Manual of Coronary Heart Diseases Kanu Chatterjee
INDEX
Page numbers followed by ‘f’ refer to figure and ‘t’ refer to table.
A
Abciximab 122
Activated partial thromboplastin time 124
Acute
aortic dissection 83
coronary syndromes 67, 95, 143, 197, 225, 278
ischemic myocardial infarction 104f
MI with LV failure 315
myocardial infarction 51, 149, 225, 288, 328
pulmonary embolus 315
right ventricular infarction 303
tricuspid regurgitation 315
Adenosine
dinucleotide phosphate receptor antagonists 116
echocardiography 76
AECG See Ambulatory electrocardiography
Allergic reactions 169
Alpha-2 agonists 87
Alteplase 167
Ambulatory
ECG monitoring 257
electrocardiography 234
Aminosulfonic acid 325
Amlodipine 114
Angina 5, 60, 62
Angina-2, treatment of 344
Anginal episodes, severity of 229
Angioplasty 344
procedures 344
Angiotensin converting enzyme inhibitors 199, 232
Antianginal
drug therapy 226
therapy 229
Antiarrhythmic drugs 264
Anti-ischemic therapies 317
Antiplatelet agents 115, 179
Antithrombin 124, 126
Antithrombotic agents 124
Aortic dissection 60, 173
evaluation for 162
Approximate cost per dose 169
APTT See Activated partial thromboplastin time
Argentine randomized trial of percutaneous transluminal coronary angioplasty versus coronary artery bypass surgery in multivessel disease 346
Arrhythmias 19
treatment of 264
Arteriovenous malformation 173
Artery elasticity
large 6
small 6
Aspirin 115
resistance 116
Asymptomatic cardiac ischemia pilot 239
Atenolol silent ischemia study 229
Athersclerotic disease 338
Atorvastatin 235
versus revascularization treatment 233
Avascular tissue, zone of 67
B
BARI See Bypass angioplasty revascularization investigation
Baseline bradycardia 231
Beta blockers 113, 182, 227, 228
medical therapy 86
Bicarbonate 325
Bivalirudin 126
Biventricular
diastolic dysfunction 306
dysfunction 289
Blood pressure 6
control 114
management 209
Body
mass index 6, 19
temperature, maintenance of 88
Bradyarrhythmias 312
Bradycardia 228
Bypass angioplasty revascularization investigation 345
C
C:T ratio See Cardiac:thoracic ratio
CABGS See Coronary artery bypass graft surgery
CABRI See Coronary angioplasty versus bypass revascularization investigation
Calcium
antagonists 264
channel blockers 114, 115, 226, 228, 229, 264
Cardiac
biomarker 106
testing 102
causes of cardiogenic shock 284
cycle 291
death and nonfatal myocardial infarction, composite endpoints of 15f
index 277, 294
ischemic pain 61
rehabilitation 207, 208, 211
rupture 286
syndrome X 252
tamponade 286, 315
thoracic ratio 66
Cardiogenic shock 113, 190, 199, 279, 284, 285, 288, 291, 293, 294
Cardiopulmonary
bypass 324
resuscitation 173
Cardiovascular
causes of chest pain 82
disease, treatment of 15
disease 1, 5, 6, 17, 38
mortality patterns 39f
Carotid intima-media thickness 6
Cervical spine 60
Chelation therapy 246
Chest pain 59, 262
evaluation of 59
management of 59
Chest X-ray 66
Cholecystitis 60
Chronic
coronary artery disease 225, 324, 342
surgical therapy in 324
diseases 44
obstructive pulmonary disease 113
Clarithromycin 228
Classic coronary artery disease risk factors 252
Clopidogrel 117, 118
hyporesponders 120
resistance 118
Coagulation system 98
Cocaine 149
Cold clammy skin 277
Combination therapy 232
Computed tomography 78
Confirmatory test selection in accelerated diagnostic protocols 83
Congestive heart failure 19, 114
Constipation 228
Continued medical therapy 199
Coronary
angiography 163f, 187
angioplasty versus bypass revascularization investigation 347
arteriogram 251
arteriography 260, 261
artery 305f
bypass graft 16, 117, 158f, 161f, 166, 324,
surgery 230, 278
calcium 28
disease 2, 64, 95, 146, 225, 262
surgical management of 324
surgery study 236
death 5
disease 78
flow 227
heart disease 1, 5, 6, 17, 19, 38, 39f, 234
insufficiency 5
intensive care unit 102
revascularization 5
vasospasm 253
Costochondral junction 101
Costochondritis 60
C-reactive protein 2, 108, 256
Creatine kinase 68, 103
Cyclic guanosine monophosphate 111
Cyclooxygenase pathway 100
D
Death or disabling stroke 168
Deep venous thrombosis 195
Defibrillator placement 193
Degenerative
and lifestyle diseases 40
diseases 40
Deleterious impact of right atrial ischemia 307
Depression 228
Deprivation score 6
Diabetes 2, 51, 101, 105, 110, 196
management 210
mellitus 23
Diastolic
blood pressure 173
dysfunction 19
pressure elevation 314
Dihydropyridines 114
Diltiazem 114, 265
Dipyridamole 246
echocardiography 76
spect 76
Direct thrombin inhibitors 126
Dizziness 228
Dobutamine
echocardiography 76
spect 76
stress echocardiography 77
Docosahexaenoic acids 18
Dopamine 318
role of 289
Double-blind atorvastatin amlodipine trial 234
Drug-eluting stents 329
DSE See Dobutamine stress echocardiography
Dyslipidemias 19, 192
Dysrhythmia See also Heart failure
E
EAST See Emory angioplasty versus surgery trial
Echocardiography 186
Edema 228
Ejection fraction 185f
Elective angiography 174
Electrocardiogram 102, 106, 149
test 70
Elevation depression arteriography 262
Emergency medical services 147
Emory angioplasty versus surgery trial 347
Endothelial dysfunction 19, 96, 263
Enhancing recovery in coronary heart disease 21
ENRICHD See Enhancing recovery in coronary heart disease
Eptifibatide 122
Erectile dysfunction 228
Esophageal spasm 60
Exercise electrocardiography 78
Exertional evidence of chest pain 260
F
Facilitated percutaneous coronary intervention 168
Fatal hypotension 112
Fatigue 228
Felodipine 114
Fibrin D-dimer 27
Fibrinogen 27
Fluorine-18-deoxyglucose 74
Framingham risk score 4, 5
calculation 64f
G
Gastroepiploic artery 338
German angioplasty bypass surgery investigation 346
Glycoprotein IIB/IIIA inhibitors 122
Graft patency 338
H
Hampton's hump 67
Headache 228
Heart
failure 5, 15, 190, 212, 228, 231
outcomes prevention evaluation trial 232
rate 227
Hemorrhagic stroke 5, 51
Heparin 124
High density
cholesterol 6
lipoprotein cholesterol 17
levels 11
High sensitivity
assay 108
C-reactive protein 6, 25
High waist-hip ratio 51
Homocysteine 2
Hyperhomocysteinemia 26
Hyperlipidemia 2, 22, 101, 105, 110
Hypertension 2, 19, 21, 51, 101, 110, 228, 277, 312
I
Impaired organ perfusion 277
Impella 294
Inequality index 54f
Infarct related artery 143
Infection and undernutrition related diseases 40
Inferior myocardial infarction 303
Inhibition of renin-angiotensin-aldosterone axis 199
Inotropic stimulation 317
Insulin resistance 19, 252
Internal
cardioverter 193
thoracic artery 326
graft 339
International normalized ratio 173
Interventricular septum 285f, 186f
Intra-aortic balloon 318
pulsation 291
pump 191, 282, 290
Intracranial hemorrhage 173
Invasive coronary angiography 80
Ischemic
heart disease 110, 225
stroke 5, 6, 173
Ivabradine 231
J
Jugular venous pressure 65
K
Kaplan-Meier survival curves 185f
Ketoconazole 228
Kidney injury 331
Kussmaul's sign 284
L
Lack symptoms of ischemia 212
Laplace's law tension 63
Left
bundle branch block 65, 106, 159
main coronary 237
artery 331
