stress \200\231, which in \202 uences the biology of the underlying endothelial cells. High laminar shear (from blood \202 owing quickly through a straight vessel) favors the g eneration of NO, which helps maintain the functional integrity of the vessel. In contrast, low shear, or \200\230differential \200\231 shear caused by turbulent \202 ow, causes dysfunction of the underlying endothelial cells, which facilitates initiation an d progression of atheroma. This helps explain why plaques are found more commonly at sites of vessel branching or curv ature, which experience more dramatic and abrupt changes and irregularities of direction an d velocity of blood \202 ow. These shear-stress-mediated effects are most marked in vessels that carry a high (basal) bl ood \202 ow, such as the coronary, carotid, renal, and ilio-femoral arteries, in which th e majority of clinically important atherosclerotic lesions develop. DEVELOPMENT OF ATHEROSCLEROTIC PLAQUES 215 Normal Fatty streak Atheroma Ulcerated plaque/ rupture and occlusive thrombosis smooth muscle Occlusive thrombus Endothelium Lumen restricted Lumen Lipid Smooth muscle and collagen cap over lipid core Ulceration/rupture with platelet and thrombosis aggregation Growth by lipid Time From 4th decade Acute syndromes (ACS/MI, sudden death) From 3rd decade Angina From 1st decade No symptoms Fig. 5.2 Cellular interactions in the development and progression of atherosclerosis. VSMC, vascular smooth muscle cells. ACS = acute coronary syndrome; MI = myocardial infarction. R eproduced with permission from Weissberg PL (2003). Atherogenesis: current understanding of the causes of atheroma. Heart 83 : 247 \200\22352. 216 CHAPTER 5 Coronary artery disease Epidemiology Cardiovascular disease is the most common cause of death in the UK, responsibl e for 238 000 deaths in 2002 or 39 % of all deaths. Coronary artery disease (CAD) results i n over 117 000 deaths a year in the UK. Advances in prevention and treatment of this diseas e have led to a fall in the death rate since the late 1970s, but the UK incidence of CAD re mains amongst the highest in the world. The cost of health care alone is estimated at over 1.7 billion a year, and the total economic cost is far greater. Regional variation There is considerable variation in mortality from CAD across the UK. Dea th rates are higher in Scotland than the South of England, in manual workers than in non-ma nual workers, and in certain ethnic groups. There are several important risk factors that a re associated with CAD and other atherosclerotic disease (see b Risk factors for coronary a rtery disease, p. 220), which together account for the majority of the CAD burden in the UK . Although identi \201 cation and treatment of individuals with these risk factors has the potential to reduce signi \201 cantly the burden of CAD, the incidence of and death rate from MI remain high. The vulnerable plaque Erosion or denudation of the endothelial layer, or rupture of the ove rlying \201 brous cap of the plaque may expose the highly thrombogenic lipid-rich core of the plaque to circulating blood. \200 Collagen, tissue factor, and other factors activat e platelets and trigger the coagulation cascade. This leads to acute thrombosis, which may rapidly occlude the vessel. \200 This results i n MI of this vascular territory, usually characterized by ST-segment elevation on the electrocardiogram (ECG). Coronary thrombosis is a dynamic process in vivo , and may be reversed, at least in part, by activation of t-PA and proteins C and S of the intrinsic ant ithrombotic/ \201 brinolytic system. Acute, subtotal occlusion of the vessel typically causes acute symptomatic deterioration and non-ST-segment elevation MI (NSTEMI) or unstable angina. Atheromatous plaques that have a thin \201 brous cap and a large necrotic lipid core, and contain a high proportion of in \202 ammatory cells and mediators, and are particularly p redisposed to destabilization or rupture, with consequent thrombosis. Conversely, plaques with a smaller lipid pool, thicker \201 brous caps, and less in \202 ammatory activity are more stable and less prone to rupture. \200 Several studies have s hown that well over half of all MIs are caused by acute destabilization of plaques that wer e previously not obstructing \202 ow in the vessel, suggesting that the likelihood of an acute coronary event is more closely related to the stability of the plaque rather than the severity of the stenosis. This page intentionally left blank 218 CHAPTER 5 Coronary artery disease Assessment of atherosclerotic risk Identi \201 cation and treatment of risk factors is ess ential for the prevention of atherosclerotic disease in both individuals and society. When multiple risk factors such as dyslipidaemia, high blood pressure, and smoking co-exist, the cardiovascular risk is greatly increased, suggesting a