LDL, particularly modi \201 ed LDL, is recognized by the scavenger receptor on the surface of macrophages in the arterial wall, which take up these cholesterol-rich particles and ev entually become the foam cells that form the lipid-rich core of atherosclerotic plaques. Increasing levels of HDL, involved in reverse cholesterol transportation from the peripheri es to the liver, protect against the development of athero- sclerosis. An increased triglyc eride level is also now recognized as an inde- pendent risk factor for coronary disease. Emerging data suggest that the nature of the lipoprotein particles plays an important part in their atherogenicity. For example, small, dense LDL particles, as seen in subjects with diabetes, are more readily taken up by macrophages and appear to be more atherogenic than l arger, less dense LDL. Lipids and risk assessment It is essential to consider the lipid pro \201 le together in t he context of the other risk factors present by estimating the 10-year cardiovascular risk. Although only total and HDL cholesterol are considered in most risk models, LDL cholestero l and triglyceride levels should also be considered in the assessment of risk (see Table 6. 6). Blood should ideally be sampled after a 12-hour fast, as triglycerides and calculated LDL c holesterol levels are affected by food intake. In general, a fasting lipid pro \201 le sho uld be obtained in individuals with known cardio- vascular disease and those at increased r isk (Box 6.4). Classi \201 cation of primary dyslipidemias is provided in Table 6.7. Secondary causes of dyslipidemia are listed in Box 6.5. Box 6.4 U.S. Preventive Services Task Force (USPSTF) recommendations \200 Strongly recommend screening men aged 35 and older for lipid disorders Recommend screening men aged 20 \200\22335 for lipid disorders if they are at increased risk for coronary heart disease No recommendation for or against routine screening for lipid disorders in men aged 20 \200\22335, or in women aged 20 and older who are not at increased risk for coronary he art disease CHAPTER 6 Preventive cardiology 270 Table 6.6 Adult Treatment Panel III classi \201 cation of LDL, total, and HDL cholesterol LDL cholesterol, mg/dL (mmol/L) Optimal Near or above optimal Borderline high High Very high <100 (2.58) 100 \200\223129 (2.58 \200\2233.33) 130 \200\223159 (3.36 \200\2234.11) 160 \200\223189 (4.13 \200\2234.88) (cid:116)190 (4.91) Total cholesterol, mg/dL (mmol/L) Desirable Borderline high High <200 (5.17) 200 \200\223239 (5.17 \200\2236.18) (cid:116)240 (6.20) HDL cholesterol, mg/dL (mmol/L) <40 (1.03) (cid:116)60 (1.55) Low High Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/ Table 6.7 WHO/Fredrickson classi \201 cation of primary dyslipidemias Phenotype Elevated particles Lipid levels Chylomicrons Triglycerides (TG) >99th percentile Type I (lipoprotein lipase de \201 ciency or apoCII de \201 ciency) Type IIa (familial hypercholesterolemia/ LDL receptor defects) Most common primary dyslipid emia LDL Total cholesterol (TC) >90th percentile; depending on type, may also see TG and/ or apolipo protein B (cid:116)90th percentile Type IIb (familial combined hyperlipidemia, defective apoprotein B-100) LDL and VLDL TC and/or TG (cid:116)90th percentile and apolipoprotein B (cid:116)90th percentile Type III (dysbetalipoproteinemia) IDL TC and TG >90th percentile Type IV (familial hypertriglyceridemia, familial combined hyperlipidemia) VLDL TC >90th percentile, TG >90th percentile, low HDL Type V Chylomicrons, VLDL TG >99th percentile LIPID MANAGEMENT IN ATHEROSCLEROSIS 271 Box 6.5 Secondary causes of dyslipidemia R \200 enal failure* \200 \200 \200 \200 \200 \200 Nephrotic syndrome* Hypothyroidism* Type 2 diabetes and obesity** Cholestasis Alcohol abuse Drugs \200 \200 \200 \200 \200 Antiretroviral protease inhibitors Thiazides Oral contraceptive pill Isotretinoin Steroids * Cholesterol elevation. ** Minor elevation in cholesterol, but greater increase in atherog enic VLDL, chylomicron remnants, and triglycerides, as well as a fall in HDL. CHAPTER 6 Preventive cardiology 272 Lipid-lowering medications Statins Atorvastatin, \202 uvastatin, pravastatin, rosuvastati n, simvastatin Statins reduce cholesterol levels by inhibiting HMG CoA-reductase, the rate- limiting enzyme in cholesterol biosynthesis. They also increase clear- ance of circulating LDL by up-regulating LDL-receptor expression, further lowering cholesterol levels. These agents are extremely effective at lowering cholesterol levels; e.g., the most potent statins, atorvastatin and rosuvastatin, can lower LDL cholesterol levels by >50%. Statin th erapy typically results in a small increase in HDL and decrease in triglycerides as well. A large evidence base has emerged over the past decade that strongly supports the use of st atins in primary and secondary prevention