ventricular
apical ballooning
cardiomyopathy 255
assist devices 191, 290, 292
ejection fraction 327, 330
assessment of 183
function 341
hypertrophy 19
mass index 6
outflow tract
obstruction 228
thrombus 146
ultrasound 6
Length of stay 175
Lipid
lowering therapy 233
management 210
Lipoprotein 2, 26
LMC See Left main coronary
Low density
cholesterol 6
lipoprotein 201
cholesterol 13
Low molecular weight heparin 124
LV
dysfunction 228, 231
ejection fraction 183
hypertrophy 149
LVADs See Left ventricular assist devices
LVEF See Left ventricular ejection fraction
M
MACE See Major acute coronary events
Major adverse cardiovascular events 168
Malignancy, presence of 146
Malignant ventricular arrythmia 333
Mayo clinic risk score 333
Mechanical assist devices 318
Methamphetamines 96, 146
Microalbuminuria 6
Migraine headaches See also Raynaud's phenomenon
Mitral regurgitation 287
Morphine 112, 179
Myocardial
infarction 5, 6, 59, 109, 110f, 143, 173, 190, 199, 207, 270f
oxygen demand 289
perfusion imaging 74
revascularization 235
role of 235
Myocarditis 60
Myoglobin 68
Myopericarditis 149
N
National Cholesterol Education Program 6
Nausea 228
NCEP, third report of 5
Negative chest pain unit evaluations 84
Nelfinavir 228
Nephropathy 203
Neuropathy 203
Nifedipine 114, 265
gits 230
Nitric oxide 282
donors of 111
Non-ST elevation myocardial infarction 68
Noncardiac cause 225
of acute chest pain 83
Noncardiac chest pain 63
Noncompressible vascular punctures 173
Nondihydropyridines 114
Nonfatal myocardial infarction 5, 6, 16
Noninvasive
computed tomographic angiography 77
stress testing before noncardiac surgery 85
Nonsustained ventricular tachycardia 193
Normal coronary arteries 272
NSTEMI See Non ST elevation myocardial infarction
Nuclear perfusion See also Echocardiography
Nutritional counseling 209
O
Obesity 2
cardiomyopathy 19
Oliguria 277
Omeprazole 119
Onset of pain 61
Optic fundoscopy for retinal vasculature 6
Optical coherence tomography 98
Optimal medical therapy 241, 242f
Optimize oxygen supply-demand 316
Oxygen 178
supplementation 111
P
Pain 262
Pancreatitis 60
PCI after successful thrombolysis 174
Percutaneous
coronary
angioplasty 234
intervention 117, 144f, 177f, 242f, 278
center 147
transluminal angioplasty 347, 348
myocardial 233
revascularization 235, 328
transluminal coronary angioplasty 16, 271
Pericarditis 60
Perioperative
control of blood glucose concentration 88
use of pulmonary artery catheters 89
Peripheral
arterial disease 5, 101
vascular disease 228
Phosphate 325
Physiologic rhythm 317
Planar thallium imaging 78
Plasma catecholamine levels 253
Plasminogen activator inhibitor 27
Platelet
inhibition and patient outcomes trial 121
role of 98
Pneumonia 60
Pneumothorax 60
Positive troponin 105
Positron emission
tomographic perfusion imaging 74
tomography 78
Post-myocardial infarction
care 183
depression 198
Potential for acute coronary syndrome 145
Prasugrel 120
Pravastatin 235
Preoperative
intensive care monitoring 88
noninvasive evaluation of left ventricular function 84
resting 12-lead ECG 85
Primary
coronary intervention 176
LV failure 277
PCI See Thrombolysis
percutaneous
coronary intervention 291
intervention 144
Printzmetal's variant angina 266
Prophylactic intraoperative nitroglycerin 88
Proximal right coronary artery 305f, 313f
Psychosocial intervention 210
PTCA See Percutaneous coronary angioplasty
Pulmonary
artery catheterization 289
capillary wedge pressure 277
edema 288
embolism 60, 83
hypertension 19, 60, 315
thromboembolism 19
R
Radionucleotide scintigraphy 260
Randomized
controlled trial 17, 144f
intervention treatment of angina 346
trial 241
Ranolazine 227, 228, 230
Rasmussen score 6
Ratio of total cholesterol 6
Raynaud's phenomenon 96, 255
RBBB See Right bundle branch block
Recurrent
chest discomfort 195
dysrhythmias See also Cardiogenic shock
Reduction in
blood pressure 15
cardiovascular event and morality after first myocardial infarction 16
incidence of disease 3
Reflux 60
Regression 333
Relief of anginal symptoms 341
Renal
failure 333
impairment 338
Reperfusion 166, 316
therapy 317
Reteplase 167
Retinopathy 203
Revascularization 129, 187, 296
with pharmacological antianginal therapy, comparison of 236
Reynolds risk score 5
Rifampin 228
Right
atrial contraction, compensatory role of augmented 307
bundle branch block 159
coronary artery 151, 304
heart mass obstruction 315
ventricular
ejection fraction 184
infarction 190, 284
mechanics and oxygen
supply-demand 305
RITA See Randomized intervention treatment of angina
Routine coronary arteriography 261
Rupture of posteromedial papillary muscle 228f
RV infarction 303
S
Saphenous vein grafts 338
Secondary prevention of coronary heart disease 207
Seldinger technique 290
Serum creatinine 338
Severe
carotid artery stenosis 336
recurrent myocardial ischemia 110f
right heart dilatation 314
uncontrolled hypertension on presentation 173
Sexual dysfunction 228
Shock 333
Short-term graft patency 338
Sick sinus syndrome 228
Significant
liver disease 228
reduction in composite end point 15
Sildenafil 112
Single-photon emission 78
computed tomography 73
Sirolimus-eluting stents 349
Sleep apnea 19
Small reduction in total mortality 14
Smoking 105
ST
depression 262
elevation 262
segment deviation 110
Stable
angina 225
ischemic heart disease 342
Statin therapy 87
St-elevation myocardial infarction 143
Stent thrombosis 145
Streptokinase 167
Stress
cardiomyopathy 253
myocardial perfusion imaging 73
testing with
echocardiogram
imaging 75
myocardial imaging 72
Stroke 6, 15, 19
St-segment elevation myocardial infarction 277
Sudden cardiac death 6
Surveillance for perioperative MI 89
Syncope 228
Systemic fibrinogen depletion 169
Systolic
blood pressure 5, 6, 173, 277
ventricular interactions, importance of 306
T
Tachycardia ensues 279
Tadalafil 112
Takotsubo cardiomyopathy 149, 253
Tenecteplase 167
Thoracic surgeons, society of 336
Thrombolysis 179
in myocardial
infarction 108
risk score 69
ischemia IIIB 345
Thrombolytic agent, administration of 166
Ticagrelor 121
Tissue plasminogen activator 27, 167
Tobacco cessation 210
Total and cardiovascular mortality and cardiovascular morbidity 14
TPA See Tissue plasminogen activator
Transesophageal echocardiography, use of 88
Transient ischemic attack 5, 6, 120
Transthoracic echocardiogram 159
Treadmill exercise
blood pressure 6
stress testing 71
testing 260
Trials comparing coronary artery bypass grafting 347
Tris-hydroxymethylaminomethane 325
Troponins 68, 95, 103
U
Unfractionated heparin 124
Unstable angina 15, 95
V
Vasoconstrictors 96
Vasospasm 96, 149
Ventricular
arrhythmias 312
fibrillation 193
septal rupture 284
Verapamil 114, 265
Volatile anesthetic agents, use of 88
von Willebrand factor 100
antigen 27
Vulnerable 226
plaque 96
W
Waist circumference 20
Weight management 209
Wellen's syndrome 102, 103f
Westermark sign 67
White blood cell 256
count 2
Wolff-Parkinson-White syndrome 149
×
Chapter Notes