synergistic interaction between the se factors. Global risk assessment Risk-assessment scoring systems are derived from large prospective p op- ulation cohorts, most commonly the Framingham study. These systems allow calculation of the \200\230absolute risk \200\231 of having a cardiovascular event (i.e. the probability of having a heart attack or stroke) within the next 10 years. Current UK practice recommen ds use of the Joint British Societies risk-assessment tables (see Fig. 5.3) or a computer p rogram. Other commonly used methods include: \200 the Framingham risk-scoring system \200 the Shef \201 eld tables \200 the European SCORE charts. Subjects with stable angi na have a 10-year event rate of approximately 20 % ; therefore, subjects without clinical d isease that have a predicted 10-year likelihood of suffering a cardiovascular event of (cid :2)20 % are con- sidered to be at \200\230high risk \200\231 and are candidates for aggres sive risk-factor management. Individuals with low-intermediate risk \200\224 scoring systems typically underes- timate the true risk in: \200 young subjects with multiple risk factors \200 subjects with a f amily history of premature cardiovascular disease \200 certain ethnic groups including in dividuals of South Asian racial origin living in the UK. Identi \201 cation of subjects with intermediate (10 \200\22320 % ) conventional risk scor es that are actually at \200\230high \200\231 risk remains a major challenge, as these ind ividuals are also likely to bene \201 t from preventive therapy. Adjunctive risk-assessment techniques may improve risk-assessment accuracy but are not curr ently used in routine clinical practice: \200 C-reactive protein (CRP) levels \200 ultr asound assessment of carotid arterial intima \200\223media thickness \200 detection of co ronary artery calci \201 cation with computed tomography (CT) scanning. Calculation of risk is unnecessary in subjects who already have clinical atherosclerotic disease, as secondary prevention measures are mandatory in these individual s. Similarly, risk calculation is not required for subjects with diabetes mellitus, whose risk approaches that of subjects with established atherosclerosis. ASSESSMENT OF ATHEROSCLEROTIC RISK 219 Fig. 5.3 Reproduced with permission from 2004 Joint British Societies Risk Prediction Table s. The University of Manchester. CVD = cardiovascular disease. 220 CHAPTER 5 Coronary artery disease Risk factors for coronary artery disease Age The UK population is aging: \200 between 197 1 and 2002, the percentage of older people (aged 65 years and over) in the UK, increased fr om 13 % to 16 % , and is projected to rise to 23 % in the next 25 years aging is a major risk factor for atherosclerotic disease, due to the degenerative process associated with aging per se , together with the cumulative impact of the worsening risk-factor pro \201 le that develops with increasing age by the age of 70 years, 15 % of men and 9 % of women have symptomatic CAD, increasing to 20 % by the age of 80 years Over 40 000 premature (<75 years) deaths are caused by CAD, 22 % of premature deaths in men and 13 % of those in women 45 % of MI occurs in people under 65 years of age but is more likely to be fatal in older i ndividuals, with 80 % of deaths due to MI seen in those aged over 65 years. Gender, menopausal status, and hormone replacement therapy (HRT) \200 CAD is more common in men than women and the onset tends to be earlier in men. The incidence of coronary heart disease (CHD) in women increases rapidly at menopause, and is similar to that seen in men in the population over 65 years. Although less common, the disease remains one of the biggest killers of women; for example, the age-adjusted mortality rates from heart disease are four to six times higher than thei r mortality rates from breast cancer. Female sex hormones probably contribute to the lower risk of atherosclerotic disease in premenopausal women. The risk of ischaemic heart disease is reduced by up to 40 % in women using HRT. HRT users are typically healthier than non-users, suggesting that these results could be explained by selection bias. Several large, randomized controlled trials of HRT in postmenopausal women (WHI (Women \200 \231s Health Initiative), HERS (Heart and Estrogen/ Progestin Study)/HERS II, ESPRIT (Estro gen in the Prevention of Reinfarction Trial), ERA (Estrogen Replacement and Atherosclerosis )) with and without atherosclerosis have now clearly shown that HRT does not reduce the ris k of cardiovascular events. HRT may, in fact, even lead to a small but statistically signi \201 cant increase in morbidity and mortality from cardiovascular and other diseases including gynaec ologic malignancy. HRT should not be recommended for primary or secondary prevention of atherosclerotic disease in postmenopausal women. RISK FACTORS FOR CORONARY