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 observed with simvastatin (40 mg) in such individuals. For the majority of patients, \201 brates are typically recommended as second-line agents in patients who are intolerant of statins, particularly if they have low HDL or high triglycerides. The likelihood of liver or muscle side-effects is increased if a \201 brate and statin are used in combination, and careful monitoring is recommended. The risk is lower if the statin is combined with feno \201 brate than with other \201 brates. Anion-exchange resins The agents colestyramine (4 \200\2238 g tds) and colestipol (5 \200 \22310 g tds) bind bile salts in the small bowel. This inhibits their reabsorption, resulti ng in upreg- ulation of the LDL receptor on hepatocytes and increased plasma choles- terol clearance. Although these drugs effectively lower cholesterol levels, most subjects experie nce intolerable gastrointestinal (GI) side-effects, limiting their widespread use. These dr ugs are generally recommended as second- or third-line therapy in subjects with hypercholes terolaemia. Inhibitors of intestinal cholesterol absorption The novel agent ezetimibe (10 mg od) binds to an intestinal cholesterol transportation protein, which inhibits absorption. LDL-C is re duced by 15 \200\22320 % . Ezetimibe is most effectively employed together with statin ther apy in those patients who do not achieve cholesterol targets at higher statin doses, and is effective as monotherapy in those who are intolerant of statins. Dietary plant stanols (3 g/day) can reduce LDL-C by up to 15 % . Nicotinic acid Nicotinic acid (100 \200\2231000 mg tds, or 375 \200\2232000 mg modi \201 e d-release (MR) preparation (Niaspan ) od) reduces hepatic VLDL synthesis and inhibits fa tty acid release from adipocytes. HDL levels are signi \201 cantly increased, and reduced hepatic synthesis results in a small reduction in LDL. Although particularly bene \201 cia l in mixed dyslipidaemias, use of the short-acting for- mulation has been limited by a high incidence of intolerable GI side-effects and facial \202 ushing. The MR formulation is c onsiderably more tolerable, and ongoing outcome studies should con \201 rm the place of th is agent in the preventive armamentarium. Fish oils Marine oil supplements containing high concentrations of omega-3 fatty acids are indicated for the treatment of severe hypertriglyceridaemia (Omacor 4 capsules/day, Maxe pa 10 capsules/day). Omacor (1 mg od, GISSI-P study) has a license for secondary prev ention post-MI, but the bene \201 ts observed with this dose do not seem to be due to lipi d-lowering effects. An extensive clinical trial program spanning a wide range of primary an d secondary prevention settings should clarify the wider role of this drug in CAD preventio n. 238 CHAPTER 5 Coronary artery disease When to treat lipids Therapeutic lifestyle changes (TLCs) are the \201 rst step in the tr eatment of dyslipidaemia. Moderate weight reduction (10 % of body weight) improves the lipi d pro \201 le and cardiovascular (CV) risk. The composition of the optimal diet is controv ersial. General dietary recommendations include: reduced cholesterol and saturated fats (especially trans-fats) \200 increased plant stano ls, sterols, and soluble \201 bre \200 adoption of Mediterranean diet. Exercise should also be taken regularly. Statin therapy should be initiated in all patients with established clinical atherosclerotic disease, including: \200 CAD \200 cerebrovascular disease \200 renova scular disease \200 peripheral arterial disease. Current UK, European, and US guidelines also recommend statin therapy in subjects with: \200 diabetes (CARDS, and subgroup analyz es of HPS, ASCOT, and other major trials). CAD equivalent 10-year CV risk of (cid:2)20 % . Although all of these patients should recei ve statins (unless contraindi- cated) regardless of their cholesterol level (HPS, ASCOT, CA RDS), it is still important to measure lipid levels to ensure that subjects are responding appropriately to therapy and achieving targets for cholesterol <4.0 mmol/L and LDL <2.0 mmo l/L. These targets are based on observa- tions from clinical trials and cohort studies sugg esting that \200\230lower is better \200\231 when it comes to cholesterol! There is less outcome-based evidence informing us when to initiate drug therapy for isolated dyslipidaemia in the absence of other risk factors. \200 Younger sub jects without a family history of CAD or other risk factors should