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Coronary Heart Disease: Risk FactorsCHAPTER 1

Bilal Aijaz,
Vera Bittner
Chapter Outline
  • • CHD Screening and Prevention
  • • Clustering and Multiplicative Effects of Risk Factors
  • • CHD Risk Estimation
    • – Framingham Risk Score (FRS)
    • – European Risk Scores
    • – Newer Risk Scores
  • • Measures to Evaluate Risk Prediction Models
  • • Traditional CHD Risk Factors
    • – Non-modifiable Risk Factors for CHD
    • – Modifiable Risk Factors for CHD
  • • Emerging Risk Factors
    • – High-sensitivity C-reactive Protein (hs-CRP)
    • – Lipoprotein (a) [LP(a)]
    • – Hyperhomocysteinemia
    • – Lipoprotein-associated Phospholipase A2 (LP-PLA2)
    • – Apolipoprotein B
    • – Fibrinogen and Other Hemostatic Factors
  • • Sub-clinical Atherosclerosis
  • • Translating Risk Factor Screening into Event Reduction
 
INTRODUCTION
Cardiovascular disease (CVD) remains the leading cause of death in the United States and many other parts of the world and results in substantial disability and loss of productivity. Coronary heart disease (CHD) and stroke are the leading contributors to this heavy CVD burden. The exact mechanisms underlying development of CVD still remain to be fully described. However, through population-based studies starting in the 1940s and 1950s and intervention trials later, multiple risk factors for the development of CVD have been identified. The term ‘risk factor’ was in fact first used in the context of CHD.1 A risk factor is any personal, environmental, psychosocial or genetic characteristic that gives an individual a higher likelihood of developing a particular disease. Even though the risk factor is a mere statistical association to an outcome, the current use of the term ‘risk factor’ often implies causality. On the other hand, a ‘risk marker’ has association with a disease but a cause and effect relationship either does not exist or remains to be proven. These terms have evolved over the years and are non-uniformly used in the literature.
Cardiovascular disease risk factors are generally categorized into traditional/conventional and novel/emerging risk factors (Table 1). Risk factors can be inherited or acquired, some are modifiable and others are not. Risk factors may be defined dichotomously by their presence or absence or measured as a continuous variable.2
Table 1   Risk factors for cardiovascular disease
Traditional risk factors
Modifiable
Non-modifiable
• Hypertension
• Diabetes
• Hyperlipidemia
• Obesity
• Tobacco use
• Physical inactivity
• Age (male ≥ 45 years, female ≥ 55 years)
• Gender
• Family history of premature coronary artery disease*
Selected emerging risk factors
• C-reactive protein
• Small LDL particles
• Lipoprotein(a)
• Homocysteine
• Lipoprotein-associated phospholipase A2
• Coagulation and hemostatic factors
• Apolipoproteins A and B
• White blood cell count
(*Definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative or before 65 years of age in mother or other female first-degree relative)
The treatment of CVD risk factors has contributed to the fall in CVD mortality in the past 30 years, at least in developed countries.2 At the same time, the prevalence of CVD and heart failure has increased due to higher survival rates and an aging population. More recent data suggest that we have reached a plateau in CVD mortality, which correlated with the obesity and physical inactivity epidemics. This highlights the challenge of CVD management: both identification and effective treatment of risk factors are required. Despite identification of patients at risk for CHD, significant gaps remain in implementing treatment. For instance, up to 15–20% of high risk patients discharged from the hospital, such as those with acute coronary syndrome, are not initiated on recommended combination therapy of aspirin, beta-blocker, statin and angiotensin converting enzyme inhibitors. Fewer are referred to comprehensive risk reduction programs like cardiac rehabilitation suggesting that lifestyle risk factors are even less likely to be addressed.3 As our quest for finding new risk factors and development of new therapeutic strategies is ongoing, we also have to devise ways to uniformly implement effective risk factor treatment.
 
CHD SCREENING AND PREVENTION
The high lifetime risk of CHD warrants population wide screening for prevention and treatment. The long lag-time between the onset of atherosclerosis and its related morbidity 3and mortality allows for detection and early intervention. Screening involves routine evaluation of asymptomatic people. The widely accepted World Health Organization (WHO) criteria for screening of disease are summarized in Table 2. Screening should be cost-effective with the goal of detecting, not excluding, disease. Using established risk factors, a significant percentage of ‘at risk’ individuals can be screened as a target for preventive strategies.4
Three to five levels of prevention are described in the context of CVD (Table 3), often with dissimilar definition. The Centers for Disease Control and Prevention describe a simple classification with three levels of prevention.5 Primordial prevention or health promotion targets the population without risk factors and aims to prevent the development of risk factors. The goal of primary prevention is to prevent the development of CVD in individuals with one or more risk factors. Secondary prevention involves patients with established clinical disease with the goal to prevent recurrent CVD events and their complications. A fourth level referred to as tertiary prevention targets late stages of the disease with the goal of restoration and rehabilitation.
 
CLUSTERING AND MULTIPLICATIVE EFFECTS OF RISK FACTORS
Initially, risk factors for CHD, such as diabetes, hypertension and hyperlipidemia, were targeted and treated individually. However, risk factors often occur in clusters and show a multiplicative effect rather than a simple additive effect.
Table 2   WHO principles for screening*
1. Condition screened should be an important health problem
2. There should be a suitable test for diagnosis
3. There should be an accepted treatment
4. Facilities for diagnosis and treatment should be available
5. The screening should be cost-effective
6. There should be a recognizable latent stage
7. The natural history should be adequately understood
8. Case finding should be a continuous process
(Source: Wilson JMG, Junger G. Principles and practice of screening for disease. Public Health Pap. Geneva: World Health Organization; 1968)
Table 3   Levels of prevention in cardiovascular disease
1. Primordial prevention
Prevention of the risk factors for disease
2. Primary prevention
Reduction in incidence of disease
3. Secondary prevention
Reduction in the prevalence or consequence of disease
4. Tertiary prevention
Reductions in complications or disability, rehabilitation or restoration of function
4
This has important implications for treatment. Most persons in a population have moderate elevation in multiple risk factors rather than an extremely high level of any single risk factor. Similarly, most cardiovascular events occur in individuals with mild-to-moderate abnormality in multiple risk factors. Targeting only high levels of individual risk factors will target only a small fraction of the population. Various expert groups stress the concept of ‘comprehensive risk factor management’.
 
CHD RISK ESTIMATION
Despite our knowledge and understanding of many CHD risk factors, a clinical challenge is to effectively predict risk of CHD in individuals to allow appropriate and cost-effective treatment. Risk estimates are also used to raise awareness about CHD, determine population attributable risk to target specific public health measures, and to communicate risk to patients.
Coronary heart disease risk estimation measures the likelihood of a person developing a serious cardiovascular event over a specific follow-up time. Several multivariable models exist to predict the risk for future CHD and CVD (Table 4), many derived from the Framingham cohorts. Risk estimation results are critically dependent on the time frame of prediction. Earlier risk scores predicted short-term and medium-term risk of ≤ 10 years. More recently, long-term and lifetime risk estimation algorithms have been developed.6,7 Risk estimation also depends on the endpoint chosen, for instance, CHD versus overall cardiovascular risk8 and within CHD, ‘hard events’ such as myocardial infarction and CHD death or ‘hard and soft endpoints’ which also include angina pectoris and revascularization.
Refining and improving risk prediction is a major area of research in cardiovascular medicine. Key issues related to CVD risk estimation include the optimal time frame for risk assessment (short term, long term or lifetime), development of age-specific absolute risk models, defining cut offs for different risk categories, determining eligibility for pharmacological treatment, integration of imaging modalities to detect atherosclerosis and determining whether using a particular risk score will eventually result in better patient outcomes.
 
Framingham Risk Score (FRS)
FRS and National Cholesterol Education Program's Third Adult Treatment Panel update (NCEP ATP III) are the most widely used risk scores (Table 4). FRS predicts the 10-year risk of CHD using a multivariable mathematical model of risk.95
Table 4   Risk prediction scores for cardiovascular disease
Risk score (year)
Study summary
Variables
End point
Framingham Risk
Score (1998)
5,209 men and women, ages 30–62 yrs
Follow-up 10 yrs
10-year risk
Age, diabetes, smoking, hypertension, total cholesterol and LDL-C
All CHD
Framingham Risk
Score for General
Cardiovascular Disease (2008)
Men and women, ages 30–74 yrs without CVD at baseline
Follow-up 12 yrs
10-year risk
Age, diabetes, smoking, treated and untreated systolic blood pressure, total cholesterol, HDL-C
BMI replacing lipids in a simpler model
CVD (coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, heart failure)
Reynolds Risk Score (2007)
24,558 women, age > 45 yrs without CVD
Median follow-up 10.2 yrs
10-year risk
Age, hemoglobin A1C, smoking, systolic blood pressure, HDL-C, hs-CRP, total cholesterol, parental history of myocardial infarction at < 60 years
Global CVD (Composite end-point of cardiovascular death, myocardial infarction, ischemic stroke and coronary revascularization)
Reynolds Risk Score, men (2008)
10,724 men, ages 50–80 yrs
10-year risk
Age, hemoglobin A1C, smoking, systolic blood pressure, HDL-C, hs-CRP, total cholesterol, parental history of myocardial infarction at < 60 years
Global CVD (Composite end-point of cardiovascular death, myocardial infarction, ischemic stroke and coronary revascularization)
Third Report of NCEP
Adult Treatment Panel
(2002, Update 2004)
SCORE (2003)
Uses Framingham
Risk Score
10-year risk
205, 178 persons, ages
45–64 yrs
10-year risk
Variables same as Framingham risk score. Diabetes is considered a CVD equivalent age, cholesterol, smoking, systolic blood pressure
Individuals with > 5%, 10-year risk are defined as high risk
Hard CHD (CHD death and non-fatal myocardial infarction) CVD death
Contd…
6
Contd…
Risk score (year)
Study summary
Variables
End point
QRISK (2007)
Derivation cohort 1.28 million patients, age 35–74 yrs.
Median follow-up 6.5 years
10-year risk
Age, body mass index, ratio of total cholesterol to HDL-cholesterol, family history of premature cardiovascular disease, smoking, systolic blood pressure, deprivation score
CVD (myocardial infarction, ischemic stroke, transient ischemic attack and coronary heart disease)
Prospective cardiovascular Münster (PROCAM) (2002)
5,389 men, age 35–65 yrs
10-year follow-up
Age, LDL-C, smoking, HDL-C, systolic blood pressure, family history of premature myocardial infarction, diabetes mellitus, triglycerides
Score 0 to > 60 with score > 53 defined as high risk (> 20% 10-year risk of cardiac event)
Hard CHD (sudden cardiac death or a definite fatal or nonfatal myocardial infarction)
Rasmussen Score (2003)
396 individuals
Blood pressure, N terminal proBNP, electrocardiogram, carotid intima-media thickness, microalbuminuria, treadmill exercise blood pressure, left ventricular ultrasound left ventricular mass index, small and large artery elasticity, optic fundoscopy for retinal vasculature
(Abbreviations: CVD: Cardiovascular disease; CHD: Coronary heart disease; LDL-C: Low density cholesterol; HDL-C: High density cholesterol; hs-CRP: High-sensitivity C-reactive protein; NCEP: National cholesterol education program)
7
The calculator is available at: (http://www.framinghamheartstudy.org/risk/hrdcoronary.html). The NCEP ATP III risk assessment tool predicts the 10-year risk of hard CHD (myocardial infarction and coronary death).10 The calculator is available at: (http://hp2010.nhlbihin.net/atpIII/calculator.asp?usertype=prof). Intensity of risk factor treatment is guided by the magnitude of absolute risk. Absolute risk is divided into three risk categories: high, intermediate and low risk (Table 5). High risk individuals include those with established CHD, diabetes, stroke, peripheral vascular disease or with multiple risk factors without established CHD, but a 10-year risk of CHD events greater than or equal to 20%. Certain individuals are considered ‘very high-risk’ and, according to the NCEP ATP III update,11 they should be the target of more intensive lipid lowering therapy. This group includes individuals with established CVD in the presence of multiple major risk factors, especially if uncontrolled, or patients with acute coronary syndromes.
The FRS predicts major CHD events well in different populations.12 Limitations of FRS are that it was developed exclusively in Caucasians. FRS does not include family history, obesity and psychosocial factors, which are important risk factors for CVD. FRS calculates only CHD risk and not the complete risk of other CVD processes including stroke, heart failure and peripheral vascular disease. The data used in the original Framingham Heart Study precede the obesity and physical inactivity epidemic. FRS is heavily influenced by age13 and gender. For instance, most non-smoking men less than 45 years and almost all women less than 65 years of age have a 10-year risk of less than 10%. Despite some limitations, FRS is the most widely used and validated risk assessment tool and is able to provide remarkably good discrimination for the majority of individuals.14
Table 5   Risk categories for 10-year risk of coronary heart disease
Risk category definition
High risk
CHD or CHD risk equivalent* or ≥ 2 risk factors and 10-year predicted risk of ≥ 20%
Moderately high risk
≥ 2 Risk factors and 10-year predicted risk of 10–20%
Moderate risk
≥ 2 Risk factors and 10-year predicted risk of ≥ 10%
Low risk
0–1 Risk factor
*Peripheral arterial disease, diabetes mellitus; Risk factors include cigarette smoking, hypertension (blood pressure ≥ 140/90 mm Hg or on antihypertensive medication), low high-density lipoprotein cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years of age; CHD in female first-degree relative < 65 years of age) and age (men ≥ 45 years; women ≥ 55 years)
8
 