ARTERY DISEASE 221 Family history of atherosclerotic disease \200 CAD is a multifactorial, polygenic disorde r, caused by interactions between lifestyle, the environment, and the effects of variations in the genetic sequence o f a number of genes. The family history is considered to be signi \201 cant when atherosclerotic disease presents in a \201 rst-degree male relative before the age of 55 years, or before 65 years in a female relative. A positive family history is associated with a 75 % increase in risk in men, and an 84 % increase in women. The risk is more than doubled if both parents are affec ted. Risk factors for coronary artery disease Non-modi \201 able risk factors Modi \201 able risk factors Smoking \200 High blood pressure \200 Dyslipidaemia \200 Diabetes mellitus \200 Obe sity and the metabolic syndrome \200 Psychological stress \200 High-calorie high-fat di et \200 Physical inactivity Increasing age \200 Male sex \200 Family history \200 Ethnic origin Emerging risk factors \200 In \202 ammation \200 Fibrinogen, and other factors involve d in thromboregulation \200 Homocysteine \200 Oxidative stress \200 Asymmetric dimeth ylarginine Ethnic origin \200 Age-standardized mortality from CAD is around 50 % higher in individuals of South Asian racial origin living in the UK compared to white individuals. Although an increased prevalence of risk factors explains much of this risk (high triglycer ides, low high-density lipoprotein (HDL), insulin resistance, and reduced physical activity ), genetic factors are thought to contribute signi \201 cantly. The observed incidence of CAD is lower in black individuals of West Indian and African orig in in the UK, although the incidence of stroke is greater than in the Caucasian population. Psychological stress \200 The burden of risk attributable to psychological stress is more dif \201 cult to quantify. Increased work stress, lack of social support, hostile personality type, anxiety, and depression are most consistently associated with increased atherosclerosis ris k. 222 CHAPTER 5 Coronary artery disease Smoking \200 Smoking increases the risk of CAD by approximately 50 % , with mortality fro m any cardiovascular disease around 60 % higher in smokers (and 85 % higher in heavy smoker s) compared to non-smokers. In the UK today, around 13 million adults (28 % of men and 26 % of women) smoke cigarettes. Although the number of smokers has declined substantially over the past 50 years, this trend has slowed down in the young, and the number of teenage girls that smoke has recently increased. Over 30 000 cardiovascular deaths per year (14 % in men and 12 % in women, with an even hig her proportion of premature deaths) are attributable to smoking. Second-hand smoke (smoke that has been exhaled by a smoker) can also increase the risk of CAD by around 25 % . Stopping smoking carries almost immediate bene \201 t, and although the long-term bene \201 ts are greatest in those who stop smoking before the age of 40 years, stopping in midd le age is also bene \201 cial. For example, in those aged 30 \200\22359 years who stop smo king after a MI, the 5-year mortality is 10 % , compared with 14 % in those who continue to smoke. Individuals at increased risk of atherosclerosis should be advised to stop smoking. See Figs. 5.4. and 5.5. Evidence now exists that focused psychosocial support, nicotine replacement, and pharmacolo gical therapy are effective in helping individuals stop smoking. These services are deliver ed in an integrated fashion by smoking-cessation clinics, which can deliver a fourfold incr ease in the likelihood that a smoker will quit, vs. use of willpower alone. Doctors born 1900 \200\2231930 97 100 91 5 3 94 e g a m o r f 81 80 81 Non-smokers 58 59 60 l a v v r u s Cigarette smokers i 10 years 40 e g a t n e c r e P 24 26 20 2 4 90 100 Age (years) 0 40 50 60 70 80 Fig. 5.4 Survival from age 35 years for continuing cigarette smokers and lifelong non-smoke rs among UK male doctors born 1900 \200\2231930, with percentages alive at each decade of a ge (adapted and reproduced with permission from Doll R, Peto R, Boreham J, Sutherland I (20 04). Mortality in relation to smoking: 50 years \200\231 observations on male British docto rs. BMJ 328 (7455): 1519). RISK FACTORS FOR CORONARY ARTERY DISEASE 223 Stopping smoking at age 25 \200\22334 100 Stopped smoking 5 3 e g a m o r f 80 Cigarette smokers 60 l a v v r u s Non-smokers i 40 e g a t n e c r e P 20 0 Stopping smoking at age 35 \200\22344 100 Stopped smoking 0 4 80 e g a m o r f Cigarette smokers 60 Non-smokers l a v v r u s i 40 e g a t n e c r e P 20 0 Stopping smoking at age 45 \200\22354 100 Stopped smoking 0 5 e g a m o r f 80 Cigarette smokers 60 Non-smokers l a v v r u s i 40 e g a t n e c r e P 20 0 Stopping smoking at age 55 \200\22364 100 Stopped smoking 0 6 e g a m o r f 80 Cigarette smokers 60 l Non-smokers a v v r u s i 40 e g a t n e c r e P 20 0 60 90 Age (years) 80 40 50 100 70 Fig. 5.5 Effects on survival of stopping smoking cigarettes at age 25 \200\22334 years (eff ect from age 35 years), age 35 \200\22344 years (effect from age 40 years), age 45 \200\223 54 years (effect from age 50 years), and age 55 \200\22364 years (effect from age 60 years) (adapted and repro- duced with permission from Doll R, Peto R, Boreham J, Sutherland I (20 04). Mortality in relation to smoking: 50 years \200\231 observations on male British docto rs. BMJ 328 (7455): 1519). 