of cardio- vascular disease. Data from large rand omized clinical trials have shown a consistent reduction (25% \200\22330%) in the relative risk of major cardiovascular events with the use of atorvastatin, pravastatin, and simvasta tin in both the primary (ASCOT, WOSCOPS, HPS, CARDS) and secondary prevention settings (MIR ACL, CARE, LIPID, 4S, HPS). In the \201 rst outcome study comparing two statins, the PROVE-IT study showed that high- dose atorvastatin (80 mg) was more effective than prav- astatin (40 mg) at preventing furth er major cardiovascular events during the \201 rst 2 \200\2233 years after presentation w ith an acute coronary syndrome. Typically recommended evidence-based doses are simvastatin 40 mg, pravastatin 40 mg, and at orvastatin 10 \200\22380 mg. Statins should not be pre- scribed to individuals with porphyr ia or severe liver or muscle disease. Caution is advised with their use in milder liver dys function and in combi- nation with \201 brates. Fibrates Feno \201 brate, gem \201 brozil Fibrates improve the lipid pro \201 le by acti vating peroxisome proliferator- activated receptor A (PPAR-A), resulting in a mild lowering of total and LDL cholesterol, a more signi \201 cant reduction in triglycerides (by 35% \200\22350%), and increases in HDL (by 15% \200\22325%). Patients with combined hyperlipidemia or other reasons for a low HDL and/or high triglyceri des respond well to \201 brates. Although the VA-HIT study showed that gem \201 brozil r educed major cardiovascular events in patients with average cholesterol and low HDL levels, subgroup analysis of the Heart Protection Study (HPS) suggested that similar bene \201 ts were observed with simvastatin (40 mg) in such individuals. For most patients with and at risk of cardiovascular events, \201 brates are typically re commended as second-line agents in patients intolerant of statins, particularly if they hav e low HDL or high triglycerides. The likeli- hood of transaminitis or myopathy is increased if \201 brates and statins are used in combination. Thus careful monitoring is recommend ed when using this combination. The risk is lower with feno \201 brate than that with othe r \201 brates. LIPID-LOWERING MEDICATIONS 273 Anion-exchange resins Cholestyramine, cholestipol These agents bind bile salts in the small bowel, which inhibits their reabsorption, resulting in upregulation of the LDL receptor on hepato- cytes and increased plasma cholesterol clearance. Although these drugs effectively lower cholesterol levels, many patients experience intolerable GI side effects that limit their widespread use. These drugs are generally recommended as second- or third-line ther- apy in subjects with hypercholesterolemia. Inhibitors of intestinal cholesterol absorption Ezetimibe This medication binds to an intes tinal transportation protein and inhibits chol- esterol absorption. LDL cholesterol is redu ced by 15% \200\22320%. The dose is 10 mg daily. Ezetimibe is most often used in combinatio n with a statin in those patients who do not achieve their LDL cholesterol target at higher statin doses. Although it is effective in lowering LDL levels and has been used as monotherapy in statin- intolerant patients, clinical outcome data are cur- rently lacking, so it should not be use d as \201 rst-line therapy as a substitute for statins. Niacin Niacin reduces hepatic VLDL synthesis and inhibits fatty acid release from adipocyte s. HDL levels are signi \201 cantly increased (by 30% \200\22335%), and reduced hepatic sy nthesis results in a small reduction in LDL. Although particularly bene \201 cial in mixed dyslipidemias, use of the short- acting form ulation is limited by a high incidence of intolerable GI side effects and facial \202 ush ing. It may also worsen glucose tolerance in diabet- ics. The modi \201 ed-release formula tion (niaspan 500 \200\2232000 mg daily) is more tolerable, and ongoing outcome studies sho uld con \201 rm the use of this agent in preventing cardiovascular events. Niacin is particularly useful in patients with low HDL and is often used in combination wit h statins. Pretreatment with aspirin can minimize \202 ush- ing, and taking it with food or water can reduce the incidence of GI side effects. Fish oils Fish oil supplements containing high concentrations of omega-3 fatty acids are in dicated for the treatment of severe hypertriglyceridemia (e.g., Lovaza 4 g/day). They act b y reducing VLDL production and in suf \201 cient doses (>3 g/day) can lower serum triglyce rides by 50%. The FDA has limited approval for Lovaza to the treatment of severe hypertriglyceridemia ((c id:116)500 mg/dL [(cid:116)5.6 mmol/L]) because of concerns that it appears to increase LDL cholesterol levels. Dietary plant stanols (3 g/day) can reduce LDL cholesterol by up to 15%. CHAPTER 6 Preventive cardiology 274 Goals of lipid-lowering