be considered for drug treatment if LDL-C > 5.0 mmol/L (or total > 7.0 mmol/L). Primary and familial hyperlipidaemias should be treated aggressively, particularly if there is a family history of premature CAD. This page intentionally left blank 240 CHAPTER 5 Coronary artery disease Diabetes and atherosclerosis Approximately 2 million people in the UK currently suffer from diabetes mellitus (DM), the vast majority of whom have type 2 diabetes ( > 90 % ). Althoug h diabetes is more common in older individuals, the incidence is increasing at a dramatic r ate in all age groups, especially young adults, driven by the obesity \200\230epidemic \200\231. The prevalence of type 2 DM is also greater in black and South Asian individuals in the UK. Macrovascular disease is the most common cause of death in DM ( > 75 % ). No diabetes Diabetes 190 180 170 160 150S 140 130 120 110 190 180 170 160 150S 140 130 120 110 P B P B 3 4 5 6 8 7 TC: HDL 9 10 11 3 4 5 6 8 7 TC: HDL 9 10 11 CHD risk <15% over next 10 years CHD risk 15 \200\22330% over next 10 years CHD risk >30% over next 10 years Fig. 5.6 The effect of type 2 DM on coronary heart disease (CHD) risk (non-smoker, age 60 y ears). Adapted from the British Cardiac Society, British Hyperlipidaemia Society, British H ypertension Society, British Diabetic Association (1998). Heart 80(suppl 2): S1 \200\223S29 . Mechanisms responsible for increased CV risk in DM A complex mix of risk factors is typical ly present in patients with diabetes including: \200 low HDL \200 high triglycerides (V LDL and remnant particles) \200 increased small, dense LDL \200 moderate hypertension \200 low-grade in \202 ammation \200 a procoagulant state (increased PAI-1, and platele t activation) \200 increased oxidative stress \200 increased levels of harmful advanced glycation end-products. Conventional risk factors only account for a relatively small prop ortion (825 % ) of the increased risk observed in diabetes. Not only are subjects with diab etes more likely to suffer a major vascular event, they are also more likely to die from th is event than if they did not have diabetes. DIABETES AND ATHEROSCLEROSIS 241 The atherosclerotic process tends to be more diffuse in individuals with diabetes, often af fecting multiple vascular territories, making percutaneous and surgical revascularization m ore technically challenging and risky. \200 Outcome is better when patients with diabetes and multivessel coronary disease undergo coronary artery bypass graft (CABG), rather than percutaneous revasculariza tion (RITA (Radiofrequency Interstitial Tumor Ablation), BARI (Bypass Angioplasty Revascula rization Investigation)). \200 Data from large studies suggest that the outcome after per cutaneous coronary intervention (PCI) in patients with diabetes is improved by use of drug- eluting stents as well as abciximab, a platelet glycoprotein (GP)IIb/IIIa antagonist. Visceral neuropathy is responsible for silent myocardial ischaemia, and reduced heart rate variability. Diabetic nephropathy further contributes to cardiac risk by increasing BP and causing deterioration in the lipid pro \201 le. Prevalence Cerebrovascular disease1 7% 2 \200\2233 \227 increased risk of fatal stroke3* Abnormal ECG2 18% 2 \200\2234 \227 increased risk of fatal heart disease3* Hypertension2 35% 15 \227 increased risk of amputation4,5 Intermittent claudication1 4.5% Compared with general population Fig. 5.7 Macrovascular disease in type 2 DM. 1 Wingard DL, Barrett-Connor EL, Scheidt-Nave C, McPhillips JB (1993). Prevalence of cardiovascular and renal complications in older adul ts with normal or impaired glucose tolerance or NIDDM. A population-based study. Diabetes C are 16 : 1022 \200\2235. 2 UKPDS 6 (1990). Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabe tes Res 13 : 1 \200\22311. 3 Balkau B, Py r l M, Shipley M et al (1997). Non-cardiovasc ular disease mortality and diabetes mellitus. Lancet 350 : 1680. 4 King \200\231s Fund (199 6). Counting the cost . BDA. 5 Most RS, Sinnock P (1983). The epidemiology of lower extremi ty amputations in diabetic individuals. Diabetes Care 6 : 87 \200\22391. 