224 CHAPTER 5 Coronary artery disease Obesity \200 Obesity increases the risk of CAD: 25 \200\22349 % of CAD in developed count ries is attributable to increased body mass index (BMI). Overweight is de \201 ned as a BMI between 25 and 30 kg/m 2 , and obesity as a BMI (cid:2)30 kg/m 2 . The prevalence of obesity is increasing rapidly worldwide. In the UK, adult obesity has increased by over 50 % in less than 10 years. \200 Of particular concer n is the dramatic increase in the prevalence of obesity in children, which has almost doubl ed in the UK in less than 10 years. This trend is likely to exacerbate the problem in adult hood, and undo many of the other recent improvements in cardiovascular health. Central obesity, in which excess fat is concentrated mainly in the abdomen, can be identi \201 ed by a high waist-to-hip ratio, and confers a particularly hi gh relative risk of CAD if the waist circumference is > 102 cm (40 in.) in men and > 88 cm (35 in.) in women. Associated metabolic abnormalities of central obesity include high triglycerides, low HDL, high blood pressure, low-grade systemic in \202 ammation, insulin resistance, and type 2 d iabetes mellitus. \200 Overweight and obese individuals also tend to be less physically active and eat lower-quality diets, which contributes further to their atherogenic risk. Diet and exercise should be considered as the \201 rst line of intervention in these individuals, together with careful surveillance for and aggressive tr eatment of diabetes, high blood pressure, and dyslipidaemia when present. In \202 ammation \200 Atherosclerosis involves an ongoing in \202 ammatory process from the time of lesion initiation, through progression and at the time of acute thrombotic com plication. This links risk factors and the disease mechanism in a way that is directly applicable to human patients. Large studies have shown that low-grade elevation in markers of in \202 ammation, most not ably CRP, predicts outcomes from atherosclerotic disease and may add to prognostic informat ion provided by traditional risk factors. A CRP level below 1 mg/L is associated with low risk, 1 \200\2233 mg/L re \202 ects interm ediate risk, and a level above 3 mg/L is associated with a high long-term risk of vascular events. Certain treatments that reduce coronary risk also limit in \202 ammation, such as statins and aspirin, which may contribute to their clinical bene \201 ts. The incremental value of CRP as a marker of risk and target of therapy in global risk management is currently a controversial topic that requires clari \201 cati on by prospective randomized trials. Homocysteine \200 The genetic disease homocystinuria is associated with aggressive, premature atherosclerosis. RISK FACTORS FOR CORONARY ARTERY DISEASE 225 Strong epidemiologic and mechanistic evidence suggests that even modest increases in homocysteine levels increase the progression of atherosclerosis. Vascular in \202 ammation and oxidative stress appear to be the responsible mechanisms. Dietary supplementation with folic acid, alone or in combination with vitamins B 6 and B 12 , can reduce levels of homocysteine and improve aspects of vascular biology in vivo as wel l as in vitro . Until results of large, outcome-driven, randomized clinical trials are available, folate B 6 /B 12 supplementation cannot be routinely recommended for prev ention of atherosclerotic disease. Antioxidant vitamins Despite excellent epidemiologic and mechanistic evidence that increase d oxidative stress is associated with vascular injury, in \202 ammation, and increased ris k of cardiovascular morbidity and mortality, it is disap- pointing that large randomized co ntrolled trials (HOPE (Heart Outcomes Prevention Evaluation), HPS (Heart Protection Study) and GISSI-P (Gruppo Italiano per lo studio della Sopravvivenza nee \200\231infarto Miocardi o)) showed that supplementation with the antioxidant vitamin E (supple- mented with vitamin s A and C in HPS) had no effect on cardiovascular outcome. Currently, antioxidant vitamin s upplementation should not be routinely recommended for prevention of atherosclerotic diseas e. Dietary measures Dietary modi \201 cation can reduce the risk of cardiovascular disease: \200 total fat intake should be reduced to below 30 % of total calorie intake \200 intak e of saturated fat and foods high in \200\230trans \200\231 fatty acids should be limited, and replaced with monounsaturated fat (canola and olive oil) dietary salt intake should be reduced \200 intake of fresh fruits and vegetables should b e increased ((cid:2)5 portions per day) \201 sh consumption, especially oily \201 sh, should be encouraged, with evidence suggesting that at least one \201 sh meal, and ideally 2 \200\2233 per week can reduce the incidence of heart attack and stroke. Physical activity \200 The contribution of physical inactivity to CAD deaths is dif \201 cult to quantify; however, people who are physically active appear to have a lower risk of CAD. This is mediated, at least in part by weight loss, a reduction in blood pressure, and impro vement of the lipid pro \201 le (particularly increased HDL). Regular, aerobic exercise of moderate intensity should be undertaken (cid:2)3 times per wee k for at least 30 minutes, but greater frequency and duration of exercise is associated wit h increasing bene \201 ts. Alcohol Moderate alcohol consumption (one or two drinks per day) is associated with a reduc ed risk of CAD, whereas higher levels of alcohol intake (in excess of 21 units/week for men or more than 14 units/week) in women, particularly in \200\230binges \200\231, is associa ted with an increased risk of CHD. 226 CHAPTER 5 Coronary artery disease Hypertension De \201 nition A continuous relationship exists between increasing blood pres sure and cardiovascular risk; therefore, it is impossible to de \201 ne hypertension pre- cisely. For practical purposes, levels of blood pressure above which the risk increases sig ni \201 cantly, and treatment can provide a clear-cut bene \201 t, are used as a working de \201 nition of hypertension (see Table 5.1 ). The average of two readings at each of a number of visits should be used to de \201 ne the blood pressure. Causes of hypertension The majority of subjects ( > 95 % ) have essential (primary) hyperte nsion, in which an underlying cause for the hypertension is not found. There are many causes of secondary hypertension (see Table 5.1 ). Symptoms and signs Hypertension is usually asymptomatic, although a patient will occasion- ally complain of headache. A history of cardiac or neurologic symptoms should always be sou ght. The cardiovascular system should be examined in detail, and fundoscopy should be perfo rmed to look for retinopathy (see Table 5.1 ). Clinical signs of an underlying cause (radiofemoral delay or weak femoral pulses, renal enl argement or bruit, or cushingoid features) and evidence of end-organ damage (heart failure, retinopathy, aortic aneurysm, carotid or femoral bruit) should be sought. Malignant hypertension is diagnosed when severe hypertension (systolic blood pressure (SBP) > 200 mmHg diastolic blood pressure (DBP) > 130 mmHg) is identi \201 ed, together with grade III \200\223IV retinopathy. \200 The patient often has a headache and occasionally visual disturbance. \200 Proteinuria and haematuria are often present. \200 This is a medical emergency requiring immediate treatment to prevent rapid progression to renal failure, heart failure, and/or stroke. Untreated, the 1-year mortality is approximately 90 % . Investigation Important investigations in all patients presenting with hypertension are: \200 ECG \200 fasting glucose \200 full lipid pro \201 le (total, HDL and LDL cholest erol and triglycerides) \200 urea and electrolytes (U&E) \200 urinalysis for blood and protein If secondary hypertension is suspected , further investigation should focus on the possible underlying cause (e.g. urinary cortisol, plasma renin-aldosterone levels, renal ul trasound, magnetic resonance angiography (MRA) of renal arteries, MAG3 renogram, and 24-hou r urinary catecholamines or vanillyl mandelic acid (VMA)). HYPERTENSION 227 Table 5.1 Blood pressure (BP) classi \201 cation Category SBP (mmHg) DBP (mmHg) Optimal BP <120 <80 Normal BP <130 <85 High \200\223normal BP 130 \200\223139 85 \200\22389 Grade 1 hypertension 140 \200\223159 90 \200\22399 Grade 2 hypertension 160 \200\223179 100 \200\223109 Grade 3 hypertension (cid:2) 180 (cid:2) 110 Adapted from British Hypertension Society (2004). Y http://www.bhsoc.org Secondary hypertension (<5 % ) Renal disease \200 Diabetic nephropathy, renovascular disease, glomerulonephritis, vasculitides, chronic pyelonephritis, polycystic kidneys Endocrine disease \200 Conn \200\231s and Cushing \200\231s syndromes, glucocorticoid-rem ediable hypertension, phaeochromocytoma, acromegaly, hyperparathyroidism Other \200 Aortic coarctation, pregnancy-induced hypertension and pre- eclampsia, obesity, excessive dietary salt or licquorice intake, drugs (non-steroidal anti- in \202 ammatory drugs (NSAIDs), sympathomimetics, illicit stimulants, e.g. amphetamine, M DMA ( \200\230ecstasy \200\231), and