According to 2002 mortality figures compiled for the World Health Organization’s (WHO) World Health Report 2003: Shaping the Future, cardiovascular diseases (CVD) (mainly ischaemic heart disease and stroke) were the leading global causes of death, accounting for approximately 16.6 million deaths, followed by cancer (7.1 million deaths), intentional and unintentional injuries (5.2 million), upper and lower respiratory infections (3.8 million), chronic obstructive pulmonary disease (COPD) and asthma (2.9 million), and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (2.8 million). Reference 1. World Health Organization. The World Health Report 2003: Shaping the Future. Geneva, Switzerland: World Health Organization; 2003.
There are 3 stages to atherosclerosis: Initiation – when lipids are deposited on the vessel wall. Progression – as inflammation increases, plaque formation builds up in the intima, fibrous caps are formed increasing the potential for atheroma. Complications – result in unstable plaque leading to myocardial infarction (MI). Libby P. J Intern Med. 2000;247:349-358.
Figure 15: CAD in relation to risk factors The data from the Framingham study show that the combination of risk factors - high blood pressure, low HDL levels, high cholesterol levels, smoking, diabetes and left ventricular hypertrophy - dramatically increases the risk of coronary artery disease within ten years.
Hypertension, dyslipidaemia, diabetes, and smoking, all risk factors for heart disease, have been shown to induce endothelial dysfunction and a proatherogenic vascular milieu. Reduced nitric oxide (NO) synthesis, increased cyclooxygenase (COX) activity, inflammation, and increased endothelin result in vasoconstriction, increased oxidative stress, a procoagulant environment, and activation of inflammatory leukocytes. These vascular changes contribute to atherosclerotic plaque development. References Liao JK. Endothelium and acute coronary syndromes. Clin Chem . 1998;44:1799-1808. Libby P. Changing concepts of atherogenesis. J Intern Med . 2000;247:349-358. Mason RP. Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research. Cerebrovasc Dis . 2003;16(suppl 3):11-17.
The angiogram shows stenoses of the left coronary artery (LCA): tight stenosis in the proximal left anterior descending (LAD) artery (black arrow); and two moderately severe stenoses of the circumflex (CX) artery (white arrows). Following the initial development of a fatty streak, arterial narrowing arises through a ‘‘response to injury’ of the arterial wall, leading to thickening and hardening, and resulting in formation of an atherosclerotic plaque. Angina is a symptom of stenosis. Should the plaque’s firbrous plaque then fissure, superimposed thrombosis (atherothrombosis) can develop, occluding the lumen, and this may lead to unstable angina, myocardial infarction, or sudden death. Faxon DP. Coronary angioplasty for stable angina pectoris. In: Beller GA ed. Chronic Ischemic Heart Disease. Vol 5. In: Braunwald E series ed. Atlas of Heart Diseases. Philadelphia: Current Medicine, 1996. Draft 3
Figure 8: Manifestations of coronary artery disease
Figure 10: Classification of stable angina pectoris The symptoms of stable angina pectoris as classified by the Canadian Cardiovascular Society (CCS).
Disruption of an atherosclerotic plaque is a complex pathophysiologic process central to the initiation of the acute coronary syndromes (ACS). A mature plaque is made up of 2 main components: a lipid-rich core and extracellular matrix proteins forming a fibrous cap. The presence of large, eccentric lipid pools and the infiltration of foam cells are features most often associated with plaque rupture or fissure, which usually occurs at the sites of the greatest mechanical stress. Fissures that occur at weak cap sites not under great mechanical stress are thought to be initiated by enzymatic degradation of the cap. Local thrombosis following plaque disruption results from interactions between the lipid core and blood. Numerous factors probably trigger the rupture of a vulnerable plaque. Rupture exposes tissue factor in the lipid core, which precipitates platelet activation, adhesion, and aggregation, resulting in the formation of an occlusive thrombus. If the process leads to complete occlusion of the artery, an acute MI results. Alternatively, if occlusion is incomplete, unstable angina or non–Q-wave MI may develop. Spontaneous or pharmacologic lysis of thrombus, or pharmacologic interruption of platelet aggregation, may lead to resolution of the syndrome. Slide 16 Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N Engl J Med . 2000;342:101-114.