European Risk Scores
Since FRS is based on a North American sample, in Europe different risk scores were established including the Systematic Coronary Risk Evaluation (SCORE) project and the QRESEARCH cardiovascular RISK algorithm (QRISK). The SCORE15 has been adopted by the Joint European Societies’ guidelines on CVD prevention. The SCORE risk prediction system uses only fatal CVD as the outcome measure. The risk chart provides more detail for middle-aged persons in whom the risk changes with age. Separate charts are available for higher and lower risk areas in Europe. Individuals with a 10-year risk of CVD death of 5% or more are considered at an ‘increased risk’ and qualify for intensive risk factor management.16 A newer, computer-based tool for total risk estimation, which operates using the SCORE data, is called the HEARTSCORE (http://www.heartscore.org/eu/high/Pages/Welcome.aspx). The QRISK17 algorithm was developed using the QRESEARCH database. The QRISK score includes family history of premature CHD, body mass index (BMI) and social deprivation that are not part of the FRS. A 2008 update (QRISK 2 score) contains additional variables including renal disease, atrial fibrillation and rheumatoid arthritis.18
 
Newer Risk Scores
Newer risk scores were developed in an attempt to overcome limitations of FRS and to incorporate emerging risk factors for CVD. A risk score's ability to reclassify patients at intermediate risk for CHD into higher risk for more aggressive management or lower risk categories for reassurance may clinically be useful. Some risk factor algorithms have eliminated laboratory based testing to reduce cost and increase availability, in particular to the primary care physicians, who are generally the first contact for the majority of the low-to-intermediate risk population.
The Reynolds risk score19 for women was developed in 24,558 women from the Women's Health Study. In addition to traditional subject-reported risk factors, it incorporates family history of myocardial infarction, high-sensitivity C-reactive protein (hs-CRP) and hemoglobin A1C. In the original study, Reynolds risk score was able to reclassify 40–50% of intermediate risk women into higher or lower risk categories. Later, a Reynolds risk score for men was developed in a cohort of 10,724 men from the Physicians Health Study II. This risk score reclassified 18% of men into a higher or lower risk category.20 The risk calculator is available at http://www.reynoldsriskscore.org.9
A general CVD risk prediction model was developed by D’Agostino et al.8 using the original and offspring cohorts of the Framingham study. The risk estimation is for all CVD events compared to only CHD events in FRS. The investigators formulated two separate risk scoring models: one based on standard risk factors including laboratory variables and another using only non-laboratory based clinical variables. This risk assessment tool also presents the concept of ‘vascular age’ of an individual. Vascular age is the chronological age with optimal risk factors that gives the same predicted risk as that of the individual whose risk is being estimated. Currently, there are no established cut-offs for what is considered high risk when using global risk score. Published studies have used a 10-year risk of a CVD event of greater than 20% as the cut-off. To overcome the limitation of short-term risk prediction, recently, long-term and lifetime risk estimation algorithms have been developed.7 Lifetime risk estimation may be useful for younger patients who have low short-term risk but high lifetime risk. In fact, data from the National Health and Nutrition Examination Survey 2003 to 2006 suggest that over 50% of US adults with a low 10-year risk have a high lifetime risk of CVD.21 Initiating earlier treatment may result in substantial benefit over the life of these individuals but also potentially exposes them to long-term pharmacological therapy, of which the safety and cost-effectiveness is not fully established.
In contrast to the traditional approach of identifying risk factors for CVD, others have proposed direct assessment of the presence and severity of atherosclerosis/vascular disease. Cohn et al. developed the Rasmussen score22 based on ten parameters including imaging modalities such as echocardiogram and carotid ultrasound. Similarly, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force issued a consensus statement recommending that all asymptomatic men (45–75 years) and women (55–75 years) with a 10-year risk of CHD greater than 5% should undergo noninvasive imaging to detect subclinical CHD.23 The SHAPE task force II is currently working to update to these guidelines.
 
MEASURES TO EVALUATE RISK PREDICTION MODELS
Several metrics exist to help clinicians evaluate the performance and utility of risk prediction scores including discrimination, calibration and reclassification.24 Discrimination is the ability of a model to separate those with or without disease. The C statistic or area under the receiver operating characteristic (ROC) curve is widely used to report the discrimination ability of a risk score. It indicates the probability of a randomly selected 10case having a higher score than a noncase. For instance, a C statistic of 0.80 predicts that a patient with disease will have a higher score compared to a healthy patient 80% of the time. 1.0 is perfect discrimination and 0.5 is random chance. A C statistic greater than 0.70 is considered an acceptable level of discrimination. The C statistic does not quantitate the difference of risk between the case and the noncase. Large odds ratios or relative risks are required to achieve an acceptable C statistic score.
Calibration of a test determines its ability to accurately predict the absolute level of risk by comparing the predicted to the observed event rate. A good model will have an observed event rate close to the predicted rate. A test may have good discrimination but poor calibration. Generally, a model cannot have a perfect discrimination and be perfectly calibrated at the same time.
Other measures include likelihood ratio tests and Bayes information criterion which are sensitive assessments, used as initial measures to ascertain the global fit of the model.25 These assess the ability of a score to predict disease incidence better than by chance alone. A penalty is paid for the number of variables included. A risk score's ability to reclassify individuals from one risk category to another is also used to evaluate the utility of the model. Both the net reclassification improvement (NRI) (difference between appropriate reclassification and inappropriate reclassification) and how much the individual moved in order to be reclassified (termed the integrative discrimination index or IDI) are important when using reclassification.
 
