Synergy of risk factors: The CHD death risk in men who smoke, have DBP>90 mm Hg, TC>250 mg/dl, the actual risk is 82/1000 v/s43/1000 if all the three risk factors are addedThus there is multiplicative effect of multiple riskfactors acting in concert.Also control of one risk factor provides substantial benefit in persons with multiple risk factors
29Diabetes MellitusPatients with either type I or type II diabetes have increasedrisk for CVDRisk of CHD is increased 2-fold in young men and 3-fold inyoung women with type 2 diabetesType II diabetics have one or more metabolic abnormalities(hypertriglyceridemia, low HDL, hypertension)They may also have normal LDL levels but LDL particlesare dense and small thus being more atherogenic
33Pathogenesis Atherosclerosis is a progressive disease The term was first proposed by pathologist Felix Marchandin 1904Athero= gruel/porridge, sclerosis=hardeningThe process begins in childhood and has clinical manifestationsin late adulthoodAdvanced lesions are a result of three processes:1. Lipid accumulation2. Accumulation of intimal SMC, macrophages,T-lymphocytes3. Formation of connective tissue matrix by proliferatedSMC
34Atherosclerotic disease can lead to stenosis and occlusion as in most muscular arteries or cause ectasia oraneurysm formation as in elastic vessels (aorta)Even in a given arterial bed it tends to involve certainpredisposed areas- proximal LAD,proximal renal arteries,carotid bifurcationThe process develops over years to decades and progressionis not linear and smooth but discontinuous withperiods of quiescence and rapid evolution.Manifestations may be varied from asymptomatic to chronicstable angina/claudication to dramatic acute MI/stroke/sudden death.
35Normal arterial wall has three layers: intima- limited by internal elastic laminamedia- between internal and external elastic laminaadventitiaIntima is the site at which the atherosclerotic lesions formLesions can form in one of the two ways:Positive remodelling- intimal thickening associatedwith dilatation of the artery, so thelumen remains largeNegative remodeling- asymmetrical intimalthickening with lumen encroachment
36Endothelium:Largest and the most extensive tissue in the body which performsseveral functions.-“Barrier” between blood and arterial wall-non-thrombogenic surface by secreting PGI2-highly active metabolic tissue capable of formingseveral vasoactive substances and connectivetissue macromoleculesEndothelial cells have receptor for several molecules:LDLGrowth factorsPharmacological agents
37Initiation of atherosclerosis Lipoprotien accumulation and modificationfatty streak formationlipid oxidationnonenzymatic glycationLeukocyte recruitment (T lymphocytes, macro)foam cell formationEvolution and complicationsSMC involvement
38LDLBinds to receptor on endothelial cell surfaceInternalizedOxidized to oxidized-LDLIngested by Increased adherenceMacrophages and migration of T-cells,monocytes from the lumeninto the wallFoam Cell
39Smooth muscle cellAccumulation of SMC in the intima is the sine qua non foratherosclerosis. It proliferates in the intima to formintermediate and advanced lesions of atherosclerosisSmooth muscle cell can exist as contractile phenotype or synthetic phenotype.It is the principal contributor to the reparative and fibroproliferative process in the development of atherosclerosisFor the lesions to form, the SMC migrates from themedia to intima
44Clinical presentation of CHD depends on age and gender Women:Angina is most common first CHD eventfollowed by MIMen:MI is the most common first event followed byangina. Sudden cardiac death is not uncommon
45Acute myocardial infarction (AMI) One of the most common diagnosis in hospitalizedpatients in industrialized nationsMortality of acute MI is 30% and one-half of thesedeaths occur before hospitalizationMortality after admission has decreased by 30% in last2 decades1 in 25 pts (4%) who survive till hospital discharge diewithin one year
47PathophysiologyAMI results when thrombus (occlusive/nonocclusive)develops at the site of ruptured plaqueVulnerable plaqueRuptureCoagulation cascade platelet adhesion,activation activation,aggregationFibrin and platelet clotCoronary occlusionMI
49Amount of myocardial damage depends upon: -territory supplied by the occluded vessel-collateral circulation-duration of occlusion-partial/total occlusion-oxygen demand of jeopardized myocardium
50Presentation:Chest pain- most common, similar to anginal pain butmore severe and prolongeddescribed as severe, crushing/squeezing/pressure‘worst pain’ everChest pain may be absent in pts with DM or in elderlyAtypical presentations:confusion, syncope, profound wkness, arrhythmia
52Examination:Anxiety, pallor, restlessnessSubsternal chest pain with diaphoresis is strongly suggestiveof AMIThose with anterior MI may have sympathetic overactivitywhereas those with inferior MI may have para-sympathetic overactivityS3/S4Transient systolic murmur due to dysfunction of mitralapparatus leading to mitral regurgitation
53Laboratory findings:EKG specific but insensitive tool for diagnosis of myocardialischemiaTotal occlusion of infarct related artery leads to STelevation (STEMI) and subsequentevolution of Q wavesPartial occlusion/early recanalization/rich collateralsleads to NSTEMI (non-ST elevation MI)
56Serum cardiac markers: Released into the circulation from necrotic heart muscleCK (creatine kinase) rises 4-8 hrs after onset of MIand normalize by hrsnot specific for myocardial necrosisMB isoenzyme of CK is more specificCardiac specific troponins: more sensitive andspecific than CK and CKMB for identificationof myocardial necrosisMyoglobin- first serum marker to rise after MI, butlacks specificity.