therapy Current Adult Treatment Panel (ATP) guidelines are more agg ressive than previous iterations, especially in patients with established coronary disease and those at high risk. This is the result of a better understanding of the cardiovascular risk associated with hyperlipidemia and the bene \201 ts of lipid- lowering therapy determ ined from large randomized trials. The \201 rst step in planning therapy is to ascertain the patient \200\231s cardio- vascu lar risk based on presence of risk factors and coronary disease or its equivalent, determin e the 10-year risk of events (Framingham score), and categorize the patient as low, moderat e, moderately high, or high risk. Each category has recommended LDL goals and guidelines fo r when to initiate therapy (see Table 6.8). It is also important to remember the importance of high triglycerides and low HDL when plan ning therapy. Some recommend focusing therapy on the serum total \200\223to \200\223HDL cho lesterol ratio and non \200\223HDL cholesterol levels, especially in patients with hypertri glyceridemia. The goal for non- HDL-C in this circumstance is a concentration that is 30 mg /dL higher than that for LDL (see Table 6.9). An elevated HDL >60 mg/dL is considered a neg ative risk factor. Therapeutic lifestyle changes, including exercise, weight loss, and dietary modi \201 cati ons, are the \201 rst step in treatment of all patients with dyslipi- demia. Moderate wei ght reduction (10% of body weight) can signi \201 cantly improve the lipid pro \201 le an d lower risk. The composition of the optimal diet is controversial, though general recommen dations include \200 Reduced cholesterol to <200 mg/day and saturated fats (especially trans fats) to <7% total calories Increased plant stanols, sterols, and soluble \201 ber (20 \200\22330 g/day) Ado ption of a Mediterranean diet \200 Exercise should also be done on a regular basis, although the resulting changes in LDL and HDL cholesterol are modest. Based on current guidelines, statin therapy should be started in all patients with establis hed clinical atherosclerotic disease, including CAD and cerebrovascular, renovascular, and peripheral arterial disease, and dia- betics and those patients with a 10-year cardiac risk of (cid:116)20% (Table 6.10). Although all of these patients should receive statins (unles s contraindi- cated) regardless of the cholesterol level (HPS, ASCOT, CARDS), it is still i mportant to measure lipid levels to ensure that subjects are responding appropriately to th erapy and achieving their guideline-based targets for cholesterol lowering. These targets a re based on observations from clini- cal trials (PROVE-IT, TNT) and cohort studies suggesti ng that \200\234lower is better \200\235 when it comes to cholesterol levels and outcomes. It is also rec- ommended that a second agent (such as niacin, a \201 brate, or ezetimibe ) be added if the LDL target is not achieved on high-dose high-potency statins (as tolerate d), although the data for this are limited. There is also less outcome-based evidence informing us when to initiate drug therapy for is olated dyslipidemia in the absence of other risk factors. Primary and familial hyperlipidem ias should be treated aggressively, par- ticularly if there is a family history of prematur e CAD. GOALS OF LIPID-LOWERING THERAPY 275 Table 6.8 NCEP Adult Treatment Panel III LDL goals: 2004 update Risk category LDL goal LDL level at which to initiate therapeutic lifestyle changes LDL level at which to consider drug therapy High risk: coronary heart disease (CHD) or CHD risk equivalent (10-year risk >20%) (cid:116)100 mg/dL (cid:116)100 mg/dL; <100 mg/dL consider drug options <100 mg/dL; optional goal of <70 mg/dL in very high risk (see Box 6.6) Moderately high risk: 2 or more risk factors (10-year risk 10 to 20%) <130 mg/dL (cid:116)130 mg/dL (cid:116)130 mg/dL; 100 \200\223129 mg/dL consider drug options Moderate risk: 2 or more risk factors (10-year risk <10%) <130 mg/dL (cid:116)130 mg/dL (cid:116)160 mg/dL Lower risk: 0 to 1 risk factor <160 mg/dL (cid:116)160 mg/dL (cid:116)190 mg/dL; 160 \200\223189 mg/dL consider drug options Adapted from National Cholesterol Education Program (NCEP) Adult Treatment Panel III at htt p://www.nhlbi.nih.gov/guidelines/cholesterol/ Box 6.6 NCEP de \201 nition of very high risk Established coronary disease PLUS: 1. Multiple major risk factors (especially diabetes) OR 2. Severe and poorly controlled risk factors (especially continued smoking) OR 3. Multiple risk factors of the metabolic syndrome (especially triglycer- ides (cid:116)200 plus non-HDL-C (cid:116)130 plus HDL-C <40) OR 4. Acute coronary syndrome CHAPTER 6 Preventive cardiology 276 Table 6.9 Adult Treatment Panel III non-HDL goals Risk category Non-HDL cholesterol (mg/dL) Coronary heart disease (CHD) or equivalent (10- year