Implantable cardiac de \201 brillators (ICD) ICDs are devices capable of recognizing ventr icular arrhythmias (VT or VF) and delivering a DC shock to terminate them. They are implant ed in the same way as pacemakers. Several studies have shown that patients with impaired LV function ben- e \201 t from thei r implantation. The MADIT II trial showed a 30% improve- ment in survival in patients with ischemic heart disease and an ejection fraction of <30%. The SCD-HeFT trial enrolled patients with ischemic and with nonischemic cardiomyopathies wi th an LVEF <35%. There was a simi- lar reduction in mortality in ischemic and nonischemic c ardiomyopathy patients who received an AICD compared with those patients receiving amiodaro ne. Cardiac resynchronization (CRT) Many patients with CHF have bundle branch block (BBB) patte rns on their ECG, in particular LBBB. A wide QRS duration is associated with a worse outcom e in patients with CHF. LBBB results in delayed depolarization and contraction of the later al LV free wall, which is thought to contribute to disease progression. Biventricular pacem akers are able to reduce this ven- tricular dysynchrony by pacing the LV via a cardiac vein . Current indications for implantation include severe symptoms (NYHA III or IV), a broad QRS complex (>130 ms), and impaired LV function (LVEF <35%). These indications alone, however, do not necessarily pre- dict patients who will bene \201 t from resynchronization. Current research is assessing the value of using noninvasive imaging techniques (tissue Doppler an d MRI) to identify true inter- and intraventricular dysynchrony. Studies in patients with HF undergoing cardiac resynchronization (CRT) have shown an improv ement in quality of life, improved exercise capacity (6-minute walk test), and, in one stud y, improved survival. Biventricular devices can now be combined with ICDs to further improve the outlook of these patients. The devices can be dif \201 cult to implant, require close and careful fol- low-up, and are expensive, which has reduced their widespread use. CHAPTER 5 Heart failure 238 Surgery for heart failure Valve surgery Patients with valve disease as the source of their heart failure should be co nsidered for valve replacement surgery. This is discussed more fully in Chapter 4 on valve disease. Coronary artery bypass grafting (CABG) Ischemic heart disease is the most common cause of h eart failure in devel- oped countries. In some cases, these patients will have evidence of either stress-induced ischemia or hibernation (muscle that has reduced function due to redu ced blood supply but is still viable). Revascularizing these patients can lead to an improvement in cardiac function. Transplantation Cardiac transplantation is reserved for those patients with end-stage heart failure (see Table 5.11). It is a major undertaking for the patient, who must be willing t o undergo intensive treatment and be emotion- ally capable of withstanding the uncertaintie s that occur before and after transplantation. There are a number of contraindications, listed below. Contraindications for heart transplantation \200 \200 \200 \200 \200 Persistent alcohol or drug abuse Treated cancer with remission and <5 years follow-up Syste mic disease with multiorgan involvement Infection Fixed high pulmonary vascular resistance Despite problems with rejection and complications of immunosuppressive therapy (infection, hypertension, renal failure, malignancy) the 5-year sur- vival is of the order of 70% \200 \22380% with many patients returning to work. Assist devices Because of the lack of organ donors for cardiac transplantation, much intere st has been shown in the development of left ventricular assist devices (LVAD) and mechanic al hearts. LVADs are automatic pumps that take over the work of the heart. They have been u sed as a bridge to trans- plantation and as a bridge to recovery in those with potentially reversible causes for their heart failure (e.g., post-viral). The next stage up from these large devices is the implantation of a permanent arti \201 ci al heart. An example is the Jarvik 2000, which has been successfully been implanted in a re latively small number of patients. SURGERY FOR HEART FAILURE 239 Table 5.11 Heart transplantation guidelines adapted from ESC/AHA guidelines Indications \200 Contraindications and cautions \200 \200 Present alcohol and/or drug abuse Chronic mental illness that cannot be adequately controll ed Treated cancer with remission and <5 years follow-up Systemic disease with multiorgan in volvement Uncontrolled infection Severe renal failure (creatinine clearance <50 mL/min) or creatinine >2.3 mg/dL, although some centers accept patients on hemodialysis Fixed high pul monary vascular resistance (6 \200\2238 Wood units and mean transpulmonary gradient >15 mmH g and pulmonary artery