Pathogenesis of ACS Exposure of the vascular subendothelium leads to adhesion of circulating platelets at the site of plaque rupture. The material present in the plaque core is highly thrombogenic, leading to platelet activation and subsequent aggregation. Aggregated platelets form a partially occlusive thrombus and facilitate activation of the coagulation pathway and deposition of fibrin, possibly leading to formation of a totally occlusive thrombus, consisting of a platelet core and red blood cells entrapped in the surrounding fibrin mesh.
Two recent publications have summarized the evidence for even lower LDL-C goals. In one of these, the National Cholesterol Education Program (NCEP) Coordinating Committee has proposed modifications to the Adult Treatment Panel (ATP) III guidelines based on results from five major new clinical trials of statin therapy: Heart Protection Study (HPS), Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Treat (ALLHAT-LLT), Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22). One of the proposed modifications to ATP III goals for very-high-risk patients (risk factors include obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) includes an optimal lower LDL-C goal of <70 mg/dl (1.8 mmol/L) for patients with CHD or CHD risk equivalents. This new recommendation is based on results from HPS and PROVE IT, which demonstrated that high-risk patients with low LDL-C levels at baseline benefit from additional lowering of LDL-C. 8 Accumulating data consistently show that the optimal LDL-C level is approximately 50 to 70 mg/dl (1.3 to 1.8 mmol/L). 8 Although this LDL-C range seems low by current standards, it is physiologically normal, that is, the range associated with the lifestyle and diet for which we are genetically programmed. In addition, this range represents a threshold for development of atherosclerosis. 9
Investigators from the NCEP Coordinating Committee assessed data from recent trials that provide the rationale for further lowering of LDL-C levels. Modifications to ATP III recommendations have been proposed on the basis of that review. 8,10 In patients with CHD or CHD risk equivalents (10-year risk >20%), an optional LDL-C goal of <70 mg/dl (1.8 mmol/L) is now proposed, especially in those with CHD plus diabetes, poorly controlled risk factors (e.g., cigarette smoking), multiple risk factors for metabolic syndrome (high triglycerides 200 mg/dl [2.6 mmol/L] plus non–HDL-C [high-density lipoprotein cholesterol] 130 mg/dl [3.4 mmol/L] with low HDL-C [<40 mg/dl (1.0 mmol/L)]), and acute coronary syndrome. In patients with a 10-year risk from 10% to 20% and LDL-C of 130 mg/dl (3.4 mmol/L), there is a new optional LDL-C goal of <100 mg/dl (2.5 mmol/L); those with LDL-C levels from 100 to 129 mg/dl (2.5 to 3.3 mmol/L) at baseline or on lifestyle therapy should also be considered for drug therapy.
Data from both HPS 11 and PROVE IT 12 suggest that reducing LDL-C to levels that are substantially below 100 mg/dl (2.5 mmol/L) may be associated with additional benefits: In HPS, reducing LDL-C from <116 to <77 mg/dl (<3.0 to <2.0 mmol/L) decreased vascular risk by approximately 25%. In PROVE IT, reducing median LDL-C to 62 mg/dl (1.6 mmol/L) instead of 95 mg/dl (2.5 mmol/L) reduced the combined endpoint (death from any cause/major cardiovascular event) by 16% (p=0.005). Based on data from clinical trials, it is estimated that for every 1% reduction in LDL-C levels, the relative risk for major CHD events is reduced by approximately 1%. 8 This may be true even when LDL-C levels are <100 mg/dl (2.5 mmol/L). In fact, there is no definite threshold beyond which lower LDL-C levels are no longer associated with reduced cardiovascular risk. 9,13,14
1. Lahore: Jan 2011 Principles of Coronary Disease Evaluation & Management Dr Syed Imran Ahmad MB, MRCP, FRCP (London) Consultant Cardiologist (Clinical & Invasive) Head, Cardiology Section, Clifton Campus, Faculty Member Ziauddin University, Karachi: & Medilink Clinic, Clifton Karachi