risk of CHD >20%) <130 Two or more CHD risk factors and 10-year risk of CHD (cid:100) 20% <160 0 to 1 CHD risk factor <190 Adapted from NCEP Adult Treatment Panel III at http://www.nhlbi.nih.gov/guidelines/ cholest erol/ Table 6.10 Suggested treatment goals in patients with cardio- metabolic risk and lipoprotei n abnormalities (2008 ACC/ADA Consensus Report) Goals LDL (mg/dL) Non-HDL apoB (mg/dL) (mg/dL) <70 <100 <80 Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more ad ditional major CVD risk factor High-risk patients, including those with 1) no diabetes or known clinical CVD but two or mo re additional major CVD risk factors or 2) diabetes but not other major CVD risk factors <100 <130 <90 Other major risk factors include smoking, hypertension, and family history of premature CAD . CAD, coronary artery disease; CVD, cardiovascular disease. From 2008 ACC/ADA Consensus Re port on Lipoprotein Management in Patients with Cardiometabolic Risk . DIABETES AND ATHEROSCLEROSIS 277 Diabetes and atherosclerosis Over 7% of U.S. adults are known to have diabetes mellitus (DM ), the vast majority of whom have type 2 diabetes. However, because of the associ- ated mic rovascular and macrovascular complications, diabetes accounts for nearly 14% of U.S. health care expenditures. Although diabetes is more common in older individuals, the incidence is increasing at a dra matic rate in all age groups, especially young adults, driven by the increased prevalence o f obesity. Macrovascular complications are the leading cause of death in patients with diabetes (see F ig. 6.5). The National Cholesterol Education Program (NCEP) report considers type 2 diabete s a coronary disease equivalent, placing these patients in the highest risk category. This classi \201 cation is based on the observation that type 2 diabetics without a prior MI ar e at the same risk for MI and cardiac mortality as nondiabetics who had a prior MI. In the Framingham Heart Study, presence of diabetes doubled the age- adjusted risk for cardiovascular disease in men and tripled it in women. Mechanisms responsible for increased CV risk in DM Diabetics have a greater burden of ather ogenic risk factors than that of nondiabetics. These include obesity, low HDL, high triglyc erides (VLDL and remnant particles), increased small, dense LDL, hypertension, low- grade i n \202 ammation, a procoagulant state (increased PAI-1, and platelet activation), increase d oxidative stress, and increased levels of harmful advanced glycation end products. Coronary atherosclerotic plaques in diabetics contain a greater amount of lipid-rich athero ma and more macrophage in \201 ltration, which may increase risk of rupture and thrombosis . Conventional risk factors only No diabetes Diabetes 190 180 170 160 150 140 130 120 110 190 180 170 160 150 140 130 120 110 P B S P B S 3 4 5 8 6 7 TC:HDL 9 10 11 9 10 11 3 4 5 8 6 7 TC:HDL CHD risk < 15 \200\22330% over next 10 years CHD risk >30% over next 10 years CHD risk < 15% over next 10 years Figure 6.5 Effect of type 2 DM on CHD risk (nonsmoker, age 60 years). Adapted with permissi on from the British Cardiac Society, British Hyperlipidaemia Society, British Hypertension Society, British Diabetic Association. Heart 1998; 80(Suppl. 2):S1 \200\223S29. CHAPTER 6 Preventive cardiology 278 account for a relatively small proportion (<25%) of the increased risk observed in diabetes . Not only are diabetic subjects more likely to suffer a major vascular event, they are also more likely to die from this event than if they did not have diabetes. The atherosclerotic process tends to be more diffuse in dia- betics, often affecting multiple vascular territor ies, and diabetics presenting with acute coronary syndrome are much more likely to have mul tivessel coronary disease. The burden of diffuse coronary disease also makes per- cutaneous and surgical revascularization more technically challenging and risky (see Figure 6.6). Outcome is better when diabetics with multivessel coronary disease undergo CABG rather than percutaneous coronary revascularization (RITA, BARI). However, data from large studies sug gest that outcome after PCI in diabetics is improved by use of drug-eluting stents as well as abciximab, a platelet glycoprotein IIb/IIIa antagonist. Prevalence Cerebrovascular disease1 7% 2 \200\2233 x increased risk of fatal stroke3* Abnormal ECG2 18% 2 \200\2234 x increased risk of fatal stroke3* Hypertension2 35% 15 x increased risk of amputation4,5 Intermittent claudication2 4.5% compared with general population Figure 6.6 Macrovascular disease in type 2 diabetes. 1. Wingard DL, et al. (1993). Diabetes Care 16:1022 \200\2231025. 2. UKPDS 6 (1990). Diabetes Res 13:1 \200\22311. 3. Balkau B, e t al. (1997) Lancet 350:1680. 4. King \200\231s Fund. Counting the Cost. BDA, 1996. 