57Cardiac imaging2D echocardiographyreveals regional wall motion abnormalityalso useful to identify mechanical complicationsof MIRadionuclide imagingused infrequently in the diagnosis of acute MImainly used to risk stratify patients with CHD
58ManagementPrehospital care:Major elements includeRecognition of symptoms by the patient andprompt medical attentionRapid deployment of EMS capable ofresuscitation and defibrillationExpeditious implementation of reperfusion
59Goals of Initial management in ED Control of cardiac painRapid identification of patients suitable for reperfusionTriage of low risk patients for subsequent careAvoiding inappropriate discharge of patients with MI
60Aspirin: 160-325 mg chewable aspirin leads to rapid buccal absorption, inhibition of cyclooxygenase in plateletsand reduction of TXA2Oxygen by nasal cannula if hypoxemia is presentSublingual nitroglycerine followed by IV infusion if neededIntravenous betablockers (decrease myocardial oxygendemand, control chest pain andreduce mortality)Morphine for pain relief (given IV in small doses)
66Door to needle time- 30 min (for patients receiving thrombolytic therapy)Door to balloon time min(for patients undergoing primary angioplasty)
67Unstable angina/NSTEMI Aspirin, antithrombin, nitrates, GP IIb-IIIa antagonistBetablockers(calcium channel blockers)Assess clinical statusHigh risk/unstable Stable(Recurrent ischemia, LV dysfunctionWidespread EKG changes, positiveenzyme markers)Stress testyesCardiac catheterization Severe ischemianoRevascularization (PCI/CABG) Medical therapy
68Chronic Stable Angina: Patients with stable angina should undergo detailed evaluationincluding history, focused physical examinationand risk factor assessmentInitial laboratory evaluation should include:hemoglobin, fasting glucose, fasting lipid profileEKG and chest x-rayPrecipitating factors for angina (anemia, arrhythmias, valvulardisease) should be identified and treated
69Ten important treatment elements of stable angina include: A aspirin and anti-anginalsB beta-blockers and blood pressure controlC cholesterol and cigarettesD diet and diabetesE education and exercise
70Patients with intermediate probability of CAD may undergo stress testing for diagnostic and prognostic purposePatients with high probability of CAD may also undergostress testing for prognostic purposeIndividuals with high risk characteristics on stress testing mayproceed with coronary angiography and subsequentrevascularisation
72Prevention:Opportunity for treating the underlying process ofatherosclerosis and preventing its acute complicationspresents enormous challenge and opportunityProspective community based Framingham heart studyprovided support for the fact that hyperlipidemia,hypertension and other risk factors correlated withcardiovascular riskSeven countries study provided a link between dietaryhabits, serum cholesterol and cardiovascular risk
73Dyslipidemia:It is the most established and best understood risk factor for atherosclerosis. National guidelines recommend cholesterol screening with fasting lipid profile in all adults.Individuals with dyslipidemia should have dietarymodificationNormal total cholesterol should not reassure individualshaving other risk factors or low HDLPrimary and secondary prevention trials in individuals with not only high but even average total and LDL cholesterol have shown significant decrease in CHD events by 24-31%.
74NCEP recommends that target LDL for: Individuals with established CVD/ DM/ estimated 10 yrsrisk for CHD events>20%<100mg/dlIndividuals with 2 or more risk factors for CADmg/dlOthersmg/dl
76Diabetes mellitus:Diabetic dyslipidemia is characterized by:normal LDL- but more dense and atherogeniclow HDLelevated triglyceridesHaving diabetes places individuals at same risk as thosewith established CVDStrict glycemic control helps to decrease microvascularcomplications but not CHD events. However, statintherapy has demonstrated unequivocal benefit indiabetic patients
77Hypertension:Trials have shown that pharmacologic therapy of HTN reducesthe risk of stroke and CHF.But evidence for reduction in coronary events has notbeen so strong.
78Smoking cessation:In FHS, smoking was found to increase the risk for CAD,stroke, heart failure, and peripheral vascular diseaseat all levels of blood pressureSmoking cessation in hypertensive patients who smoke1 ppd was estimated to reduce cardiovascular riskby 35-40%2-3 yrs after cessation, the risk for CAD declines to that ofsubjects who have never smoked