systolic pressure >60 mmHg) Recent thromboembolic complication Unhea led peptic ulcer Evidence of signi \201 cant liver impairment Other coexisting disease wit h a poor prognosis Patients must be willing and able to withstand the physical and emotional demands of the pr ocedure and its postoperative sequelae. Objective evidence of limitation, e.g., peak oxygen consumption <10 mL/min/kg on cardiopulmonary exercise test with evidence for anaerobic met abolism* Patients dependent on intravenous inotropes and mechanical circulatory support \200 \200 Patients with signi \201 cant exercise limitation that have a peak oxygen consumption <55% predicted or between 11 and 15 mL/min/kg also warrant consideration for cardiac transplant ation if they have recurrent unstable myocardial ischemia untreatable by other means, or re current episodes of congestive heart failure in spite of adherence to optimum medical thera py. CHAPTER 5 Heart failure 240 Palliative care for heart failure The demographic spread of most patients with heart failur e means that the hi-tech and expensive therapies outlined earlier are not available and con sideration must be made about end-of-life issues. Increased input from specialist palliativ e care teams will help to allow patients and their rela- tives live with a chronic and term inal disease and help the patient die with dignity. WORSENING HEART FAILURE 241 Worsening heart failure When a patient is seen with worsening heart failure, it is importan t to try and ascertain the cause. The most frequent reasons for symptom deteri- oration are shown below. Causes of worsening heart failure Noncardiac \200 \200 \200 \200 \200 \200 Noncompliance Newly prescribed drugs (see Table 5.12) Renal dysfunction Infection Pulmonary embolus Anemia (lifestyle changes, medication) Cardiac \200 \200 \200 \200 \200 Atrial \201 brillation Other tachyarryhthmias Bradycardia/heart block Worsening valve dis ease Myocardial ischemia (including infarction) Table 5.12 Side effects of drugs for heart failure Drugs Complications Diuretics Common: postural hypotension, gout, urinary urgency Serious: electrolyte imbalance (hypokal emia, hypomagnesemia, hyponatremia), arrhythmia ACE inhibitors Common: cough, hypotension including postural Serious: worsening renal function, renal infa rction in renal artery stenosis, angioedema B-Blockers Common: tiredness, bradycardia, coldness Serious: asthmatic attack, exacerbation of heart f ailure, heart block Spironolactone Common: gynecomastia, tiredness, rashes Serious: hyperkalemia, hyponatremia Digoxin Common: nausea Serious: life-threatening arrhythmias Angiotensin-II receptor antagonists Common: hypotension including postural Serious: worsening renal function, renal infarction in renal artery stenosis Amiodarone Common: photosensitivity, nausea, thyroid dysfunction, sleep disturbance, corneal microdepo sits. Serious: thyrotoxic storm, proarrhythmia, pulmonary or hepatic \201 brosis Intropes Common: nausea, palpitation Serious: arrhythmia, cardiotoxicity CHAPTER 5 Heart failure 242 Diastolic heart failure Approximately one-third of patients with heart failure have diastol ic heart failure. This is de \201 ned as symptoms and signs of heart failure but with pres erved (normal) LV systolic function. A number of clinical settings are associated with diastolic dysfunction. Most causes of dia stolic dysfunction relate to impaired left ventricular diastolic relaxation. The most commo n underlying diseases are hyperten- sion and ischemia as a result of coronary artery diseas e. Other causes include aortic stenosis, hypertrophic cardiomyopathy, and in \201 ltrative (such as in cardiac amyloidosis) and restrictive cardiomyopathies. Pericardial restraint, such as in constrictive pericarditis and cardiac tam- ponade, impair s ventricular \201 lling. In addition, mitral valve stenosis causing left ventricular out \202 ow obstruction leads to elevated left atrial pressure and, in severe cases, cardiac failure that is solely due to impaired \201 lling. Pathophysiology Ventricular relaxation may be impaired. This is an energy-dependent pro- ce ss and is sensitive to hypoxia. Myocardial ischemia can induce diastolic dysfunction via th is mechanism. Ischemia may be caused, not only by epi- cardial coronary artery disease but possibly also by changes in the micro- vascular coronary supply. Increased compliance of the left ventricle leads to a stiff chamber and impaired \201 lli ng. There is evidence that this altered compliance is mediated by an increase in myocardial collagen. Most conditions causing left ventricular hypertrophy are associated with impairment of dias tolic function; however, in conditions where myocardial hypertrophy is not associated with \201 brosis, such as chronic anemia, hyper- thyroidism, and exercise training, diastolic stiffness is normal. Clinical