2. Global Disease Mortality Mortality (millions) World Health Organization. The World Health Report 2003: Shaping the Future. 2003. Cardiovascular disease Malignant neoplasms Injuries Respiratory infections COPD and asthma HIV/AIDS Perinatal conditions Digestive diseases Diarrhoeal diseases Tuberculosis Childhood diseases Malaria Diabetes
3. Atherosclerosis Is a Chronic Inflammatory Disease With LDL-C at the Core Libby P. J Intern Med. 2000;247:349-358. PHASE I: Initiation PHASE II: Progression PHASE III: Complication
4. CAD in relation to risk factors Probability of CAD occurring within next 10 years HBP (150-160) + + + + + + HDL (33-35) - + + + + + Chol (240-262) - - + + + + Cigarettes - - - + + + Diabetes - - - - + + LVH - - - - - + Kannel WB, Europ.Heart J. 1992; 13:34-42
5. Integrated Cellular Mechanisms of Cardiovascular Disease Endothelial Dysfunction Dyslipidaemia Hypertension Liao. Clin Chem . 1998:44:1799-1808; adapted from Mason. Cerebrovasc Dis. 2003;16(suppl 3):11-17. Diabetes Smoking NO Synthesis Vasoconstriction Thrombosis Superoxide COX Activity Thromboxane A 2 Prostaglandin H 2 Prostacyclin Inflammation Leukocyte adhesion Endothelial permeability Angiotensin II T-cell activation Endothelin Vasoconstriction Calcium mobilization
6. Coronary Arteries
9. Coronary Artery Disease Angiogram of the left coronary artery and its branches
12. Classification of stable angina Severity I Conduct of daily work and activities without complaints (angina occurs only when load is extreme or over a very extended period of time) Severity II Slight restriction of daily work and activities (angina occurs when individual walks fast, climbs stairs or feels stressed) Severity III Marked restriction of daily work and activities(angina occurs after walking a short distance, or climbing a flight of stairs) Severity IV Daily work and activities not possible (angina constantly present)
13. Angina Pectoris <ul><ul><li>Angina is common </li></ul></ul><ul><ul><li>- affects over 10% of men and women > 60 </li></ul></ul><ul><ul><li>Angina is disabling </li></ul></ul><ul><ul><li>- quality of life can be poor </li></ul></ul><ul><ul><li>Angina affects outcome variably </li></ul></ul><ul><ul><li>- 3% to 20% annual rate of cardiac events </li></ul></ul>
14. Angina Pectoris <ul><ul><li>The Holy Trinity of treatment </li></ul></ul><ul><ul><ul><li>Oral Nitrates </li></ul></ul></ul><ul><ul><ul><li>Beta Blockers </li></ul></ul></ul><ul><ul><ul><li>Calcium Antagonists </li></ul></ul></ul><ul><ul><ul><li>Statins and Anti platelets </li></ul></ul></ul>
15. New mechanistic approaches to stable angina Sinus node inhibition (ivabradine) Late I Na inhibition (ranolazine) Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) O H 3 C O H 3 C O N CH 3 O CH 3 O CH 3 O O NO 2 H N N N N O N CH 3 H CH 3 CH 3 O O H N SO 2 NH N O OH CH 3 CH 3 OCH 3 H N N N O
16. Acute Coronary Syndrome
17. Pathophysiology of ACS: Disrupted Plaque Unstable angina or NSTEMI Temporary resolution of instability Future high-risk lesion Acute STEMI Adapted from Yeghiazarians et al. N Engl J Med . 2000;342:101-114. Plaque rupture Thin cap High macrophage content Large lipid core Incomplete coronary occlusion Complete coronary occlusion Spontaneous lysis, repair, and wall remodeling
18. Pathogenesis of ACS White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
19. Cumulative 6-month mortality from CAD 0 1 2 3 4 5 6 5 10 0 15 20 25 Months after hospital admission Deaths / 100 pts / month Acute MI Unstable angina Stable angina Duke Cardiovascular Database N = 21,761; 1985-1992 Diagnosis on adm to hosp
20. EARLY RISK STRATIFICATION <ul><li>In all patients with CP the likelihood of Acute coronary Ischaemia should be determined ( High, Intermediate and Low ) </li></ul><ul><li>The process of early RS focuses on: Anginal Symptoms Clinical Examination ECG findings Biomarkers of Cardiac Injury </li></ul>