242 CHAPTER 5 Coronary artery disease Recommendations for risk reduction in diabetes Blood glucose should be aggressively control led by means of diet and exer- cise coupled with appropriate intensity of hypoglycaemic dru g therapy. \200 Target glycosylated hemoglobin (HbA 1c ) is (cid:2)7 % . \200 Intense b lood sugar control is better at reducing progression of microvascular disease and neuropath y than prevention of macrovascular events (UKPDS study). Aggressive blood pressure (UKPDS, HOT studies) and lipid management (CARDS, ASCOT, HPS) has a greater impact on prevention of CAD and stroke than ti ght glucose control, and reduces progression of nephropathy. CV risk in diabetes is similar to that seen in patients with established CAD, at least afte r the disease has been present for several years. Because of their rapid progression of art erial disease, it is recommended that patients with diabetes receive aggressive preventive therapy with statins, aspirin, and inhibition of the renin-angiotensin system (see Table 5. 5 ). Table 5.5 Therapeutic recommendations for CV prevention in diabetes Measure Target HbA 1c \211 7 % Aggressive lifestyle oral hypoglycaemic therapy Cholesterol <4.0 mmol/L, or d > 25 % LDL <2.0 mmol/L, or d > 30 % Statin therapy (regardless of baseline lipid levels) Aggressive blood pressure control <130/<80 mmHg ACE-I or ARB in most, especially if there is evidence of nephropathy. This page intentionally left blank 244 CHAPTER 5 Coronary artery disease The metabolic syndrome and insulin resistance The metabolic syndrome is a term describing a frequently observed cluster of adverse factors within an individual. \200 It is characte rized by: \200 visceral obesity \200 insulin resistance \200 moderate hypertension \200 dyslipidaemia (low HDL and high triglycerides with average cholesterol levels) low-grade in \202 ammation Several de \201 nitions of this syndrome have been proposed, but of these the American National Cholesterol Education Program \200\224 Adult Treatment Panel ( NCEP ATP-III) diagnostic criteria (see Table 5.6 ) are the most practical and widely used, as well as being a robust predictor of vascular risk. The prevalence of this syndrome is increasing in parallel with the increase in numbers of obese and overweight individuals It has been described in a high proportion of American children and adolescents. It is projected to contribute substantially to the burden of atherosclerotic disease in soc iety in the next few decades. Table 5.6 ATP-III criteria for diagnosis of the metabolic syndrome Variable Threshold Waist circumference > 102 cm ( > 40 in.) men > 88 cm ( > 35 in.) women Fasting glucose > 6.1 mmol/L (11 mg/dL) Blood pressure > 130/ > 85 mmHg HDL cholesterol <1 mmol/L (40 mg/dL) men <1.3 mmol/L (50 mg/dL) women Triglycerides > 1.7 mmol/L ( > 150 mg/dL) \211 3 out of 5 criteria must be satis \201 ed for \201 rm diagnosis. THE METABOLIC SYNDROME AND INSULIN RESISTANCE 245 Mechanisms of increased risk Visceral obesity causes insulin resistance, leading to: \200 increases in blood glucose \200 adverse changes in blood lipids \200 increased levels of in \202 ammatory cytokines such as tumor necrosis factor alpha (TNF-A), causing endothelial dysfunction increases in vascular tone and BP \200 local proatherosclerotic changes in the vascular w all. Increased leptin and reduced adiponectin levels in \202 uence insulin sensi- tivity. Their incremental clinical value remains a subject of investigation. It has been proposed t hat the degree of insulin resistance is less important than the impact of other risk factor s including lipids, BP, in \202 ammation and pro-thrombotic factors, but these issues also remain under investigation. Hyperglycaemia Central obesity Hypertension Insulin resistance syndrome Dyslipidaemia Atherosclerosis Increased clotting factors Microalbuminuria Fig. 5.8 Insulin resistance is an independent predictor of cardiovascular disease. 1 \200 \2234 . 1 Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP (1992). Prosp ective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 41 : 715 \200\223 22. 2 Haffner SM , Miettinen H (1997). Insulin resistance implications for type II diabetes mellitus and coronary heart disease Am J Med 103 : 152 \200\22362. 3 Reaven GM (1994). Syn drome X: 6 years later. J Int Med 236 (suppl 736): 13 \200\22322. 4 Abuaisha B, Kumar S, Ma lik R, Boulton AJ. (1998). Relationship of elevated urinary albumin excretion to components of the metabolic syndrome in non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pr act 39 : 93 \200\2239. 