assessment Clinical features of HF may be similar, regardless of whether LV systo- lic function is impaired or preserved. The clinical presentation should be considered alon g with assessment of systolic and diastolic function (see Table 5.13). Table 5.13 Assessment of diastolic heart failure Diagnostic criteria for diastolic HF Signs and symptoms of HF plus Possible diastolic HF LVEF >50% but not at the time of HF Probable diastolic HF LVEF >50% within 72 hr of HF event De \201 nite diastolic HF LVEF >50% within 72 hr of HF event, and Abnormal LV relaxation, \201 lling and/or distens ibility at cardiac catheterization or by non-invasive imaging Adapted with permission from Vasan RS, Levy D (2000). Circulation 101(17):2118. DIASTOLIC HEART FAILURE 243 Diagnosis A de \201 nitive diagnosis of diastolic heart failure can be made when the rate of relaxation of the LV in diastole is slowed. This physiological abnormality is characteri stically associated with the \201 nding of an elevated left ventricu- lar \201 lling pr essure in a patient with normal left ventricular volumes and contractility. Noninvasive methods (e.g., Doppler echocardiography) have been developed to assist in the d iagnosis of diastolic dysfunction, but these tests have signi \201 cant limitations, becau se cardiac \201 lling patterns are readily altered by nonspeci \201 c and transient chan ges in loading conditions in the heart as well as by aging, changes in heart rate, or the p resence of mitral regurgitation. Every effort should be made to exclude other possible explanations or disorders that may present in a similar manner (see Box 5.5). Principles of treatment Unlike LV systolic dysfunction, there is little evidence-based data on how to treat patients with presumed diastolic dysfunction. Causes of diasto- lic heart failure include ischemia, hypertension, and hypertrophy, which should be identi \201 ed an d treated accordingly. Current recommendations suggest the use of B-blockers, rate-slowing calcium channel antagon ists (verapamil or diltiazem), ACE inhibitors, and diuretics. Management of this group is d if \201 cult and should probably be tailored to the individual, with the following in mind : \200 Control of systolic and diastolic hypertension \200 Control of ventricular rate in patients with atrial \201 brillation \200 Diuretics to control pulmonary congestion and peripheral edema \200 Coronary revascularization in patients with coronary artery dis ease in whom symptomatic or demonstrable myocardial ischemia is judged to be having an adve rse effect on diastolic function Restoration of sinus rhythm in patients with atrial \201 brillation Box 5.5 Differential diagnoses with HF and preserved LV ejection fraction \200 \200 \200 \200 Incorrect diagnosis of HF Inaccurate measurement of LVEF Primary valvular disease Restricti ve (in \201 ltrative) cardiomyopathy (e.g., amyloidosis, sarcoidosis, hemochromatosis) Per icardial constriction Severe hypertension, ischemia High-output cardiac failure (anemia, th yrotoxicosis, AV \201 stulas) Chronic pulmonary disease with right HF Pulmonary hypertens ion Atrial myxoma \200 \200 \200 \200 \200 Reprinted with permission from the ACC/AHA Guidelines: Hunt et al. (2005). Circulation 112: e154 \200\223e235. 2005, American Heart Association, Inc. CHAPTER 5 Heart failure 244 High-output heart failure In high-output states, the only way that the oxygen demands of th e periph- eral tissues can be met is by an increase in cardiac output. If there is underlyi ng heart disease, the heart may be unable to chronically augment its output, and HF results . Causes of high-output states are listed in Box 5.5. Anemia When the Hb levels fall below 8 g/dL, the anemia produces a high cardiac output. How ever, even when severe, anemia rarely causes heart failure or angina in patients with norma l hearts. Look for an underlying cardiac prob- lem or valve disease. Try to determine the e tiology for the anemia. Patient should be on bed rest and transfused with packed red blood cells accompanied with IV diuretics. Systemic arteriovenous \201 stulas The increase in cardiac output depends on the size of the \201 stula. The Branham sign consists of slowing of the heart rate after manual compr es- sion of the \201 stula. It also raises arterial blood pressure. Surgical repair or ex cision is the ideal treatment. Pregnancy (see p. 421) Thyrotoxicosis Raised levels of thyroxine produce increased heart rate and cardiac con- tra ctility, reduction in systemic vascular resistance, and enhanced sympa- thetic activation. Thyrotoxicosis does not usually precipitate heart failure unless there is reduced cardiac r eserve. Atrial \201 brillation occurs in about 10% of patients, exacerbating the HF. Respiratory muscle weakness may contribute to the dyspnea. Beriberi Paget \200\231s disease There is a