21. Why Early Risk Stratification? <ul><li>Assessment of prognosis, based upon the likelihood of death/MI should set the pace of Initial Evaluation & Management of ACS. </li></ul><ul><li>The process of RS is needed for </li></ul><ul><ul><li>Selection of the site of care (CCU, Monitored unit, OPD) </li></ul></ul><ul><ul><li>Selection of Therapy specially newer agents like GP IIb/IIIa inhibitors </li></ul></ul><ul><ul><li>Determination for the need of an early invasive course. </li></ul></ul>
22. Tools for Risk Assessment (12-lead ECG) <ul><li>It remains the sheet-anchor of the decision making for evaluation and management in CP </li></ul><ul><li>A tracing during CP is of particular importance. </li></ul><ul><li>High Risk: </li></ul><ul><li>ST-segment deviation > 0.05 mV </li></ul><ul><li>New or presumed new LBBB </li></ul><ul><li>Sustained VT </li></ul><ul><li>Intermediate Risk: </li></ul><ul><li>T wave inversion or presence of Q waves </li></ul><ul><li>Low Risk: </li></ul><ul><li>No ECG changes during CP </li></ul>
24. Anginal Symptoms <ul><li>High Risk: </li></ul><ul><li>Accelerating Tempo of CP in preceding 48 hrs or prolonged CP for >20 min </li></ul><ul><li>Intermediate Risk: </li></ul><ul><li>Recent prolonged angina at rest for >20 min now resolved; Rest angina of <20 min. </li></ul><ul><li>Low Risk: </li></ul><ul><li>New onset Angina with no other High/Intermediate risk features on symptoms or ECG. </li></ul>
25. BIOMARKERS <ul><li>Biomarkers of Cardiac Injury should be measured in all patients with suspected ACS </li></ul><ul><li>Cardiac Specific Troponin (cTnT or cTnI) is the preferred marker, if available. </li></ul><ul><li>CK-MB is also acceptable </li></ul><ul><li>Total CK (without MB), AST, LDH are considered useless now in this setting. </li></ul>
26. Principles of Hospital Care in ACS <ul><li>Bed Rest </li></ul><ul><li>Continuous ECG monitoring in a CCU for Ischaemia/Arrhythmia </li></ul><ul><li>Nitrates S/L followed by an IV infusion </li></ul><ul><li>Pulse Oximetry with Oxygen if needed </li></ul><ul><li>Morphine Sulphate IV if pain persists and specially with LVF </li></ul><ul><li>Beta Blockade with first dose IV, if CP persists </li></ul>
27. Principles of Hospital Care in ACS <ul><li>ACE-I , early on ( a lot of evidence with drugs like Ramipril : also evidence with ARB e.g. Valsartan) </li></ul><ul><li>Antiplatelets (Aspirin and Clopidogrel) </li></ul><ul><li>Anticoagulants (UFH/LMWH or Fondaparinux) </li></ul><ul><li>Statins </li></ul><ul><li>Early Invasive vs. planned ischaemia driven </li></ul>
28. Lipid Management in Clinical Practice <ul><li>For patients with CHD or diabetes , a new, lower optimal goal for LDL-C is <70 mg/dl —NCEP Coordinating Committee Circulation 2004;110:227–239 </li></ul>What is an appropriate therapeutic target for LDL-C?
29. Changes to NCEP ATP III LDL-C Goals NCEP=National Cholesterol Education Program; ATP III=Adult Treatment Panel III Adapted from Grundy SM et al Circulation 2004;110:227–239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486–2497. Modification Modification 2+ risk factors (10-year risk 20%) CHD or CHD risk equivalents (10-year risk >20%) Risk Category Optional goal of <100 mg/dl (2.5 mmol/L) for 10%–20% risk group Optional goal of <70 mg/dl (1.8 mmol/L) <130 mg/dl (3.4 mmol/L) ATP III <100 mg/dl (2.5 mmol/L) ATP III LDL-C Goal Publication
30. Rationale for Lower LDL-C Goals <ul><li>Both HPS and PROVE IT suggest that additional benefit may be obtained by reducing LDL-C levels to substantially less than 100 mg/dl (2.5 mmol/L) </li></ul><ul><li>Recent trials indicate that there is no threshold below which lower LDL-C concentrations provide no further benefit </li></ul>Adapted from Grundy SM et al Circulation 2004;110:227–239; HPS Study Group Lancet 2002;360:7–22; Cannon CP et al N Engl J Med 2004;350:1494–1502; O’Keefe JH et al J Am Coll Cardiol 2004;43:2142–2146; Stamler J et al JAMA 2000;284:311–318; Chen Z et al BMJ 1991;303:276–282.
35. Prognosis in CAD <ul><li>More closely related to </li></ul><ul><ul><li>Left Ventricular Function; & </li></ul></ul><ul><ul><li>Extent of Coronary Disease </li></ul></ul><ul><ul><li>than </li></ul></ul><ul><ul><li>The severity of Symptoms </li></ul></ul>