TRADITIONAL CHD RISK FACTORS
 
Non-modifiable Risk Factors for CHD
Certain risk factors for CHD are non-modifiable including age, male gender and family history of CHD. Although, these risk factors are non-modifiable, they are an essential part of the risk prediction algorithms and identification of patients at higher risk for CHD events. Based on the Framingham Heart Study and NCEP ATP III recommendations, a positive family history of premature CHD is defined as a coronary event in parents before age 55 years in men and 65 years in women. Parental CHD, on an average, doubles the risk of CHD in an adult offspring. CVD in siblings also increases the risk of incident CVD even after adjustment for traditional risk factors and parental history of CVD. Compared to parental CVD, sibling CVD is reported to be a stronger predictor of CVD.26 The reported variability in risk with family history of 11CVD is possibly due to recall bias, difference in family size and referral bias.26
 
Modifiable Risk Factors for CHD
 
Lifestyle Risk Factors
Lifestyle risk factors including physical inactivity, diet and psychosocial factors are established risk factors for CHD and carry considerable public health importance as targets for intervention. In the INTERHEART study,27 healthy lifestyle behavior including eating fruits and vegetables, exercising regularly and avoiding smoking led to 80% lower relative risk for myocardial infarction.
Smoking: Cigarette smoking is an important risk factor not only for CVD but also due to its impact on non-cardiovascular morbidity and mortality. It is the single most important preventable cause of disease and early death.28 Smoking is a major public health threat in low-to-middle income countries where CVD is already on the rise.
Cigarette smoking has several detrimental effects on the cardiovascular system including increase in heart rate and blood pressure, increased thrombogenesis, endothelial dysfunction, increased plaque instability and less favorable effects on lipids. These processes lead to a proinflammatory state and atherosclerosis. Cigarette smoking also decreases high density lipoprotein cholesterol (HDL-C) levels. These effects are directly proportional to the amount of tobacco smoked. There is no evidence that using filters or other barriers reduces the risk. Smoking cigars and pipe raises the risk of CHD, as does passive smoking. It is unclear if decreasing, but not quitting, tobacco use provides any benefit or not.29 Quitting smoking both for asymptomatic persons and those with established CVD is an extremely effective preventive measure for decreasing CVD mortality. Past smokers continue to reduce their risk over 10 years and eventually reach that of a non-smoker. For secondary prevention, patients who quit smoking decrease their risk of recurrent myocardial infarction by 50%.30 Patients who quit smoking after coronary artery bypass have better survival and lower rates of angina and hospital admissions compared to patients who continue to smoke.31
In the clinical setting, it is important that every patient undergoes a full assessment of smoking status. This includes amount, type and duration of cigarette smoking, any other tobacco products used, social and family environment and reason for smoking. Physicians should assess the patient's knowledge about specific harmful effects of smoking on the cardiovascular system. Practitioners can use the clinical 12practice guidelines issued by the US Department of Health and Human Services to effectively intervene on tobacco users. The five steps recommended for intervention, referred to as the 5As, are summarized in Table 6. It is important to continue to address smoking cessation at every visit. Physicians can also use the opportunity at the time of an acute myocardial infarction to provide smoking cessation counseling, as patients are more likely to be motivated to quit. Multiple options exist to help with smoking cessation including providing self-help materials to patients,32 behavioral counseling33 and group therapy. Support from spouse and family may also be important. Data regarding acupuncture and hypnotherapy for smoking cessation is inconsistent and these are not currently recommended. Physicians should be aware of different pharmacological therapy options available including several nicotine preparations, the anti-depressant drug bupropion and the more recently introduced medication vareniciline. In most patients, smoking cessation is associated with only mild weight gain. Any deleterious effects of even modest-to-major weight gain are likely minor compared to the harmful effects of continued smoking.34 At a public health and policy level, restricting smoking in public places and at work, limiting tobacco advertising and promotion, and preventing tobacco sales to minors are some of the ways by which tobacco use can be decreased.
Physical inactivity: Physical activity is any bodily movement that expends energy. It is generally measured by self-reporting or occasionally by activity monitors. Cardiorespiratory fitness is a physiological characteristic of a person measured by exercise testing. Regular physical activity improves cardiorespiratory fitness. Any planned physical activity with the intent of improving one's health or fitness is considered exercise. It is important to note that not all physical activity is exercise.
Table 6   The 5As for intervention for tobacco dependence*
1. Ask about tobacco use
Identify and document tobacco use Status for every patient at every visit
2. Advise to quit
In a clear, strong and personalized manner urge every tobacco user to quit
3.Assess willingness to make a quit attempt
Is the tobacco user willing to make a quit attempt at this time?
4. Assist in quit attempt
For the patient willing to make a quit attempt, use counseling and pharma-cotherapy to help him or her quit
5. Arrange follow-up
Schedule follow-up contact, preferably within the first week after the quit date
(*Fiore et al. Treating Tobacco Use and Dependence: Clinical Practice Guideline. Rockville, MD: US Dept of Health and Human Services; 2000)
13
Physical inactivity is an important and increasingly common lifestyle factor contributing to the global burden of CVD. Data from several lines of investigation link physical inactivity to CHD morbidity and mortality. Physical inactivity and excess caloric intake have greatly contributed to the global obesity epidemic. Physical activity exerts multiple cardiovascular benefits including decreased risk of developing hypertension, insulin resistance, and dyslipidemia and beneficial effects on endothelial function and thrombogenesis. The minimum recommended level of physical activity includes moderate intensity exercise for 30 minutes on at least 5 days of the week. The daily 30 minutes can be accumulated in as little as 10-minute sessions and may include walking, cycling, gardening, elliptical, swimming, recreational sports, etc. There are no recommendations for the maximum amount of physical activity and the ‘optimal’ level likely varies among different individuals and the endpoint desired (metabolic change vs peak fitness). Nearly half of the population fails to meet even the recommended minimum physical activity.35 The small amount of excess risk reported with vigorous physical activity is negligible compared to the beneficial effects of regular physical activity. In patients with established CHD, physical activity and cardiac rehabilitation decrease risk of future coronary events and mortality.36
Guidelines to help physicians evaluate physical activity level and counsel appropriately have been published.37 Physicians should assess the level of physical activity (both leisure time and at work) for all patients. Physical activity can be measured by recall questionnaire, diary or using a pedometer. Exercise prescriptions can provide more specific instructions to help with compliance. Referral to exercise programs or rehabilitation centers should be made as appropriate.
Nutrition: Diet is an important risk factor for CVD and also directly influences multiple CVD risk factors. Several dietary factors including the intake of fruits, vegetables, fatty acids, fiber, alcohol, excess salt and the ratio of carbohydrates, fat and lipids have been studied in relation to CHD risk (Table 7). Both epidemiological studies and intervention trials have demonstrated the importance of a balanced diet for CHD prevention.
Dietary lipids have an important role in the formation of atheromatous plaque. Diets, high in saturated and trans-fatty acids, are linked to higher rates of CHD.38 Saturated fatty acids increase low density lipoprotein cholesterol (LDL-C) concentration. The principal source of saturated fatty acids is animal products and some commercially prepared meals. Consumption of polyunsaturated fatty acids decreases LDL-C.14
Table 7   Select studies involving dietary interventions and cardiovascular outcomes
Reference, Year, Study design, Duration (N)
Study population
Intervention
Outcome
Results
Dasinger ML, et al. Comparison of Atkins, Ornish, Weight Watchers and Zone diets for weight loss and heart disease risk reduction, 2005, RCT, 12 months (N = 160)
160 adults aged 22–72 yrs
Assigned to Atkins, Zone, Weight Watchers or Ornish diets
1 year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report
Modest weight loss and reduction in total/HDL-C, C reactive protein, insulin without any significant difference among different diets
Howard BV, et al. Low fat dietary pattern and risk of cardiovascular disease, 2006, RCT, 8.1 yrs (N = 48,835)
48,835 post-menopausal women aged 50–79 yrs
Assigned to reduced fat, high fruits, vegetables and grains group or a comparison group
Fatal and nonfatal CHD, fatal and nonfatal stroke, and CVD (composite of CHD and stroke)
No difference in CVD, CHD or stroke
Hooper L, et al. Dietary fat intake and prevention cardiovascular disease: Systematic review, 2001, Meta-analysis, at least 6 months of follow-up
27 studies (30,902 persons years of observation) included
Advice about reducing or modifying dietary fat intake
Total and cardiovascular mortality and cardiovascular morbidity
Small reduction in total mortality 0.98; 95% confidence of interval 0.86–1.12) and cardiovascular mortality (0.91; 0.77–1.07). Cardiovascular events reduced by 16% (0.84; 0.72–0.99)
Contd…
15
Contd…
Reference, Year, Study design, Duration (N)
Study population
Intervention
Outcome
Results
Hooper L, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease, 2004, meta-analysis of RCTs and cohort studies, follow-up for at least 6 months, (N = 36,913)
36,913 participants from 48 RCTs and 41 cohort studies
Dietary or supplemental omega 3 fatty acids
Total mortality, cardiovascular events or cancers
No reduction in end point in persons taking additional omega 3 fats
de Lorgeril M, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study, 1999, RCT, 5 yrs (N = 423)
423 patients with CHD
Mediterranean diet versus western prudent
Composite endpoints of cardiac death and nonfatal myocardial infarction. Additional endpoints also included (unstable angina, stroke, heart failure, pulmonary or peripheral embolism
Significant reduction in composite end point (risk ratio 0.28, 0.015–0.53)
Sacks FM, et al. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) Diet, 2001, RCT, 5 yrs (N = 412)
412 participants
Comparing DASH diet (rich in vegetables, fruits and low-fat dairy products) to typical western diet