linear relationship between the extent of bone involveme nt and rise in cardiac output. Involvement of about 15% of the skeleton is required before the rise is seen, and patients may tolerate the early stages well for years. Concomitant valvular disease or ischemic heart disease results in decompensation. Successfu l treatment of Paget \200\231s disease with bisphospho- nates may reverse the rise in cardi ac output over several months. Box 5.5 Causes of high-output states \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Thyrotoxicosis Beriberi heart disease Paget \200\231s disease of the bone Fibrous dysplasia Polycythemia rubra vera Carcinoid syndrome Multiple myeloma Anemia Acquired arteriovenous \201 stula Hemangioma Hereditary hemorrhagic telangiectasia Hepatic hemangioendothelioma Pregnancy Acromegaly 245 Chapter 6 Preventive cardiology Background 246 Atherosclerosis: pathophysiology 247 Development of atherosclerotic plaques 249 Epidemiology 251 Assessment of atherosclerotic risk 252 Risk factors for coronary arter y disease 256 Hypertension 262 Treatment of high blood pressure 264 Combining antihypertens ive drugs 267 Lipid management in atherosclerosis 269 Lipid-lowering medications 272 Goals of lipid-lowering therapy 274 Diabetes and atherosclerosis 277 The metabolic syndrome 280 M etabolic syndrome: management 282 Aspirin for primary prevention 283 CHAPTER 6 Preventive cardiology 246 Background While great strides have been made over the past several decades in the manageme nt of symptomatic ischemic heart disease, with dramatic improvements in outcomes from acute coronary syndromes, the identi \201 - cation and modi \201 cation of atherosclerotic ris k factors has also contributed signi \201 cantly to overall public health. The \201 eld of preventive cardiology focuses on the management of car- diovascular disea se risk factors in order to prevent disease occurrence and reduce the incidence of subseque nt clinical events in those with estab- lished cardiovascular disease. Primary prevention i nvolves controlling risk in order to prevent disease, while secondary prevention strategies focus on early disease detection and interventions to limit progression of disease. In this chapter, the pathophysiology of atherosclerosis will be reviewed, which provides th e basis for understanding risk factors and how to man- age them. ATHEROSCLEROSIS: PATHOPHYSIOLOGY 247 Atherosclerosis: pathophysiology Atherosclerosis is a disease of the large and medium-sized arteries, char- acterized by a gradual buildup of fatty plaques within the arterial wall. This may eventually result in a signi \201 cant narrowing of the vessel lumen, impairing b lood \202 ow. These plaques may also become unstable and thrombose leading to an acute coronary syndrome. Pathophysiology The atherogenic process is characterized by dysfunction of the endothelial lining of the vessel, associated with in \202 ammation of the vascular wall. This leads to the buildup of lipids, in \202 ammatory cells, and cellular debris within the intima and subintimal layers of the vessel, resulting in plaque formation and remodeling of the arteri al wall. This process is complex, involving a series of interactions between endothelial and smooth muscle cells, leukocytes and platelets in the vas- cular wall. Endothelial dysfunction The atherosclerotic process appears to be triggered by endothelial cell injury from exposure to stimuli such as tobacco toxins, oxidized low-den- sity lipopro tein (LDL), advanced glycation end products, elevated homo- cysteine, or infectious agents. This initiates a cascade of events resulting in cellular dysfunction (see Fig. 6.1). The hallmark of endothelial dysfunction is a change in the balance of production of endothe lium-derived vasoactive molecules. There is a reduced bioavailability of endothelial nitric oxide (NO), which possesses important vasodilator, antithrombotic, and antiproliferative p roperties, in parallel with increased generation of the potent vasoconstrictor agents, endo thelin-1 and angiotensin-II, which also promote cell migration and growth. Dysfunctional en dothelial cells also express adhesion molecules and secrete chemokines promoting cell migra tion and adhesion. Levels of plasminogen activator inhibitor and tissue factor are increased, tissue plasminog en activator and thrombomodulin are reduced, and low NO release results in increased platel et activation and adhesion. CHAPTER 6 Preventive cardiology 248 Hyperlipidemia Smoking Diet Type 2 diabetes mellitus Genetic factors Cytokines/inflammation Hypertension Endothelial dysfunction and activation Reactive oxygen species Aging Expression of adhesion molecules and recruitment of circulating monocytes Decreased NO production Impaired fibrinolysis (dt-PA, dPAI-1) Platelet adhesion Atherosclerosis Plaque activation and rupture