cocaine Grading of hypertensive retinopathy I. Tortuous arteries, with thickened bright walls ( \200\230silver wiring \200\231) II. Art eriovenous nipping (narrowing in a vein where crossed by an artery) III. Flame hemorrhages and cotton wool spots (small retinal bleeds and exudates) IV. Papilloedema 228 CHAPTER 5 Coronary artery disease Treatment of high blood pressure When to treat \200 Patients with malignant hypertension or with persistent BP > 160/100 mmHg after lifestyle measures Subjects with BP > 140/90 mmHg after lifestyle measures who have evidence of end-organ dama ge (left ventricular hypertrophy (LVH) on ECG, proteinuria or retinopathy) or a calculated 10-year risk of a cardiovascular event (cid:2)20 % Subjects who have clinical evidence of CAD, peripheral or cerebrovascular disease if BP > 140/90 mmHg. Blood pressure targets \200 Most patients should have their BP lowered to a target of <140/85 mmHg. Patients with diabetes, have been shown to bene \201 t from more aggressive BP reduction (UKPDS (UK Prospective Diabetes Study) and HOT (Hypertension Optima l Treatment) studies), and a target of <130/80 mmHg is more appropriate. Lifestyle measures \200 Minimize dietary salt intake (<100 mmol/day) \200 Reduce alcoho l to <21 units (men) and <14 units (women) per week \200 Take regular aerobic exercise if not contraindicated (at least 30 min, 3x/week) Achieve and maintain healthy BMI (20 \200\22325 kg/m 2 ) \200 Consume at least 5 portions /day of fresh fruit and vegetables \200 Stop smoking, and reduce dietary fat content, esp ecially saturated and trans-fatty acids. Uptake of these lifestyle measures is often dif \201 cult to sustain, and imple- mentation is most successful in a multidisciplinary professional setting when supported by clear wri tten information, including individualized strategies and goals. Choice of drug therapy Large meta-analyzes of studies of BP-lowering therapy have clearly s hown that the degree of blood pressure lowering is the best determinant of risk reduction. Comparative studies, such as ALL-HAT (Antihypertensive and Lipid-Lowering Treatment to Prev ent Heart Attack), have typically shown that there is little evidence favoring one class of drug over another with respect to overall cardiovascular outcome. \200 Thiazide diuretic s are effective and cheap and widely recommended as \201 rst-line antihypertensive therapy. Although calcium-channel blockers may be less protective than other agents against the development of heart failure, their safety and effectiveness in preventi ng atherosclerotic events is now con \201 rmed, despite previous concerns. TREATMENT OF HIGH BLOOD PRESSURE 229 Treatment with the angiotensin receptor blocker (ARB) losartan demonstrated a small advanta ge, particularly in reducing stroke, compared to beta-blocker therapy in high-risk hyperten sive patients with LVH (LIFE (Losartan Intervention for Endpoint reduction) study). Compelling indications for speci \201 c class of antihypertensive agents See Table 5.2 . Table 5.2 Indications for antihypertensive drugs Class of drug Compelling indication Alpha-blocker Benign prostatic hypertrophy Heart failure/LV-dysfunction Angiotensin- converting enzyme inhibitors (ACE-Is)/ARBs Established CAD Type 1 diabetic nephropathy, secondary stroke prevention ACE-I intolerant (ARB indicated) Type 2 diabetic nephropathy Hypertension + LVH Beta-blockers MI Angina Heart failure Calcium-channel blockers Elderly Systolic hypertension Angina Thiazide diuretics Elderly Heart failure Systolic hypertension Adapted from British Hypertension Society (2004). Y http://www.bhsoc.org 230 CHAPTER 5 Coronary artery disease Combining antihypertensive drugs Most hypertensive individuals require more than one drug t o control their blood pressure. Combining drugs at an earlier stage in the up-titration of therapy often results in better control with fewer side-effects than maxi- mizing the dose of individual agents. The British Hypertension Society has produced a practical algorithm that helps guide approp riate combination of antihypertensive drugs in clinical practice (see Table 5.3 ). \200 T his is based on the A-B-C-D principle (A = ACE-I or ARB, B = B-blocker, C = calcium-channel antagonist, D = diuretic). A or B are effective \201 rst-line drugs in the young, who typically have high-renin hype rtension that responds well to these drug classes. \200 C or D are more effective \201 rst-line agents in the elderly and black individuals, who typically have lower levels of re nin and are less responsive to these agents. Drugs can be substituted or added in a stepwise fashion according to the response, until BP is controlled. Care should be taken if prescribing B + D together, as this combination may slightly increa se the incidence of type 2 diabetes. ACE-I and ARB therapy can both reduce risk of developi ng this condition. Other