246 CHAPTER 5 Coronary artery disease Genetic variation Environmental factors Central adiposity Innate immunity Adipokines Cytokines Adipocyte Monocyte/ macrophage Inflammatory markers Insulin resistance Metabolic syndrome \206\221 BP \206\223 HDL \206\221 TG Atherosclerosis Plaque rupture/thrombosis Cardiovascular events Fig. 5.9 Pathophysiology of atherosclerotic cardiovascular disease in the metabolic syndrom e. Central adiposity and innate immunity play key roles in the development of insulin resis tance, chronic in \202 ammation, and metabolic syndrome features through the effects of ad ipokines (e.g. leptin, adiponectin, resistin) and cytokines (e.g. TNF-A, interleukin-6) on liver, skeletal muscle, and immune cells. In addition, monocyte/macrophage-, and adipocyte- derived factors may have direct athero- thrombotic effects that promote the development of atherosclerotic cardiovascular events. Common genetic variants and environmental factors ma y impact the development of atherosclerosis at multiple levels, through in \202 uences on central adiposity, innate immunity, glucose and lipoprotein metabolism, and vascular functi on. TG = triglycerides. Reproduced with permission from Reilly MP, Rader J (2003). The meta bolic syndrome: more than the sum of its parts. Circulation 108 : 1546 \200\22351. This page intentionally left blank 248 CHAPTER 5 Coronary artery disease Metabolic syndrome: management Weight loss and exercise are the cornerstones of management of the met- abolic syndrome. Management of insulin resistance with insulin-sensitizing drug s (metformin and thiazolidenediones) has theoretical bene \201 ts but is currently under i nvestigation (see below) As far as management of the dyslipidaemia is concerned, treatment with statin is clearly indicated if 10-year CV risk is (cid:2)20 % , or if LDL-C is elevate d (ATP-III recommend a threshold of > 3.3 mmol/L). The nature of the risk-factor pro \201 le in the metabolic syndrome frequently results in the underestimation of 10-year risk, but at present no studies are currently available to support the use of speci \201 c evidence -based drug therapy in this syndrome. Insulin sensitizers (thiazolidenediones, \200\230glitazones \200\231) \200 The primary m ode of action is to improve insulin sensitivity in muscle and adipose tissue (see Fig. 5.10 ). 1 , 2 They are licensed as monotherapy, particularly in overweight patients with type 2 DM for whom metformin is not suitable. They are associated with modest weight gain. 3 \200 They maintain lasting glycaemic contr ol and, by targeting insulin resistance, improve a range of CV risk factors. 4 There may be a role for this class of drugs in the prevention of DM: the TRIPOD study enrol led 266 Hispanic women, in S California at high risk of developing DM, and randomized them to the thiazolidenedione, troglitazone, or placebo for 30 months. There was a 50 % reductio n in risk of developing DM with troglitazone use, and the bene \201 ts were sustained for > 6 months after discontinuing the drug. 5 1 H llsten K, Virtanen KA, L nnqvist F, et al (2002). Rosiglitazone but not metformin enh ances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newl y diagnosed type 2 diabetes. Diabetes 51 : 3479 \200\22385. 2 Virtanen KA, H llsten K, Par kkola R, et al (2002). Different effects of rosiglitazone and metformin on adipose tissue g lucose uptake in type 2 diabetes. Diabetes 51 (suppl. 2): A145. Abs 585-P. 3 Carey DG, Cowi n GJ, Galloway GJ, et al (2002). Effect of rosiglitazone on insulin sensitivity and body co mposition in type 2 diabetic patients [corrected]. Obes Res 10 : 1008 \200\22315. 4 St John Sutton M, Rendell M, Dandona P, et al (2002). A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diab etes. Diabetes Care 25 : 2058 \200\22364. 5 Buchanan TA, Xiang AH, Peters RK, et al (2002). Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmac ological treatment of insulin resistance in high-risk hispanic women. Diabetes 51 :2796 \200\223803. METABOLIC SYNDROME: MANAGEMENT 249 Carbohydrate Gut Digestive enzymes Decrease plasma glucose levels Decrease excessive lipolysis and reduces free fatty acids Pancreas Blood glucose Adipose tissue Insulin Decrease excessive hepatic glucose production Muscle Liver Improve insulin-mediated glucose uptake Fig. 5.10 Glitazones decrease insulin resistance at target tissues. Dyslipidaemia1 Hypertension2 Microalbuminuria4 Glitazone positive effects Clotting factors3 Vascular inflammatory markers5 Fig. 5.11 Glitazones have positive effects on a range of cardiovascular risk factors. 1 Bru nzell J et al (2001). Diabetes 50 (suppl 2): Abs 567-P. 2 Bakris GL, Dole JF, Porter LE, et al (2001). Rosiglitazone improves blood pressure in patients with type 2 diabetes mellitus . Diabetes 49 (suppl 1): A96, Abs 388. 