Thrombosis Acute coronary syndrome/CVA Figure 6.1 Endothelial dysfunction is the underlying process in atherosclerosis, from lesio n initiation, progression, through to acute cardiovascular events. Endothelial dysfunction is caused by a variety of genetic factors (and aging), as well as environmental factors tha t can be modi \201 ed. DEVELOPMENT OF ATHEROSCLEROTIC PLAQUES 249 Development of atherosclerotic plaques Endothelial dysfunction creates a local milieu that facilitates initiation and development of the atherosclerotic plaque (see Fig. 6.2). Circul ating leu- kocytes, predominantly monocytes, are attracted and bind to activated endothelia l cells and migrate into the subendothelial layer where they transform into macrophages. He re they act as local \200\234scavenger \200\235 cells tak- ing up modi \201 ed LDL choles terol, ultimately becoming the characteristic \200\234foam cells \200\235 of established a therosclerosis. The earliest lesions are known as fatty streaks, which consist predomi- nantly of lipids an d foam cells. These lesions may develop into \201 brous plaques, as a consequence of furt her lipid accumulation accompanied by local migration, proliferation, and \201 brous tran sformation of smooth mus- cle cells. These cells are responsible for the deposition of extr acellular connective tissue matrix, leading to formation of a \201 brous cap. This cap ov erlies a central core consisting of foam cells, extracellular lipid, necrotic cellular debr is, and a mixture of other in \202 ammatory cells, including T lymphocytes. This process is facilitated by ongoing endothelial dysfunction, together with local generat ion of powerful mitogens such as platelet-derived growth factor (PDGF), transforming growth factor B (TGF-B), and insulin- like growth factor (IGF) from endothelial cells, macrophage s, and activated platelets. Further growth of the plaque initially causes outward remodeling of the vessel wall, thus m inimizing the impact on the cross-sectional area of the lumen. However, progressive plaque accumulation results in luminal nar- rowing and ultimately vessel obstruction (see Fig. 6.2 ). Plaque initiation and progression tend to occur more predictably at certain locations of th e vascular system. Blood \202 ow through arteries causes local \200\234shear stress, \200\235 which in \202 uences the biology of the underlying endothelium. High laminar shea r (from blood \202 owing quickly through a straight vessel) favors the generation of NO, which helps maintain the functional integrity of the vessel. In contrast, low shear, or \200\234differential \200\235 shear, caused by turbulent \202 ow, results in dysfunction of the underlying endothelium, which facilitates ini- tiation a nd progression of atherosclerosis. This is a consequence of differ- ential gene activation pro \201 les in response to laminar (athero-protective), as opposed to turbulent (athero-i nducing), blood \202 ow, which may explain why plaques are more commonly found at sites o f vessel branching or curvature. These sites experience more dramatic and abrupt changes in blood \202 ow velocity. These shear stress \200\223mediated effects are most marked in the coronary, carotid, renal , and iliofemoral arteries, in which the majority of clinically important atherosclerotic l esions develop. The vulnerable plaque Erosion of the endothelial layer, or rupture of the overlying \201 brous cap, may expose the highly thrombogenic, lipid-rich core of the plaque to cir- culati ng blood. Collagen, tissue factor, and other factors activate platelets and trigger the coa gulation cascade, leading to acute thrombosis, which CHAPTER 6 Preventive cardiology 250 Normal Fatty streak Atheroma Ulcerated plaque/ rupture and occlusive thrombosis Smooth muscle Occlusive thrombus Endothelium Lumen restricted Lumen Lipid Ulceration/rupture with platelet thrombosis and aggregation Smooth muscle and collagen cap over lipid core Growth by lipid Time From 1st decade No symptoms From 4th decade Acute syndromes (ACS/MI, sudden death) From 3rd decade Angina Figure 6.2 Cellular interactions in the development and progression of atherosclerosis. VSM C, vascular smooth muscle cells. Reproduced with permission from Weissberg PL (2000). Heart 83(2):247 \200\223252. may rapidly occlude the vessel. Myocardial infarction (MI) can result, usu- ally characteri zed by ST-segment elevation. Coronary thrombosis is a dynamic process in vivo and may be reversed, at least in part, by activation of tissue plasminogen activator and proteins C and S of the intrinsic antithromb otic/ \201 brinolytic system. Acute, subto- tal occlusion of a coronary artery typically c auses acute non-ST-segment elevation MI (STEMI) or unstable angina. Atheromatous plaques that have a thin \201 brous cap and a large necrotic lipid core and containing a high proportion