5. Most RS, Sinnock P (1983). Diabetes Care 6:67 \200\22391. DIABETES AND ATHEROSCLEROSIS 279 Visceral neuropathy is responsible for silent MI and reduced heart rate variability. Diabet ic nephropathy further contributes to cardiac risk by increasing blood pressure and causing deterioration in the lipid pro \201 le. Recommendations for risk reduction in diabetes Blood glucose should be aggressively control led by means of diet and exercise coupled with appropriate hypoglycemic drug therapy. Targe t HbA1c is (cid:100)7%. However, intense blood sugar control is better at reducing progress ion of microvascular disease and neuropathy than prevention of macrovascular events (UKPDS study). Aggressive blood pressure (UKPDS, HOT studies) and lipid manage- ment (CARDS, ASCOT, HPS, A LLIANCE, SPARCL) has a greater impact on prevention of coronary disease and stroke than tig ht glucose control and reduces progression of nephropathy. Cardiovascular risk in diabetics is similar to that seen in patients with established coron ary disease; therefore, appropriate preventive strategies employing guideline-based therapi es are recommended (see Table 6.11). Table 6.11 Therapeutic recommendations for CV prevention in diabetes Measure Target Aggressive lifestyle oral hypoglycemic therapy HbA1c (cid:100)7% Statin therapy (regardless of baseline lipid levels) LDL <100 mg/dL Aggressive blood pressure control Aspirin <130/<80 mmHg ACE inhibitor or ARB is used in most patients, especially if there is evidence of nephropat hy. CHAPTER 6 Preventive cardiology 280 The metabolic syndrome The metabolic syndrome describes a frequently observed cluster of ad verse risk factors within an individual. It has also been referred to as syndrome X and the insulin resistance syndrome. The syndrome is characterized by visceral obesity, insulin re sistance, moderate hypertension, dyslipidemia (low HDL and high triglycerides with average cholesterol levels), and low- grade in \202 ammation. Several de \201 nitions of this syndrome have been proposed, but the NCEP ATP-III diagnost ic criteria (Table 6.12) 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 o bese and overweight individuals. It has been described in a high proportion of American chi ldren and adolescents. Thus, the meta- bolic syndrome is projected to contribute substantia lly to the societal bur- den of atherosclerotic disease in the next few decades. Unless effective interventions to slow, and hopefully reverse, this trend are delivered at a population level, much of the progress that has been made in the \201 ght against coron ary disease is likely to be overturned. Mechanisms of increased risk Visceral obesity causes insulin resistance, which is associate d with increase in blood glucose and abnormalities in the lipid pro \201 le. Increased lev els of in \202 ammatory cytokines such as TNF-A, some of which are produced by adipocytes, cause endothelial dysfunction that increases vascular tone and blood pressure, as well as promoting local pro-atherosclerotic changes in the vascular wall (see Fig. 6.7). Increased leptin and reduced adiponectin levels in \202 uence insulin sensi- tivity, as we ll as some of the adverse metabolic consequences of obesity, but their incremental clinical value remains a subject of investigation. It has been proposed that the degree of insulin resistance is less important than the impact of other risk factors, including lipids, blood pressure, in \202 am- mation and pro-thrombotic factors, but these factors also remain un der investigation. Table 6.12 ATP-III criteria for diagnosis of the metabolic syndrome Variable Threshold Waist circumference >40 \200\235 Men >35 \200\235 Women Fasting glucose >100 mg/dL Blood pressure >130/>85 mmHg HDL cholesterol <40 mg/dL in men <50 mg/dL in women Triglycerides >150 mg/dL Three out of \201 ve criteria must be satis \201 ed for \201 rm diagnosis. Drug treatm ent for hyperglycemia, hypertension, low HDL, and elevated triglycerides satis \201 es the criteria for these variables. THE METABOLIC SYNDROME 281 ENVIRONMENTAL FACTORS GENETIC VARIATION Innate immunity Central adiposity Adipokines Cytokines Adipocyte Monocyte/ macrophage Inflammatory markers Insulin resistance METABOLIC SYNDROME iBP iTG dHDL ATHEROSCLEROSIS Plaque rupture/thrombosis CARDIOVASCULAR EVENTS Figure 6.7 Pathophysiology of atherosclerotic cardiovascular disease in the metabolic syndr ome. Central adiposity and innate immunity play key roles in the development of insulin res istance, chronic in \202 ammation, and metabolic syndrome features through the effects of adipokines (e.g., leptin, adiponectin, resistin) and cytokines (e.g., tumor necrosis factor -A, interleukin-6) on liver, skeletal muscle, and immune cells. In addition, monocyte/macro phage and adipocyte-derived factors may have direct atherothrombotic effects that promote t he occurrence of atherosclerotic cardiovascular