Reduction in blood pressure
DASH diet with a low sodium level led to a mean systolic blood pressure reduction of 7.1 mm Hg in participants without hyper-tension, and 11.5 mm Hg in participants with hypertension
Contd…
16
Contd…
Reference, Year, Study design, Duration (N)
Study population
Intervention
Outcome
Results
Liu S, et al. Fruit and vegetable intake and risk of cardiovascular disease: The Women's Health Study, 2000, Prospective observational, 5 yrs (N = 39,876)
39,876 female health professionals without CVD or cancer
Assessing fruit and vegetable intake
Nonfatal myocardial infarction, stroke, percutaneous transluminal coronary angioplasty, coronary artery bypass graft or death due to CVD
Significant inverse association between fruit and vegetable intake and CVD risk. Compared to median serving of 2.6/day the relative risk in those consuming 10.2 servings/day was 0.68 (0.51, 0.92; P = 0.01).
Tuttle KR, et al. Comparison of low-fat versus Mediterranean-style dietary intervention after first myocardial infarction (from The Heart Institute of Spokane Diet Intervention and Evaluation Trial), 2008, RCT, 46 months (N = 202)
202 patients with CHD
Comparison of Mediterranean diet, low fat diet and controls
Reduction in cardiovascular event and morality after first myocardial infarction
Primary outcome did not differ between Mediterranean and low fat diets but was significantly lower in either diet compared to the usual diet with adjusted odd ratio of 0.28 (0.13–0.63, p = 0.002)
Contd…
17
Contd…
Reference, Year, Study design, Duration (N)
Study population
Intervention
Outcome
Results
Swain JF, et al. Characteristics of the diet patterns tested in the optimal macronutrient intake trial to prevent heart disease (OmniHeart): options for a heart-healthy diet, 2008, RCT, 19 weeks (N = 164)
164 participants with prehypertension and hypertension
Comparison of carbohydrate rich, high protein and high fat diet
Estimated cardiovascular risk
All three diets reduced blood pressure, total and low-density lipoprotein cholesterol levels, and estimated CHD risk
(Abbreviations: RCT: Randomized controlled trial; CHD: Coronary heart disease; CVD: Cardiovascular disease; HDL-C: High density lipoprotein cholesterol)
18
Primary food sources of polyunsaturated fatty acids include vegetable oil, soya bean and rapeseed. Eicosapentaenoic acids (EPA) and docosahexaenoic acids (DHA) are members of the n-3 fatty acid group derived from fish oil. Intake of EPA and DHA reduces plasma triglycerides, increases HDL-C and has beneficial effects on the cardiovascular system. Multiple proposed mechanisms for the benefit of fish consumption and omega-3 fatty acids include anti-inflammatory, antiarrhythmic and antithrombotic effects.39 Guidelines recommend less than 30% of total calories from dietary fat and less than 7% from saturated fats.40,41 Dietary primary prevention trials show benefit of reduced saturated fatty acid intake and increase in polyunsaturated fat intake on clinical cardiovascular endpoints.42 Such dietary data should not be extrapolated to include intake of corresponding supplements.
High sodium intake is linked to hypertension, CHD and death. Current recommendations for the general population are to consume less than 5–6 gram of salt daily (equivalent of roughly 2,000–2,400 mg of sodium).41,43 A diet rich in fiber and natural products, fruits and vegetables decreases risk of CHD.38 The idea of combining foods or different diets, a portfolio, to achieve cholesterol control was suggested in the 1990s. The dietary portfolio contains four main elements including soy, nuts, viscous fibers and plant sterols and has been shown to reduce cholesterol.44
Nutrition is often neglected when counseling about CVD prevention and treatment. Healthcare providers quote lack of time and knowledge as barriers to successful nutrition counseling. Misleading information from the media is compounded by the lack of clinical trials. Despite patient counseling, the results are often disappointing in bringing substantial change in nutrition habits. In general, a cardioprotective or healthy diet is well balanced and includes different food sources. It should include the recommended amounts of fatty acids and sodium. The diet should be rich in fruits, vegetables, whole grains and high fiber foods. Fish should be consumed at least twice weekly.40 A balanced diet also helps to maintain a healthy body weight. Consultation with a dietitian should be sought whenever available.
Obesity: Obesity is an independent risk factor for CVD and increases mortality. Obesity is also associated with multiple other CVD risk factors (Table 8), which in turn adversely affects the heart.45 Obesity has reached epidemic proportions in many industrialized countries and its prevalence continues to increase, posing a major global health problem. Prevalence of childhood and adolescent obesity is also on the rise. Sedentary lifestyle, ease of access to food, increase in portion size and caloric intake are important reasons for the current obesity epidemic.19
Table 8   Effects of obesity on different organ systems and diseases
• Increase heart rate, blood volume and cardiac output
• Left ventricular hypertrophy
• Diastolic dysfunction
• Obesity cardiomyopathy and congestive heart failure
• Arrhythmias
• Venous stasis and insufficiency
• Pulmonary thromboembolism
• Endothelial dysfunction
• Hypertension
• Dyslipidemia
• Insulin resistance
• Proinflammatory state
• Sleep apnea
• Pulmonary hypertension
• Stroke
• Coronary heart disease
Genetic factors and certain other environmental factors also predispose some individuals to excess weight.
Mechanisms by which obesity is associated with CVD are not completely understood. Adipocytes act as an endocrine organ and may play a central role in the pathogenesis through the release of adipocytokines. The role of different fat depots is also under active research. Several measures exist to define obesity, the commonest being body mass index (BMI). The BMI is calculated as weight (kg)/height (m2). Obesity is defined as BMI of greater than or equal to 30 (Table 9). Other indexes of obesity include waist circumference and waist-hip ratio, increases in which are also linked to adverse cardiovascular outcomes. Different cut-offs for abnormal waist circumferences according to ethnicity are summarized in Table 10. Both BMI and waist circumference should be recorded for overall risk assessment and tracked over time as a vital sign.
Weight loss can prevent and improve obesity related risk factors and CVD. Interventions for weight management include dietary changes, increased physical activity, pharmacological therapy and surgical treatment.
Table 9   Classification of obesity by body mass index
Body mass index (kg/m2)
• Underweight
< 18.5
• Normal
18.5–24.9
• Overweight
25.0–29.9
• Obesity Class
  • – I
  • – II
  • – III
30.0–34.9
35.0–39.9
≥ 40
20
Table 10   Ethnic specific values for abnormal waist circumference
Ethnic group/region
Waist circumference
North America
Male
≥ 102 cm
Female
≥ 88 cm
Europe
Male
≥ 94 cm
Female
≥ 80 cm
South Asians
Male
≥ 90 cm
Female
≥ 80 cm
Chinese
Male
≥ 90 cm
Female
≥ 80 cm
Japanese
Male
≥ 90 cm
Female
≥ 90 cm
South and Central America
Use South Asian recommendations
Middle East (Arab) and Eastern Mediterranean
Use European recommendations
A weight reducing diet combined with exercise can result in significant weight loss.46 Reduction in calorie intake, regardless of the proportion of macronutrients (fats, proteins or carbohydrates), results in clinically meaningful weight loss.47
Despite great interest in pharmacotherapy for obesity, its clinical use is limited by modest weight loss, high relapse rate and side effects of the medications. Fenfluramine and dexfenfluramine were withdrawn due to their adverse effects on heart valves. Orlistat, a gastrointestinal lipase inhibitor, induces weight loss by decreasing fat absorption.48 It is FDA approved and is available also for over the counter use for weight loss. Common side effects include oily stools, diarrhea and gas. Rimonabant, a selective cannabinoid-1 receptor blocker, improved weight and cardiovascular risk factors,49 but was not approved in the United States over concerns about psychiatric side effects and did not reduce cardiovascular events in one large clinical trial.50
Surgical treatment for obesity includes various malabsorptive or restrictive procedures. In patients who have failed an adequate diet and exercise program, with severe obesity (BMI ≥ 40) or medically complicated obesity with a BMI greater than or equal to 35, bariatric surgery may be considered.51,52 Long-term follow-up of patients after bariatric surgery continues to show weight loss, improvement in CVD risk factors and lower mortality.53
Psychosocial factors: Several psychosocial factors are associated with increased risk of CVD including depression, stress, anxiety, social isolation, lack of social support and stress at work.54 In a meta-analysis, depression was shown to 21increase the risk of CHD by 64%.55 In the MRFIT study greater depressive symptoms were associated with increased 18-year mortality.56 Depression especially after coronary events is not only common but also increases the incidence of recurrent coronary event by threefold.57 Lower socioeconomic class and adverse events in life are also associated with CVD. Poor socio-economic status is linked to increased risk of CHD through multiple mechanisms including unhealthy diet, lack of access to health care, excessive stress and tobacco use.
Type A behavior with associated hostility and anger raises the risk of CHD.58 Social isolation and lack of social support may increase the risk of CHD by 2–3 fold in men and 3–5 fold in women.59 Marital discord worsens prognosis in acute coronary syndrome. Psychosocial risk factors tend to cluster in the same individuals and groups; for instance, job stress is linked to depression, hostility, anger and social isolation. This compounds the risk of CVD.
Psychosocial factors raise the risk of CVD through several mechanisms including greater likelihood of unhealthy behaviors such as smoking, alcohol and drug use and increased calorie intake and direct physiologic effects such as increased platelet activation and increase in inflammatory cytokines60 and neuroendocrine reactivity61 to stress.
Management of psychosocial risk factors is challenging in part due to the difficulty in defining an individual's level of risk and in part due to complex treatment. Moreover, the influence of these factors in any individual may change over time. Few trials show benefits of behavioral intervention on CVD risk or outcomes. Meditation decreases blood pressure and carotid artery intimal thickness in men. Extended cardiac rehabilitation (stress management combined with physical training and cooking sessions) improved depression, anxiety and quality of life at one year in patients with CHD.62 In the Recurrent Coronary Prevention Project, behavioral counseling resulted in reduced type A behavior and decrease in cardiac risk.63 Behavioral treatment in The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial reduced depression and social isolation in post-MI patients, but did not improve survival.64 To reduce psychosocial risk factors, emphasis needs to be placed on modifying stress, improving quality of life and recognizing and treating depression and other mood disorders.
 