therapy \200 The lipid-lowering arm of the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study was terminated early due to a sizeable reduction in major vascular ev ents seen in patients with hypertension and \200\230average \200\231 cholesterol levels tr eated with atorvastatin 10 mg daily for less than 4 years. Aspirin 75 mg daily is recommended in hypertensive patients with evidence of clinical atherosclerotic disease or (cid:2)20 % 10-year cardiovascular eve nt risk, after adequate BP control is achieved (<150/90 mmHg). Statin therapy should be initiated in these high-risk individuals, regardless of baseline cholesterol levels. Target lipid levels are total cholesterol (TC)<4.0 mmol/L, LDL- C<2.0 mmol/L, or a > 25 % o r > 30 % reduction in TC or LDL-C respectively, whichever is the greater. COMBINING ANTIHYPERTENSIVE DRUGS 231 Table 5.3 Combining antihypertensive drugs: (The BHS A-B-C-D principle) <55 years and non-black > 55 years or black STEP 1 A or B C or D STEP 2 A + C or D STEP 3 A (or B) + C + D Add B-blocker/spironolactone/or other diuretic STEP 4 Adapted from British Hypertension Society (2004). Y www.bhs.co.uk Other drugs to consider i nclude hydralazine, A -methyl dopa, clonidine, moxonidine, and minoxidil, but it is advisab le that use of these drugs is supervised by a specialist. 232 CHAPTER 5 Coronary artery disease Lipid management in atherosclerosis Dyslipidaemia and risk of atherosclerosis Numerous epid emiologic studies have con \201 rmed that a direct relationship exists between cholesterol level and risk of CAD, even with the normal range of cholesterol. Increasing LDL-C levels appears to be the main driver of this pathologic relationship, but other atherogenic lipopr otein particles including very low-density lipoprotein (VLDL), chylomicron remnants, and li poprotein(a) (Lp(a)) also appear to play an important role. LDL, particularly modi \201 ed LDL, is recognized by the scavenger receptor on the surface of mac- rophages in the arteri al wall, which take up these cholesterol-rich particles and eventually become the foam cell s that form the lipid-rich core of athero- sclerotic plaques. Increasing levels of HDL, inv olved in reverse cholesterol transportation from the peripheries to the liver, protect agai nst the development of atherosclerosis. Increased triglyceride levels are now also establis hed as an independent risk factor for CAD. Emerging studies suggest that, in addition to th e circulating lipid concentrations, the nature of the lipoprotein particles plays an import ant part in their atherogenic risk. For example, small dense LDL particles, as seen in subj ects with diabetes, are more readily taken up by macrophages and appear to be more atheroge nic than larger less-dense LDL. Lipids and risk assessment It is critical to consider the lipid pro \201 le in the context of the other risk factors present in the individual, by calculating 10-year cardiovascular risk. Although only TC and HDL-C are considered in most risk models, the levels of LDL and cholesterol and triglycerides should also be considered in the overall picture. Although b lood should ideally be drawn for lipid analysis after a 12-hour fast, TC and HDL-C levels a re only minimally affected by eating and are still valid in a non-fasting sample, unlike tr iglycerides and calculated LDL-C. Measure a fasting lipid pro \201 le if the patient: \200 is over 50 years of age \200 has clinical atherosclerotic disease \200 has \211 other risk factors for atherosclerosi s \200 has clinical signs of hyperlipidaemia (xanthomata, xanthelasmata, or corneal arcus at age <50 years) has a family history of premature CAD or hyperlipidaemia. Most subjects at increased global risk of CAD have cholesterol levels between 4.0 and 6.5 m mol/dL, but a signi \201 cant proportion of individuals have primary or secondary dyslipid aemic syndromes with characteristic abnormalities in the lipoprotein pro \201 le. Normal ranges for plasma lipid levels Total cholesterol 4.0 \200\2236.5 mmol/L (150 \200\223250 mg/dL) LDL cholesterol <4.1 mmol/L (<160 mg/dL) HDL cholesterol 0.8 \200\2232.0 mmol/L (30 \200\22375 mg/dL) Triglycerides 0.8 \200\2232.0 mmol/L (70 \200\223175 mg/dL) LIPID MANAGEMENT IN ATHEROSCLEROSIS 233 Table 5.4 Primary hyperlipidaemias Postscript roman numerals = WHO phenotype; chol/trig levels given in mmol/L. Eruptive xanthomata; lipaemia retinalis; hepatosplenomegaly Familial hyperchylomicronaemia (lipoprotein lipase de \201 ciency or apoCII de \201 cienc y) I Chol <6.5 Trig 10 \200\22330 Chylomicrons i LDL i Chol 7.5 \200\22316 Trig <2.3 Tendon xanthoma; corneal arcus; xanthelasma Familial hypercholesterolaemia II (LDL receptor defects) LDL i Familial defective apolipoprotein B-100 II a Tendon xanthoma; arcus; xanthelasma Chol 7.5 \200\22316 Trig <2.3 LDLi The commonest 1 lipidaemia ; may have xanthelasma or arcus) Chol 