events. Common genetic variants and environ mental factors may impact the development of atherosclerosis at multiple levels through in \202 uences on central adiposity, innate immunity, glucose and lipoprotein metabolism, and vascular function. Reproduced with permission from Reilly MP, Rader D (2003). Circulation 108(13):1546 \200\2231551. CHAPTER 6 Preventive cardiology 282 Metabolic syndrome: management The treatment of patients with the metabolic syndrome is ess entially the same as treatment of the individual variables. Weight loss and exercise are th e cornerstones of management, and cardiovascular risk factors should be further treated if they persist despite lifestyle modi \201 cations. Management of insulin resistance with insulin-sensitizing drugs (met- formin, and thiazolid enediones; see Fig. 6.8) has theoretical bene \201 ts but is currently under investigation , as the ability of such an approach to improve outcomes compared to weight reduction and e xercise alone is not yet well supported by clinical trials. As far as management of the dyslipidemia is concerned, treatment with a statin is clearly i ndicated if the 10-year cardiac risk is (cid:116)20%, or if LDL cholesterol is elevated as per the ATP-III guidelines. The nature of the risk factor pro \201 le in the metabolic syndrome fre- quently results i n the underestimation of 10-year risk, but at present no studies are currently available to support use of speci \201 c evidence-based drug therapy in this syndrome. Most, if not al l, of these patients should also take a daily aspirin for primary prevention. Cardohydrate 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 Figure 6.8 Glitazones decrease insulin resistance at target tissues. ASPIRIN FOR PRIMARY PREVENTION 283 Aspirin for primary prevention The Physician \200\231s Health Study (PHS) was the \201 rs t reported trial of aspirin in the primary prevention of cardiovascular disease. The study was stopped early because of a statistically signi \201 cant 44% reduction in \201 rst M I. The decision to prescribe aspirin for primary prevention should be an individual clinical j udgment that weighs the bene \201 t of reducing risk of a \201 rst MI, the risk factor p ro \201 le of the patient, and the adverse effects of long-term administration, speci \201 cally gastrointestinal bleeding. An impor- tant consideration is that, when aspirin is used for primary prevention, the absolute bene \201 t is much smaller than that for secon dary prevention, while the risk of major gastrointestinal bleeding is the same. The United States Preventive Services Task Force recommends aspirin for all apparently heal thy men and women whose 10-year risk of a \201 rst CHD event is 6% or greater. The Americ an Heart Association uses a 10% or greater cut-off risk for which the bene \201 ts of aspi rin are likely to out- weigh the risks of chronic administration. Current data suggest that aspirin is underutilized, both for primary and secondary preventi on. Approximately 40% of adults over age 40 in the United States have the metabolic syndrom e and a 10-year risk of a \201 rst cardiac event of 16% to 18%. Thus, wider use of aspiri n in such patients seems warranted. A single daily dose of 81 mg aspirin is appropriate for primary prevention. This page intentionally left blank 285 Chapter 7 Diseases of the myocardium and pericardium Effusive \200\223constrictive pericarditis 312 Myocardial diseases Classi \201 cation 286 Dilated cardiomyopathy 288 Hypertrophic cardiomyopathy 290 Restrict ive cardiomyopathy 295 Arrhythmogenic right ventricular Calci \201 c pericarditis without constriction 312 Viral pericarditis 313 Tuberculous pericarditis 313 TB constrictive perica rditis 314 TB effusive \200\223constrictive cardiomyopathy 297 Ischemic cardiomyopathy 299 Valvular cardiomyopathy 299 Hypertensive cardiomyopathy 299 Alc oholic cardiomyopathy 299 Metabolic cardiomyopathy 299 Takotsubo cardiomyopathy pericarditis 314 TB pericardial effusion 315 Uremic pericarditis 317 Neoplastic pericardial disease 318 Myxedematous effusion 319 Nontuberculous bacterial ( \200\234broken heart syndrome \200\235) 300 General system disease 301 Nutritional cardiomyopathy 301 Muscular dystrophies 301 Neuromus cular disorders 302 Sensitivity or toxic reactions 302 Peripartum 302 Myocarditis 303 (purulent) pericarditis 320 Radiation pericarditis 321 Drug- or toxin-induced pericarditis 321 Postcardiotomy syndrome 322 Postinfarction pericarditis 322 Rheumatic fever 322 Autoimmune pericarditis 323 Traumatic pericarditis 323 Fungal pericarditis 323 Amoebic pericarditis 32 4 Constrictive pericarditis Pericardial diseases Etiology 305 Syndromes of pericardial disease 306 Acute pericarditis without vs. restrictive myocardial disease 325 effusion 307 Pericardial effusion tamponade 309 Pericardial \202 uid analysis 326 