of in \202 ammatory cells and mediators are particularly pred isposed 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. Several studies have shown that well over half of all MIs are caused by acute destabilizati on of plaques that were previously not \202 ow limiting (i.e., <50% stenosis), 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. EPIDEMIOLOGY 251 Epidemiology Cardiovascular disease, including coronary disease, stroke, and peripheral art erial disease, is the leading cause of death in the United States, account- ing for more th an 900,000 deaths annually. At age 40, the lifetime risk of developing coronary disease is 49% for men and 32% for wome n. Although mortality rates have decreased by approximately 25% over the past 30 years, the rate of decline has slowed since 1990. Autopsy data have con \201 rmed a decreased prevalence of coronary atherosclerosis in both men and women since the late 1970s. A substantial component of this reduction is the modi \201 cation of risk factors, particularly decreased smoking and better hypertension treatm ent. A concerning trend in recent times is the rising prevalence of obesity and diabetes, partic ularly among younger people. This trend may explain the declining mortality rate reduction from cardiovascular disease. Approximately 14 million people in the United States have symptomatic coronary disease. Thi s number is likely an underestimation of the total population disease burden, as many patie nts are asymptomatic or have silent or clinically unrecognized manifestations of disease. Much of our understanding of cardiovascular disease risk factors is derived from large epid emiologic studies, including the Framingham Heart Study and the Nurses Health Study. As we will discuss, the important modi \201 able risk factors for cardiovascu- lar disease include smoking, diet, hypertension, dyslipidemias, physical inactiv- ity, obesity, and di abetes. It is important to recognize that many patients with cardiovascular disease have mu ltiple risk factors, each of which requires appropriate management for optimal risk reducti on. Atherosclerosis is a systemic disease Atherosclerosis in one vascular territory is often as sociated with disease elsewhere, as the risk factors for coronary disease, stroke, and peri pheral vascular disease are similar. It is important to recognize this association, as clin ically evident disease in one vascular bed may be a harbinger of silent, and potentially mo di \201 able, disease in another, particularly the coro- nary arterial system. Cardiac eve nts are the leading cause of mortality in patients with peripheral vascular disease. For this reason, cerebrovascular disease and peripheral vascular disease are considered cor onary disease equivalents. Appropriate preventive strategies and goals should be applied in these patients. CHAPTER 6 Preventive cardiology 252 Assessment of atherosclerotic risk Identi \201 cation and treatment of risk factors is ess ential for the prevention of atherosclerotic disease in individuals and society. When multi ple risk factors such as dyslipidemia, high blood pressure, and smoking coexist, as is comm only the case, the cardiovascular risk is greatly increased, suggest- ing a synergistic int eraction among these factors. For example, the absolute risk of a cardiovascular event occurring in a patient with high b lood pressure is greatly in \202 uenced by their age, sex, lipid pro \201 le, presence of diabetes and other factors. Thus, modern approaches to risk management should involve careful consideration of the comb ined impact of all important factors operating in the individual that contribute to their r isk of atherosclerotic disease. Global risk assessment Several risk assessment systems are currently available, derived fro m large, prospective population cohorts, most commonly the Framingham study (Tables 6.1, 6. 2). These systems allow the calculation of the \200\234absolute risk \200\235 of having a cardiovascular event (i.e., the probability of having a heart attack or stroke) within the next 10 years, which is derived from patients \200\231 risk factor variables (age, sex, cho lesterol, HDL, BP, smoking). Subjects with established coronary disease or stable angina have a 10-year event rate of ap proximately 20%. Therefore, subjects without clinical disease that have a predicted 10-year likelihood of suffering a car- diovascular event of (cid:116)20% are considered to be at h igh risk and are candi- dates for aggressive risk factor management. Although these conventional scoring systems have the potential to iden- tify most high-risk individuals in Western populations, a signi \201 cant propor- tion of events occur in sub jects calculated to be at intermediate and low risk. For example, risk is typically underes timated when using conventional methods in