3 Freed M et al (2000). Diabetologia 43 (suppl 1): A bs 1024. 4 Bakris GL, Weston WM, Rappaport EB, et al (1999). Rosiglitazone produces long-te rm reductions in urinary albumin excretion in type 2 diabetes (abstract). Diabetologia 42 ( suppl 1): Abs 865 and poster. 5 Greenberg A , Haffner S, Weston W, et al (2001). Rosiglitaz one reduces c-reactive protein, a marker of systematic in \202 ammation, in type 2 diabeti c patients. Diabetologia 44 (suppl 1): A222, Abs 853. 250 CHAPTER 5 Coronary artery disease Angina pectoris Angina pectoris refers to the pain caused by myocardial ischaemia. Ischaemi a is usually caused by coronary stenosis due to atheroma but may be caused by tachycardia, anemia, aortic stenosis, LVH of other aetiolo- gies, syndrome X (chest pain with normal cor onary arteries), and coronary artery spasm (Prinzmetal). These conditions may co-exist and will be exac- erbated by physical exertion or emotional stress, which increase cardiac work load and energy requirement. Coronary artery spasm, in contrast, normally occurs at rest. History and examination \200 Angina pectoris is characterized by a deep and diffusely dis tributed central chest discomfort. Certain features of pain are of discriminative value. Patients will not be able to point to where the pain is coming from with one \201 nger, but will use an open palm or \201 st over the center or left parasternal aspect of their chest. \200 The pain is not sharp, ( some patients confuse \200\230sharp \200\231 with \200\230severe \200\231). \200 Pain l asts longer than a few seconds and rarely exceeds an hour without varying in severity. Most episodes will last 1 \200\2235 minutes. \200 The response to glyceryl trinitrate (GTN), if there is one, will be almost immediate. Responses that take more than 5 minutes are unlikely to be related to the drug. Chest wall tenderness suggests musculoskeletal pain and does not accompany angina. Dyspnoea, fatigue, nausea, and recurrent belching may also represent underlying ischaemia a nd can occur in the absence of the classical central chest pain. The clue to underlying isc haemic heart disease (IHD) lies in their precipitation by exertion or emotional stress. Angina is often classi \201 ed according to its temporal pattern and its relation to exert ion because this loosely re \202 ects prognosis. \200 Stable angina \200\224 characteri zed by pain occurring after a relatively constant level of exertion. Unstable angina \200\224 characterized by pain on minor exertion or at rest, which is eith er new onset or a dramatic worsening of existing angina. \200 Crescendo angina \200\224 characterized by pain on ever-diminishing levels of exertion, usually over a period of days. \200 Decubitus angina \200\224 provoked by lyin g \202 at. The Canadian Cardiovascular Society (CCS) system provides a quantitative means to describe exertional capacity and is divided into four classes: I. Minimal limitation of ordinary activity. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation. II. Slight limitation of ordinary activity; angina occurs on walking or climbing stairs rapidly; walking in cold, in wind, or under emotional stress. ANGINA PECTORIS 251 III. Marked limitation of ordinary physical activity; angina occurs on walking 50 \200\223100 m on level ground or climbing 1 \202 ight of stairs at a normal pa ce in normal conditions. IV. Inability to perform any physical activity without discomfort; angina symptoms may be present at rest. Physical examination \200 This rarely reveals any direct evidence of IHD but will help wi th risk strati \201 cation and to exclude co-existing disease. Measure the pulse rate. This may be slowed by inferior ischaemia due to atrioventricular (A V) node ischaemia. A resting tachycardia, if present, usually represents activation of the sympathetic nervous system but may be due to an arrhythmia precipitated by ischaemia. \200 BP measurement is essential to look for evidence of hypertension (predisposing to atherom a), or hypotension (may re \202 ect cardiac dysfunction or over-medication). Precordial examination should include palpation for LVH, cardiac enlargement, or dyskinesis, and auscultation for added heart sounds (heart failure or acute ischaemia), aortic stenosis or mitral regurgitation (due to papillary muscle dysfunction). Examine for signs of heart failure by listening for \201 ne, late-inspiratory crepitation s at the lung bases, and looking for dependent pitting oedema (typically bilateral ankle leg oedema, but sacral oedema may be the only