Hypertension
Hypertension defined as a blood pressure of greater than or equal to 140/90 mm Hg is a major risk factor for CVD. In fact, there is a strong, graded relationship between blood pressure and fatal coronary events: risk doubles for every 2220 mm Hg increase in systolic blood pressure or 10 mm Hg increase in diastolic blood pressure. Various mechanisms by which hypertension leads to coronary events include hemodynamic stress on blood vessels and heart, increased myocardial oxygen demand, diminished coronary blood flow and impaired endothelial function. Several trials have shown reduction in cardiovascular morbidity and mortality by reduction in blood pressure.65
The seventh report of the Joint National Committee (JNC) on prevention, detection, evaluation, and treatment of high blood pressure recommends a treatment goal of less than 140/90 mm Hg for all individuals, however, in patients with CHD, renal insufficiency, congestive heart failure, peripheral vascular disease and diabetes a stricter goal of less than 130/80 mm Hg is recommended.66 Treatment of pre-hypertension (blood pressure 120–139/80–89 mm Hg) with Candesartan reduced the risk of incident hypertension in the TROPHY trial.67 Whether lowering of blood pressure to ‘normal’ (< 120/80 mm Hg) is beneficial is not clear. The next JNC guidelines are expected to be released in 2012.
Nonpharmacological interventions such as dietary modification,68 moderation of alcohol consumption, smoking cessation, increasing physical activity and weight loss improve blood pressure and are recommended for any level of hypertension. Multiple drug classes exist to treat hypertension including beta blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, vasodilators and centrally acting agents. First-line therapy is usually tailored to drug availability, cost, comorbid medical conditions and side effect profile of medications. Blood pressure lowering is more important than the choice of drug class. In a meta-analysis of 29 randomized controlled trials,69 Turnbull et al. found that there were no significant differences in the primary endpoint of major cardiovascular events between regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, diuretics or beta-blockers.
 
Hyperlipidemia
There is a strong positive association between total cholesterol and LDL-C and CVD risk. Elevated triglycerides and low HDL-C are also independent risk factors for CVD. Individuals with severely elevated levels of LDL-C due to genetic abnormalities show premature atherosclerosis. Conversely, individuals with certain loss of function variants of the PCSK9 gene, who have moderate life-long reduction in LDL-C, have up to 88% reduction in risk of CHD.70 Different 23mechanisms by which LDL-C increases CHD include delivery of cholesterol to blood vessels, proinflammatory properties, role in plaque formation and plaque instability. High levels of HDL-C convey reduced risk of CHD. HDL-C exerts its protective effects on the cardiovascular system through numerous mechanisms including reverse cholesterol transport, antioxidant properties, inhibition of apoptosis and dysfunction of endothelial cells and inhibition of LDL oxidation.71 Low HDL-C and elevated triglycerides frequently occur with the presence of small dense LDL particles. This pattern of dyslipidemia is referred to as diabetic or atherogenic dyslipidemia.
Elevated LDL-C is the primary target for therapy and reduction in LDL-C substantially reduces CHD risk. In patients with elevated triglycerides (> 200 mg/dL), non-HDL-C (total cholesterol minus HDL-C) is a secondary target for therapy due to a strong association with CHD risk.72 Non-HDL-C highly correlates with levels of apolipoprotein B which is the major apolipoprotein of all major atherogenic lipoproteins. The non-HDL-C treatment goal is 30 mg/dL higher than LDL-C.
Lifestyle changes are important for management of hyperlipidemia including reduction in intake of saturated fats and cholesterol, increasing fiber intake, increasing physical activity and weight reduction. Pharmacological therapy is required to treat hyperlipidemia in many patients. The availability of HMG-CoA reductase inhibitors (statins) has revolutionized treatment for both primary and secondary prevention of CVD. Multiple large randomized controlled clinical trials have shown benefits of using statins for treatment of hyperlipidemia with an estimated 20–40% reduction in major cardiovascular events and mortality.73 The reduction in risk for an individual depends both on their initial overall risk for CVD as well as the degree of elevation in cholesterol, in particular LDL-C. Statins are usually first-line agents but combination therapy is sometimes required when LDL-C elevation is pronounced or multiple lipid abnormalities are present. Available agents include bile acid sequestrants, nicotinic acid, fibrates, ezetimibe or high doses of EPA/DHA. For low HDL-C, after controlling LDL-C and instituting lifestyle changes, niacin or fibrates can be used. Caution should be used when combining fibrate therapy with statins as it increases the risk of myopathy. Markedly elevated triglyceride levels (> 500 mg/dL) should be treated to prevent pancreatitis.
 
Diabetes Mellitus
Diabetes is a strong and independent risk factor for CVD. Whether diabetes confers a risk of events similar to that of established CHD is controversial,74,75 but current guidelines 24consider diabetes a CHD equivalent. Mechanisms by which diabetes causes CHD include increase in platelet aggregability, increase in inflammatory mediators, impaired endothelial function, dyslipidemia, increase in highly small, dense highly atherogenic LDL-C, among others.
Intensive glycemic control (hemoglobin A1C ∼7%) prevents microvascular complications but the impact on macrovascular complications including cardiovascular events is less well established. Recent large trials including the ACCORD76 and ADVANCE77 failed to show benefit of tighter control of diabetes (Hemoglobin A1C <6–6.5%) compared to usual glycemic control (Hemoglobin A1C 7–7.9%) on major cardiovascular events. The American Diabetes Association and other major societies recommend a target Hemoglobin A1C goal of less than 7%.78
Lifestyle interventions for prevention and treatment of diabetes are well established and are the recommended initial strategy.79,80 Several different classes of drugs exist for treatment of diabetes, the details of which are beyond the scope of this chapter.
 
Alcohol
Numerous prospective studies have suggested an inverse relation between moderate alcohol consumption (1–2 drinks per day) and CHD.81 Mechanisms by which alcohol may exert beneficial effects on CHD include antioxidant effects, increase in HDL-C and antithrombotic action.82 It is unclear if any particular type of alcoholic beverage is more protective. At the same time, alcohol use is associated with several health problems including cardiomyopathy, sudden cardiac death, cardiac arrhythmias, hypertension and stroke. Alcohol is an addictive substance and abuse of it remains a major public health problem.
Due to limitations of observational data, lack of clinical trials and the health hazards associated with its use, alcohol intake is not recommended as a cardioprotective strategy.83 For patients with current or past abuse, systemic diseases including hepatic or cardiac problems, it is best to advise against alcohol use. On a case-by-case basis, for individuals who drink, 1–2 drinks per day for men and 1 drink for women is acceptable to advise.
 
EMERGING RISK FACTORS
More than a hundred non-traditional or emerging risk factors have been reported.84 Whether they independently predict risk of CHD or add incremental information to existing risk factors continues to generate controversy and poses an obstacle to their incorporation into risk assessment and routine clinical practice. 25For a risk factor to be accurate and effective in predicting risk, it must meet certain criteria: It must have a strong, consistent association with the disease in a dose-response manner that is biologically plausible. It should be measured easily with acceptable reference values. It should be an independent predictor of major CHD events. It should reclassify a substantial number of individuals who were previously stratified by traditional risk factors and the results should be generalizable to different population groups.14 Before a novel risk factor or marker is incorporated into guidelines, its predictive value must be tested in multiple ways in different populations.
A recent US Preventive Services Task Force Recommendation Statement concludes that the current evidence is insufficient to assess the balance of benefits and harms of using non-traditional risk factors for screening asymptomatic men and women.14,85 Similarly, NCEP ATP III guidelines do not recommend routine use of emerging risk factors for risk assessment.
The emerging risk factors include both laboratory-based tests for biomarkers of atherosclerosis and noninvasive imaging modalities for detecting atherosclerosis. Some of the more commonly used emergent risk factors will briefly be reviewed.
 