Pericardiocentesis 326 Further reading 327 Constrictive pericarditis 311 CHAPTER 7 Diseases of the myocardium and pericardium 286 Myocardial diseases Classi \201 cation Heart muscle diseases include a diverse range of ca rdiomyopathies and myocarditides. They are classi \201 ed according to the predominant pat ho- physiological process (Box 7.1). Arrhythmogenic right ventricular cardiomyopathy (dysplasia) has been included in its own ri ght and a few conditions remain unclassi \201 ed because they do not easily \201 t into any of these categories (systolic dysfunction with minimal dilatation, \201 broelastosis, ventricular non-compaction, and mito- chondrial disease). Speci \201 c cardiomyopathies are heart muscle diseases associated with speci \201 c card iac or systemic disorders and include conditions previously excluded from this classi \201 cation (Box 7.2). Myocarditis is an in \202 ammatory process involving myocytes, interstitium, and vascular components. It can be caused by a large number of infectious agents. CLASSIFICATION 287 Box 7.1 WHO/ISFC classi \201 cation of cardiomyopathies \200 \200 \200 \200 Dilated cardiomyopathy Hypertrophic cardiomyopathy Restrictive cardiomyopathy Arrhythmogeni c right ventricular cardiomyopathy (dysplasia) WHO, World Health Organization; ISFC, International Society and Federation Cardiology. Box 7.2 Speci \201 c cardiomyopathies \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Ischemic Valvular Hypertensive Alcohol Metabolic Nutritional General system disease Muscular dystrophies Neuromuscular disorders Sensitivity and toxic r eactions Peripartum CHAPTER 7 Diseases of the myocardium and pericardium 288 Dilated cardiomyopathy Dilated cardiomyopathy (DCM) is characterized by cardiac chamber enl argement and impaired systolic dysfunction, although diastolic dysfunc- tion is almost alwa ys also present. The syndrome of heart failure (HF) often ensues. The prevalence is 5 \200 \2238 per 100,000, and it is 3 times more frequent in blacks and males than whites and fema les. The etiology of DCM is presented in Box 7.3. Symptoms Clinical presentation can be abrupt with acute pulmonary edema but more often pati ents present with symptoms of heart failure such as breathless- ness, in particular exertio nal dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and fatigue. Arrhythmias (e.g. AF, particularly with high alcohol intake) are also com- mon and patients are at risk for VT and sudden cardiac death (SCD). Diagnosis Diagnosis is established by physical examination, electrocardiography, chest X-ra y, and echocardiography (see also Box 7.4). \200 ECG may show evidence of LVH, previous myocardial infarction (MI), or arrhythmias. A sinus tachycardia is common with nonspeci \201 c T-wave changes and poor R wave in anterior ches t leads. Chest X-ray Echocardiography sizes as well as LV systolic and diastolic function a nd valvular function. There is usually biventricular dilatation with poor septal motion. Th ere may be mural thrombus in either or both ventricles. Often a small pericardial collectio n is found. Ejection fraction and fractional shortening are low. Dilatation of the ventricl es results in mitral and tricuspid regurgitation. Exercise testing oxygen consumption is us eful to assess functional capacity. Ambulatory ECG prognostically signi \201 cant ventricu lar arrhythmias. Cardiac catheterization patients with a dilated cardiomyopathy to do the f ollowing: \200 \200 \200 may show an enlarged cardiac size and pulmonary edema. allows accurate assessment of cardia c chamber with or without measurement of maximum ventilatory monitoring is essential to assess for the presence of should be performed with caution in all Exclude signi \201 cant coronary disease Assess severity of mitral regurgitation and pulmo nary artery pressures Ventricular biopsy: not routinely performed Treatment Management of DCM focuses on relieving symptoms and improving prognosis. Therapie s are designed to correct the maladaptive neuro- hormonal abnormalities involving the sympa thetic system and renin \200\223 angiotensin \200\223aldosterone axis. The management of he art failure is discussed in Chapter 5. DILATED CARDIOMYOPATHY 289 Box 7.3 Etiology of dilated cardiomyopathy Although originally considered to be idiopathic, experimental and clin- ical data now suggest that genetic, viral, and autoimmune factors p lay a role in its pathophysiology. Several genetic mutations have been identi \201 ed as the causative prob- lem in familial DCM, while certain viruses have been shown to cause sporadic cases of DCM. The following list is not exhaustive and there is some overlap with speci \201 c cardiomyopathies. \200 \200 \200 \200 \200 Inherited (may account for >25% of cases) Myocarditis (infective, autoimmune, toxic) Metabo lic (hemochromatosis, thyrotoxicosis). Nutritional (vitamin de \201 ciencies \200\224thiam ine [beriberi]) Persistent tachycardia (tachycardia-induced cardiomyopathy) DCM is essentially a diagnosis of exclusion, and potentially reversible causes, including c oronary artery disease, valvular heart disease and adult congenital heart disease, should b e sought. Careful attention should be paid to dietary history and alcohol consumption, as s ome reversibility is possible with modi \201 cation of these factors. Box 7.4 Additional investigations for DCM \200 \200 \200 \200 \200 \200 \200 Renal function Liver function tests Serum ferritin, iron, transferrin Thyroid function Vira l serology Infective screen (HIV, hepatitis C, enteroviruses) Autoantibodies CHAPTER 7 Diseases of the myocardium and pericardium 290 Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is characterized by maladapti ve left ventricular hypertrophy (LVH) inappropriate for the degree of afterload. Prevalence is thought to be 1 \200\2232 per 1000. The hypertrophy is classically localized to the proximal interventricular septum, resulting in a dynamic out \202 ow tract obstruction in association with systolic anterior motion ( SAM) of the mitral valve lea \202 ets (present in 35% of patients). However, there is considerable phenotypic variability and the hyper- trophy can be concentr ic, apical, or mid-cavitary, resulting in an intracavi- tary gradient (often in association with an apical aneurysm). In addition, genetic studies have demonstrated that affected fam ily members may have little or no cardiac hypertrophy despite the presence of a disease cau sing mutation (variable penetrance). The reason for this marked phenotypic variability is p oorly understood but is almost certainly multifactorial. HCM has also been associated with accessory atrioventricular pathways and conduction abnormalities in certain families. Etiology HCM is an autosomal dominant inherited cardiac condition. However, there is marked allelic and nonallelic heterogeneity with multiple mutations (more than 450) in at least 2 0 genes now identi \201 ed as causing the disease. Most of these mutations are in genes en coding proteins of the sarcomere. In contrast to mutations causing DCM, mutations frequentl y affect sar- comeric proteins involved in force generation as opposed to force trans- miss ion. This is, however, not consistent and some genes have different mutations causing both HCM and DCM. Other mutations have been found in genes encoding nonsarcomeric proteins. Histologically there is myo \201 brillar disarray and extensive \201 brosis. Small intra mural arterioles are also hypertrophied. The \201 ndings may be patchy but are concentrat ed in the septum. Subvalvular obstruction occurs between the anterior lea \202 et of the mitral valve and th e hypertrophied septum. The mitral valve apparatus moves anteriorly in systole (a combinati on of malaligned papillary muscles and Venturi effect of a high-velocity jet in the out \202 ow tract). The valve becomes thickened and mitral regurgitation occurs. Obstruction of the LV out \202 ow tract is not always present. It is possible to have asym metric septal hypertrophy (ASH) alone. Occasionally there is obstruction more evident towar d the apex rather than at the out \202 ow tract. Symptoms Patients often are asymptomatic and are increasingly picked up incidentally from t he wider use and availability of echocardiography or as part of fam- ily screening after id enti \201 cation of an affected family member. Symptoms, when they do occur, may include t he following: \200 Fatigue and breathlessness due to impaired diastolic \201 lling and decreased cardiac out put. Atrial transportation is very important for maintaining cardiac output; symptoms typic ally get much worse with AF. HYPERTROPHIC CARDIOMYOPATHY 291 Chest pain (angina) can result from increased cardiac work secondary to the LVH, a relative blood supply \200\223demand mismatch and plugging of intramural arterioles. High diastolic pressures increase the diastolic wall stress and impair diastolic coronary blood \202 ow . Atrial and ventricular arrhythmias are common and can result in palpitations, presyncope and syncope, or even sudden death. Presyncope and syncope can also occur due to increased o ut \202 ow tract obstruction during exercise, at times of relative intravascular dehydrati on, or from certain maneuvers (i.e., Valsalva). Approximately 10% \200\22315% of patients m ay eventually develop left ventricular dilatation and failure. Sudden cardiac death The risk of SCD in these patients is extremely dif \201 cult to deter mine because of the marked phenotypic variability, and most risk factors have low sensitivi ty and speci \201 city. The annual incidence of SCD across the entire population with HCM is about 1%. Markers of risk for SCD in HCM \200 \200 \200 \200 \200 \200 \200 