manifestation if the patient has been recumb ent for some time). Look for evidence of peripheral vascular disease by palpating for aortic aneurysm, feeling the carotid and limb pulses, listening for carotid, renal or femoral artery bruits, and ass essing tissue integrity and capillary re \201 ll of the legs and feet. Examine for signs of hypercholesterolaemia: the eyes for xanthelasmata and corneal arcus, a nd the skin and tendons (especially the Achilles) for xanthomata. Differential diagnosis The differential diagnosis of anginal chest pain is wide and include s: \200 anxiety and hyperventilation \200 musculoskeletal chest wall pain \200 cervic al or thoracic root pain \200 pneumothorax, pneumonia, or pulmonary embolus \200 oesoph ageal problem (in \202 ammation/spasm) \200 other upper GI problem (gastritis, peptic ul cer, pancreatitis, cholecystitis) pericarditis \200 aortic dissection \200 mitral valve prolapse \200 coronary emboli ( LV mural thrombus, atrial myxoma). 252 CHAPTER 5 Coronary artery disease Investigations Further risk strati \201 cation will add to the diagnostic certainty achiev ed by history and examination. Measure full blood count (FBC), U&E, a full fasting lipid pr o \201 le (total, LDL, and HDL cholesterol and triglyceride levels), and blood glucose. Ch est X-ray (CXR) is not mandatory, but should be per- formed if there is suspicion of heart failure, a pulmonary condition, or an abnormality of the bony structures of the chest wall. 12-lead ECG A resting ECG may not con \201 rm the diagnosis but can point towards ischaemi c heart disease. The presence of T-wave inversion (2 mm) or Q waves suggests previous myoca rdial injury. The presence of ST depres- sion and, to a lesser extent, T-wave inversion dur ing pain is a marker of ischaemia, and patients with these signs should be further investig ated. If ST-segment deviation is observed at rest, an acute coronary syndrome must be exclu ded. 12-lead ECG can also help identify other causes of chest pain (LVH, arrhythmia, perica rditis). Tests for inducible ischaemia Tests such as exercise ECG, stress echocardiography (ECHO), o r myo- cardial perfusion scanning are a useful adjunct to con \201 rm the diagnosis and ai d management. Management Lifestyle : Stop smoking. Encourage daily aerobic exercise within limits of exer cise capacity. Look at occupational needs and advise adjustment if symptom level not compat ible. Advise healthy diet, collaborating with dieticians if required. Aspirin : (75 mg/24 h) In all cases unless active peptic ulcer disease or bleeding diathesi s. Those with past peptic ulcer disease may take a gastro- protective agent such as a H 2 a ntagonist or proton pump inhibitor. Anti-anginals : B-blockers: 1st line (e.g. atenolol 25 \200\223100 mg od or metoprolol 25 \200\22350 mg tds). Start on suspicion of IHD. Avoid onl y if contraindicated (asthma with con \201 rmed B-agonist response (mortality improved in patients with angina and concomitant chronic obstructive pulmonary disease (COPD) if they c an tolerate the reduced peak expiratory \202 ow rate (PEFR)), uncontrolled severe LV dysf unction, bradycardia, coronary artery spasm). Calcium antagonists : (e.g. amlodipine 5 \200\22310 mg od or diltiazem MR 90 \200\223180 mg bd) if B -blocker contraindicated. Nitrates : (e.g. GTN spray) Used for control of breakth rough angina. Long-acting nitrates (e.g. isosorbide mononitrate MR 60 \200\223120 mg od) ar e a useful addition to B -blockers for prevention of attacks. Statins : Reduce mortality by approximately one-third in all risk groups. However, the underlying risk of events must be taken into account when considering starting the drug because absolute risk reduction in y oung patients with low-risk IHD may be very small, with a possible harm of myositis, hepati c failure, and reduced compliance with other medications. ANGINA PECTORIS 253 Chest pain clinics Rapid-access or open-access chest pain clinics have transformed the prim ary and secondary care interface for UK patients since their incorpo- ration into the Natio nal Service Framework. They have facilitated the shift of care of stable angina from genera list to specialist, and increased rates of angiography and revascularization. It is not kno wn if this has an effect on mortality but it has certainly prioritized cardiac care and rat es of diagnosis of IHD. The clinics usually involve a standardized referral form, which can be used by either a general practitioner (GP) or hospital physician. The emphasis is on early exclusion of non-cardiac disease and risk strati \201 cation for IHD. Thus, in the \201 rst visit, the patient would see a specialist, perform an exercise test, and have baseline risk factors estimated. At the end of the consultation, the patien t will be reassured that there is a low likelihood of IHD or will begin the path of treatme nt of risk factors and symptoms, ultimately leading to revascularization if required. 