High-Sensitivity C-Reactive Protein (hs-CRP)
hs-CRP has been extensively studied to help in risk stratification for CHD events. CRP is an acute phase reactant that is made by the liver. Inflammatory conditions result in a rise in CRP levels. Several CVD risk factors are also associated with higher levels of CRP. For cardiovascular risk prediction, an hs-CRP assay exists with levels less than 1.0 mg/L considered low risk, between 1.0–3.0 as intermediate risk and greater than 3.0 as high risk. hs-CRP independently predicts coronary events,86 however, the risk is modest with about 1.5 times elevated risk of coronary events in patients with CRP greater than 2.0, after adjustment for traditional CHD risk factors.87 The American Heart Association and Centers for Disease Control and Prevention endorse using hs-CRP as an optional test to help with further classification in particular of those patients who are at intermediate risk by FRS (Class IIa).88
Weight loss, physical activity, smoking cessation, cholesterol therapy with statins and niacin all decrease hs-CRP levels. In a subgroup of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/Tex-CAPS) study Ridker et al.89 showed that participants with LDL-C below and hs-CRP above the median benefited from lovastatin therapy [relative risk, 0.58 (0.34, 0.98)] in contrast to those 26participants with both LDL-C and hs-CRP below the median whose coronary events were not reduced [relative risk, 1.08 (0.56–2.08)]. Results from the randomized controlled JUPITER trial90 suggest that hs-CRP could be used to select patients (women ≥ 60 years, men ≥ 50 years) for primary prevention with statins. For secondary prevention, a sub-analysis from the PROVE IT study showed that lowering hs-CRP in patients with acute coronary syndrome with statins resulted in lower risk of future coronary events.91
 
Lipoprotein (a) [Lp(a)]
Lp(a) consists of an LDL particle linked to an apo-A polypeptide chain. Levels of Lp(a) are genetically determined. There are no observed gender differences but racial differences exist. Whether Lp(a) is causally linked to CHD remains controversial.92 A recent study using genetic data suggested causal relation of elevated Lp(a) to myocardial infarction.93
The European Atherosclerosis Society recommends screening for Lp(a) in patients at intermediate or high risk for CHD.94 Levels of Lp(a) less than 50 mg/dL were recommended as the treatment goal using niacin, while acknowledging that randomized controlled trials are lacking. A North American panel endorsed testing for Lp(a) in patients who are moderate to high risk according to FRS, and decreasing the LDL-C treatment goal by 30 mg/dL in patients with high levels of Lp(a) (> 200 ng/mL).95
 
Hyperhomocysteinemia
Homocysteine is an intermediary product of methionine metabolism. Homocysteine can cause endothelial dysfunction and result in a procoagulant state. Many cross-sectional and prospective observational studies report a positive association between homocysteine levels and CVD. Untreated patients who are homozygous for homocystinuria have serum homocysteine concentrations five times above normal and increased risk of vascular events.
Dietary intake of folate, vitamin B6 and B12 affect homocysteine levels. Despite observational data linking homocysteine to CVD, multiple randomized controlled trials using supplementation with vitamin B12 and folic acid showed no reduction in the risk of major cardiovascular events in patients with or without pre-existing vascular disease.96,97 The 2007 American Heart Association guidelines for prevention of CVD in women recommend against using folic acid supplementation, with or without B6 and B12 for CVD prevention.9827
 
Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)
Lp-PLA2 is an enzyme expressed by inflammatory cells in atherosclerotic plaques. In observational and epidemiological studies, Lp-PLA2 was modestly associated with an increased risk of CHD.99 There is an approximately 10% increase in coronary events per one standard deviation higher Lp-PLA2 activity and mass. In one study100 Lp-PLA2 increased the ROC curve minimally suggesting some clinical improvement in risk discrimination. Eventhough the FDA has approved a test for Lp-PLA2 for CHD, there is no trial evidence to date that Lp-PLA2 modification changes risk.
 
Apolipoprotein B
Apoliporotein B (Apo B) is a structural component of several lipoprotein particles which are atherogenic. Standardized assays for measurement of Apo B are available. Apo B is associated with increased risk of CHD.101 Whether Apo B measurement predicts CHD risk beyond commonly assessed risk factors in the FRS is uncertain.102
Plasma Apo B levels may be useful as a treatment target. A target value of less than 85 mg/dL for patients at high risk for CHD is proposed by the Canadian Cardiovascular Society.103 American Association of Clinical Chemistry recommends a treatment goal of less than 80 mg/dL in patients whose target LDL-C by NCEP ATPIII guidelines is less than 100 mg/dL.104
 
Fibrinogen and Other Hemostatic Factors
Several hemostatic factors involved in coagulation and fibrinolysis are associated with increased risk of CHD105 (Table 11). Fibrinogen levels in the upper third of the control distribution are associated with a 2.0–2.5 times excess risk of future CVD.106
Table 11   Hemostatic factors associated with cardiovascular disease
• Fibrinogen
• Fibrin D-dimer
• Factor VII
• Factor VIII
• Plasminogen activator inhibitor
• Tissue plasminogen activator
• von Willebrand factor antigen
• Activated partial thromboplastin time
• Thrombin-antithrombin
• Activated protein C ratio
28
The current assays are not standardized and whether fibrinogen and other hemostatic factors add to traditional risk factors is unclear. Physical activity can decrease levels of fibrinogen but there is no evidence from randomized trials that fibrinogen modification by lifestyle or pharmacological therapy decreases CHD events.
 
SUB-CLINICAL ATHEROSCLEROSIS
Detecting sub-clinical atherosclerosis with noninvasive imaging modalities has generated great interest. This is distinct from the general ‘risk factor’ concept. Whether early detection of atherosclerosis should lead to modification in therapy and whether such modification in therapy offers clinical benefit is not clear.
The presence of calcium in coronary arteries correlates with atherosclerosis and is measured using cardiac tomographic imaging. Coronary artery calcium (CAC) score, which quantifies the extent of coronary calcium, is reported as percentiles of calcification according to age and sex. A ‘negative’ test has a CAC score of 0 and is associated with a low risk of subsequent coronary events. Numerous studies show that CAC testing is an independent predictor of coronary events in both men and women, from multiple racial and ethnic groups.107,108 CAC score has high sensitivity and negative predictive value for angiographically obstructive CAD but its positive predictive value is low.24 To date, it is unclear whether CAC testing should lead to change in therapy if that results in a favorable impact on clinical outcomes. Cost and radiation exposure also limit widespread CAC screening. CAC score may be used in select intermediate risk patients for further risk stratification.
Vascular intimal thickening is one of the earliest changes of atherosclerosis. Carotid arteries can easily be visualized because of their location and using ultrasound techniques the intima-media thickness can be determined noninvasively, without exposure to radiation. Increased carotid intima-media thickness is an independent predictor of cardiovascular risk.109 Carotid intima-media thickness also correlates with multiple CVD risk factors.110 Statin treatment decreases carotid intima-media thickness. There is lack of consensus on examination techniques and reference standards for quantifying intima-media thickness.85 Recently, the American Society of Echocardiography published a consensus statement proposing standardization of imaging and measurement protocols.111 Correct patient selection, assessment of clinical benefit of treatment and lack of outcome data limits widespread use at present.29
Ankle brachial index is a noninvasive test to diagnose and assess the severity of peripheral vascular disease. It is the ratio of systolic blood pressure in the ankle, measured at the level of the posterior tibial or dorsalis pedis artery, to that of the brachial artery. A lower value of ankle brachial index is not only an indicator for the severity of peripheral vascular disease but also correlates independently with major coronary events and stroke.112,113 When used in conjunction with FRS, a low ankle brachial index (≤ 0.90) approximately doubled the risk of cardiovascular events and death.114
At a population level, the best approach currently is probably to use the traditional risk factors for CHD screening. It is generally agreed that the established risk factors for CHD have very good ability to discriminate those at risk for CHD and account for over 90% of population attributable risk.27 We need to ensure that the traditional risk factors and risk prediction tools are applied routinely in clinical practice. At the same time, clinicians should be aware of the emerging risk factors and may use their clinical judgment to use additional screening modalities to better gauge an individual patient's risk.
 
TRANSLATING RISK FACTOR SCREENING INTO EVENT REDUCTION
It is our responsibility to fully implement strategies to ensure that any risk factors identified are fully treated. Barriers to such implementation exist at the physician, patient, system and societal level.115 Physicians can, through better communication and education, ensure better adherence to risk factor reduction strategies. Specific verbal and written instructions and prompt follow-up can help increase adherence. Monitoring progress goals and providing feedback can help patients to stay on track, particularly with lifestyle modifications. There should be open communication between the specialists and primary care physicians. Enabling easy access to electronic medical records from index hospitalization as well as specialist visits should help primary care physicians to deliver risk factor reduction treatment on a long-term basis.
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