6.5 \200\2239 Trig <2.3 Common hypercholesterolaemia II a LDL i VLDL d HDL d Next commonest 1 lipidaemia; xanthelasma; arcus Familial combined hyperlipidaemia II b, IV or V Chol 6.5 \200\22310 Trig 2.3 \200\22312 IDL i HDL d LDL d Dysbetalipoproteinaemia (remnant particle disease) III Palmar striae; tuberoeruptive xanthoma Chol 9 \200\22314 Trig 9 \200\22314 VLDL i Familial hypertriglyceridaemia IV Chol 6.5 \200\22312 Trig 3.0 \200\2236.0 Type V hyperlipoproteinaemia Trig 10 \200\22330; chylomicrons Eruptive xanthomata; lipaemia retinalis; hepatosplenomegaly Primary HDL abnormalities \200 Hyperalphalipoproteinaemia: i HDL, chol > 2. \200 Hypoal phalipoproteinaemia (Tangier disease): d HDL, chol <0.92. Primary LDL abnormalities \200 Abetalipoproteinaemia (ABL): trig <0.3, chol <1.3, missing LDL, VLDL and chylomicrons. Autosomal recessive disorder of fat malabsorption causing vita min A & E de \201 ciency, with retinitis pigmentosa, sensory neuropathy, ataxia, pes cavus and acanthocytosis. Hypobetalipoproteinaemia: chol <1.5, LDL d , HDL d . Autosomal codominant disorder of apoli poprotein B metabolism. i longevity in heterozygotes. Homozygotes present with a similar cl inical picture to ABL. Chol = cholesterol; Trig = triglyceride. Reproduced from Longmore M, Wilkinson I, Davidson E et al (2010). Oxford handbook of clinic al medicine , 8th ed (2010). with permission from Oxford University Press. WHO = World Heal th Organization. 234 CHAPTER 5 Coronary artery disease Secondary causes of dyslipidaemia \200 Renal failure a \200 Nephrotic syndrome a \200 Hypothyroidism a \200 Type II diabetes and obesity b \200 Cholestasis \200 Alcohol a buse \200 Drugs: anti-retroviral protease inhibitors \200 thiazides \200 oral contraceptive pill \200 isotretinoin \200 steroids a Cholesterol elevation. b Minor elevation in cholesterol, but greater increases in atherogenic VLDL, chylomicron remnants, and triglycerides, as well as a fall in HDL. This page intentionally left blank 236 CHAPTER 5 Coronary artery disease Lipid-lowering therapy Statins (e.g. atorvastatin, \202 uvastatin, pravastatin, rosuvasta tin, simvastatin) Statins reduce cholesterol levels by inhibiting HMG-CoA-reductase, the rate-limiting enzyme in cholesterol synthesis. They also: \200 increase clearance of circ ulating LDL by upregulating LDL-receptor expression. are extremely effective at lowering cholesterol levels; for example, the most potent statin s, atorvastatin and rosuvastatin can more than halve LDL-C levels at higher doses. increase HDL and decrease triglyceride levels. A signi \201 cant evidence base has been bu ilt up over the past decade that strongly supports the widespread use of statins in primary and secondary prevention, and con \201 rmed their safety. \200 Data from large randomiz ed clinical trials have shown a consistent reduction (around 25 \200\22330 % ) in the relative risk of major cardiovascular events wit h the use of atorvastatin, pravastatin, and simvastatin in both the primary (ASCOT, WOSCOPS (West of Scotalnd Coronary Prevention Study), HPS, CARDS (Collaborative Atorvastatin Diabe tes Study)) and secondary prevention settings (MIRACL (Myocardial Ischemia Reduction with A cute Cholesterol Lowering), CARE (Cholesterol and recurrent Events), LIPID (Long-term Inter vention with Pravastatin in Ischaemic Disease), 4S (Scandinavian Simvastatin Survival Study ), HPS). In the \201 rst outcome study comparing two statins, the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study showed that high-dose atorvastatin (80 mg) was more effective than pravastatin (40 mg) at preventing further majo r cardiovascular events during the \201 rst 2 \200\2233 years after presentation with an acute coronary syndrome. Typically, recommended evidence-based doses are simvastatin 40 mg nocte, pravastatin 40 mg od, and atorvastatin 10 \200\22380 mg od. Statins should not be prescribed to individuals w ith porphyria or severe liver or muscle disease, and caution is advised with their use in m ilder liver dysfunction, renal impairment, and in combination with \201 brates. Fibrates (e.g. beza \201 brate, cipro \201 brate, feno \201 brate, gem \201 brozil) \200 Fibrates improve the lipid pro \201 le by activating peroxisome proliferator- activa ted receptor alpha (PPAR-A), resulting in a mild lowering of TC and LDL-C. They also cause a signi \201 cant reduction in triglycerides and increase in HDL. Subjects with combined hyperlipidaemia, or other reasons for a low HDL and/or high triglycerides, respond well to \201 brates. The VA-HIT (Department of Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial) study showed that gem \201 brozil (600 mmg bd) reduced maj or cardiovascular events in subjects with average cholesterol and low HDL (<1.0 mmol/L) lev els. LIPID-LOWERING THERAPY 237 Subgroup analysis of the HPS suggested that similar bene \201 ts were