254 CHAPTER 5 Coronary artery disease Acute coronary syndromes Acute coronary syndrome (ACS) is an operational term used to descr ibe a constellation of symptoms resulting from acute myocardial ischaemia. An ACS resulting in myocardial injury is termed myocardial infarction (MI). ACS includes the diagnosis of u nstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segmen t elevation myo- cardial infarction (STEMI). The term ACS is initially generally, assigned by ancillary/triage personnel on initial contact with the patient. Guidelines for identi \201 cation of ACS are summarized in Table 5.7 on b NSTEMI/UA: risk strati \201 cation, p. 295. De \201 nition The current nomenclature divides ACS into two major groups, on the basis of delivered treatment modalities (see Fig. 5.12): \200 STEMI \200\224 an ACS where patien ts present with chest discomfort and ST-segment elevation on ECG. This group of patients mu st undergo reperfusion therapy on presentation NSTEMI and UA \200\224 ACS where patients present with ischaemic chest discomfort associat ed with transient or permanent non-ST-elevation ischaemic ECG changes. If there is biochemi cal evidence of myocardial injury, the condition is termed NSTEMI, and in the absence if bi ochemical myocardial injury the condition is termed UA (see b Non-ST elevation myocardial i nfarction (NSTEMI)/unstable angina (UA), p. 290). This group of patients is not treated wit h thrombolysis. Initial management of ACS \200 All patients with suspected ACS should be placed in an env ironment with continuous ECG monitoring and de \201 brillation capacity. The referring doctor should be instructed to give aspirin (300 mg PO if no contraindication s) and not to give any IM injections (causes a rise in total creatine kinase (CK) and risk of bleeding with thrombolysis/ anticoagulation). Immediate assessment should include: \200 rapid examination to exclude hypotension, note the presence of murmurs, and identify and treat acute pulmonary oedema secure intravenous (IV) access \200 12-lead ECG should be obtained and reported within 10 minutes. Give: \200 oxygen (initially only 28 % if history of COPD) \200 diamorphine 2 .5 \200\22310 mg IV prn for pain relief \200 metoclopramide 10 mg IV for nausea \200 GT N spray 2 puffs/unless hypotensive Take blood for: \200 FBC/U&E \200\224 Supplement K + to keep it at 4 \200\2235 mmol/L \200 glucose: may be i acutely post-MI, even in non-diab etic patients, and re \202 ects a stress-catecholamine response and may resolve without tr eatment biochemical markers of cardiac injury (see b STEMI: diagnosis, p. 258). ACUTE CORONARY SYNDROMES 255 lipid pro \201 le \200\224 total cholesterol, LDL, HDL, triglycerides; serum cholesterol and HDL remain close to baseline for 24 \200\22348 hours but fall thereafter an d take (cid:2)8 weeks to return to baseline. Portable CXR will assess cardiac size and pulmonary oedema and exclude mediastinal enlargement. General examination should include peripheral pulses, fundoscopy, and abdominal examination for organomegaly and aortic aneurysm. Conditions mimicking pain in ACS \200 Pericarditis \200 Dissecting aortic aneurysm \200 Pulmonary embolism \200 Oesophageal re \202 ux, spasm or rupture \200 Biliary tr act disease \200 Perforated peptic ulcer \200 Pancreatitis Acute coronary syndromes No ST elevation ST elevation No enzyme rise NSTEMI Unstable angina NQ-MI QwMI Fig. 5.12 Nomenclature of ACS: patients with ACS may present with or without ST elevation o n the ECG. The majority of patients with ST elevation (large arrows) ultimately develop Q-w ave MI (QwMI), whereas a minority (small arrow) develop a non-Q-wave MI (NQ-MI). Patients w ithout ST-elevation are experiencing either UA or an NSTEMI, depending on the absence or pr esence of cardiac enzymes (e.g. troponin) detected in the blood. Adapted and reproduced wit h permission from Antman EM, Braunwald E (1997). Acute myocardial infarction. In Braunwald EB (ed). Heart Disease: a textbook of cardiovascular medicine . Philadelphia, PA WB Saunder s. 256 CHAPTER 5 Coronary artery disease