young subjects with multiple risk factors, subje cts with a family history of premature cardiovascular disease, and certain ethnic groups, i ncluding individuals of South Asian racial origin. Identi \201 cation of subjects with int ermediate (10% \200\22320%) conventional risk scores that are actually at high risk remains a major challenge, as these individuals are also likely to bene \201 t from aggressive pr eventive therapy. It has been proposed that measurement of C-reactive protein (CRP) levels, ultrasound assess ment of carotid artery intima-medial thickness, and coronary artery calcium scoring with CT scanning may improve risk assessment, especially in patients at intermediate risk based on traditional risk factor assessment. These techniques are highly promising and under intens e investigation, but their clinical utility and cost have not yet been con \201 rmed in la rge prospective clinical studies, and they are not currently used in routine clinical pract ice. However, in selected asymptomatic patients at intermediate risk based on traditional scorin g systems, the use of these techniques may be appro- priate if the results will alter the m anagement strategy by reclassifying a patient as low or high risk. Likewise, routine use of stress testing for coronary artery disease (CAD) screening in asymptomatic subjects is also not currently recommended. ASSESSMENT OF ATHEROSCLEROTIC RISK 253 Table 6.1 Framingham risk scoring system for men Age Diabetes Years Points Points 30 \200\22334 35 \200\22339 40 \200\22344 45 \200\22349 50 \200\22354 55 \200\22359 60 \200 \22364 65 \200\22369 70 \200\22374 \200\2231 0 1 2 3 4 5 6 7 No Yes 0 2 Smoker Points 0 2 No Yes LDL-C HDL-C mg/dL mmol/L Points mg/dL mmol/L Points <100 100 \200\223129 130 \200\223159 160 \200\223190 >190 <2.59 2.60 \200\2233.36 3.37 \200\2234.14 4.50 \200\2234.92 >4.92 \200\2233 0 0 1 2 <35 35 \200\22344 45 \200\22349 50 \200\22354 >60 <0.90 0.91 \200\2231.16 1.17 \200\2231.29 1.30 \200\2231.55 >1.56 2 1 0 0 \200\2231 Systolic blood pressure, mmHg <120 120 \200\223129 130 \200\223139 140 \200\223159 (cid:116 )160 Coronary heart disease (CHD) risk Diastolic <80 mmHg 0 0 1 2 3 Diastolic 80 \200\22384 mmHg 0 0 1 2 3 Diastolic 85 \200\22389 mmHg 1 1 1 2 3 Diastolic 90 \200\22399 mmHg 2 2 2 2 3 Diastolic \211 100 mmHg 3 3 3 3 3 Total points 10-year CHD risk (%) Total points 10-year CHD risk (%) < \200\2233 \200\2232 \200\2231 0 1 2 3 4 5 1 2 2 3 4 5 6 7 9 6 7 8 9 10 11 12 13 14 11 14 18 22 27 33 40 47 56 Use to calculate the risk of developing clinical coronary heart disease (CHD) in men who do not have known CHD. To calculate the Framingham risk estimate, add points for age, presenc e of diabetes, smoking status, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and blood pressure. Find the total point score on the bottom table to determine the 10-year risk of C HD. Reprinted with permission from Wilson PW, et al. (1998). Prediction of coronary heart d isease using risk factor categories. Circulation 97:1837 \200\2231847. CHAPTER 6 Preventive cardiology 254 Table 6.2 Framingham risk scoring system for women Age Diabetes Years Points Points 30 \200\22334 35 \200\22339 40 \200\22344 45 \200\22349 50 \200\22354 55 \200\22359 60 \200 \22364 65 \200\22369 70 \200\22374 \200\2239 \200\2234 0 3 6 7 8 8 8 No Yes 0 4 Smoker Points 0 2 No Yes LDL-C HDL-C mg/dL mmol/L Points mg/dL mmol/L Points <100 100 \200\223129 130 \200\223159 160 \200\223190 >190 <2.59 2.60 \200\2233.36 3.37 \200\2234.14 4.50 \200\2234.92 >4.92 \200\2232 0 0 2 2 <35 35 \200\22344 45 \200\22349 50 \200\22354 >60 <0.90 0.91 \200\2231.16 1.17 \200\2231.29 1.30 \200\2231.55 >1.56 5 2 1 0 \200\2232 Systolic blood pressure, mmHg Diastolic <80 mmHg Diastolic 80 \200\22384 mmHg Diastolic 85 \200\22389 mmHg Diastolic 90 \200\22399 mmHg Diastolic \211 100 mmHg \200\2233 <120 0 120 \200\223129 0 130 \200\223139 2 140 \200\223159 3 (cid:116)160 Corona ry heart disease (CHD) risk 0 0 0 2 3 0 0 0 2 3 2 2 2 2 3 3 3 3 3 3 Total points 10-year CHD risk (%) Total points 10-year CHD risk (%) < \200\2232 \200\2231 0 1 2 3 4 5 6 7 1 2 2 2 3 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 8 9 11 13 15 17 20 24 27 32 Use to calculate the risk of developing clinical coronary heart disease (CHD) in men who do not have known CHD. To calculate the Framingham risk estimate, add points for age, presenc e of diabetes, smoking status, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and blood pressure. Find the total point score on the bottom table to determine the 10-year risk of C HD. Reprinted with permission from Wilson PW, et al. (1998). Prediction of coronary heart d isease using risk factor categories. Circulation 97:1837 \200\2231847. ASSESSMENT OF ATHEROSCLEROTIC RISK 255 CAD risk equivalents Patients with atherosclerotic disease in other vascular territories, i ncluding peripheral arterial disease, abdominal aortic aneurysms, and carotid dis- ease, ar e at high risk (10-year risk >20%) and should be managed aggres- sively in terms of seconda ry prevention. Diabetic patients have a similar risk for cardiac events as those with established coronary disease and are therefore high risk (10-year risk >20%) as well. CHAPTER 6 Preventive cardiology 256 Risk factors for coronary artery disease Age The U.S. population is aging. In the United St ates, the proportion of the population aged (cid:116)65 years is projected to increase from 12.4% in 2000 to 19.6% in 2030. The number of persons aged (cid:116)65 years is expected t o increase from approximately 35 million in 2000 to an estimated 71 million in 2030, and th e number of persons aged (cid:116)80 years is expected to increase from 9.3 million in 2000 to 19.5 million in 2030. Aging is a major risk factor for atherosclerotic disease because of the degenerative proces s associated with aging and the cumulative impact of the worsening risk factor pro \201 le that develops with increasing age. For men, the reported prevalence increases with age, from 7% at ages 40 \200\22349 years to 13% at 50 \200\22359 years, 16% at 60 \200\22369 years, and 22% at 70 \200\22379 years. Th e corresponding estimates for women are substantially lower than for men: 5%, 8%, 11%, and 14%, respectively. Although about 45% of myocardial infarctions occur in people under 65 years of age, this co ndition is more likely to be fatal in older individuals, with 80% of deaths due to MI seen in those over 65. Gender, menopausal status, and hormone replacement therapy (HRT) CAD is more common and ten ds to occur at an earlier age in men than in women. The incidence of CHD in women increases rapidly at menopause and is similar to that seen in men in the population over 65. Althoug h less common, the disease remains the leading cause of death in women. For example, the ag e-adjusted mortality rates from heart disease are four to six times higher than their morta lity rates from breast cancer. Although cardiovascular risk factors promote disease in both genders, the strength of the a ssociation differs. For example, diabetes and low high- density lipoprotein (HDL) cholester ol are stronger risk factors for women than for men. Female sex hormones probably contribute to the lower risk of athero- sclerotic disease in p remenopausal women. Additionally, observational studies showed that the risk of ischemic he art disease is reduced by up to 40% in women using HRT. However, HRT users are typically he althier than nonusers, suggesting that these results could be explained by selec- tion bias . Several large, randomized, controlled trials of HRT in postmenopausal women (WHI, HERS/HERS II, ESPRIT, ERA) with and without atheroscle- rosis have suggested that HRT does not reduc e the risk of cardiovascular events and, in fact, leads to a small but statistically signi \201 cant increase in morbidity and mortality from cardiovascular disease. The age at entr y into these trials has recently brought the broad implications of these data into question . However, HRT should not be recommended for primary or secondary prevention of atherosclerotic disease in postmenopausal women. RISK FACTORS FOR CORONARY ARTERY DISEASE 257 Family history of atherosclerotic disease CAD is a multifactorial, polygenic disorder, caus ed by interactions among lifestyle, the environment, and the effects of variations in the g enetic sequence of a number of genes (see Table 6.3 and Box 6.1). The family history is con sidered signi \201 cant when atherosclerotic disease presents in a \201 rst-degree male relative before the age of 55, or before age 65 in a female relative. A positive family history is associated with a 75% increase in risk in men, and an 84% incr ease in women. The risk is even greater if both parents are affected. In the Physician \200\231s Health Study, compared to no parental history of an MI, a matern al history, a paternal history, and both maternal and paternal history were associated with a relative risk of cardiovascular disease of 1.71, 1.40, and 1.85 in men and 1.46, 1.15, a nd 2.05 in women. In the Framingham Offspring Study, cardiovascular disease in a sibling was associated with a signi \201 cant increase in cardiovascular disease risk with an adjusted odds ratio of 1 .45. Table 6.3 Risk factors for coronary heart disease Nonmodi \201 able risk factors \200 \200 \200 \200 Modi \201 able risk factors \200 \200 \200 \200 \200 \200 \200 \200 Age Male gender Family history Ethnic origin Smoking High blood pressure Dyslipidemia Diabetes mellitus Obesity and the metabolic syndro me Psychological stress High-calorie high-fat diet Physical inactivity Box 6.1 Emerging risk factors and disease markers \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 