6 weeks + gentamicin for \201 rst 2 weeks + rifampicin 600 mg bd PO for 6 weeks. Meticillin-resistant staphylococci \200\224 NVE: IV vancomycin for 4 \200\2236 weeks 9 gen tamicin for 1st week. PVE: vancomycin + rifampicin for 6 weeks + gentamicin for 2 weeks. Enterococcus species \200 As for streptococcus with moderate penicillin resistance (above ). HACEK species \200 NVE: IV cephalosporin (e.g. ceftriaxone) for 4 weeks, or 6 weeks fo r PVE. ANTIBIOTICS IN ENDOCARDITIS 195 Coxiella burnetii (Q fever) \200 NVE and PVE: requires prolonged (3 \200\2234 years) ther apy with tetracycline (e.g. doxycycline) and second agent (co-trimoxazole, rifampicin, quinolone) with careful mo nitoring of immunoglobulin G (IgG) titres. Usually requires surgery. Empirical therapy \200 Infective endocarditis is usually a clinical diagnosis and must be considered in any patient with a typical history, fever, and a murmur with no other explana tion. Often antibiotics need to be started before the culture results are available. Be gui ded by the clinical setting (see Table 4 .1 1 ). Table 4.1 Presentation of endocarditis Presentation Choice of antibiotic Gradual onset (weeks) Benzylpenicillin + gentamicin Acute onset (days) or history of skin trauma Flucloxacillin + gentamicin Vancomycin (or teicoplanin) + gentamicin + rifampicin Recent valve prosthesis (possible meticillin-resistant S. aureus (MRSA), diphtheroid, Klebs iella , corynebacterium, or nosocomial staphylococci) IV drug user Vancomycin Suggested antibiotic doses Benzylpenicillin Flucloxacillin Vancomycin Gentamicin Rifampicin Cipro \202 oxacin 4 MU (2.4 g) q4h IV 2 g qds IV 15 mg/kg q12h IV over 60 min, guided by levels 3 mg/kg divid ed in 1 \200\2233 doses guided by levels 300 mg q12h po 400mg q12h IV for 1 week, then 750 mg q12h PO for 3 weeks IV antibiotics should be given via a tunneled CVP (central venous pressure (Hickman)) line. Antibiotic therapy may be modi \201 ed for sensitivities. \200 Suggested antibiotic comb inations are shown above; however, individual units may have speci \201 c policies; individual patients should be discussed w ith your local microbiologist. 1 Oakley CM (1995). The medical treatment of culture-negative infective endocarditis. Eur H eart J 16(suppl B): 90 \200\2233. 196 CHAPTER 4 Infective endocarditis Stopping endocarditis treatment Duration of treatment \200 Controversial \200\224 a tren d toward shorter courses. Microbiology and ID opinion is important, especially in resistant and/or uncommon organisms. The box below shows one suggested protocol. The duration of treatment varies depending on the severity of infection and the infecting o rganism. IV therapy is usually for at least 2 weeks, and total antibiotic therapy for 4 \200\2236 weeks. If the patient is well following this period, antibiotic treatment may be stopped. Provided no surgery is indicated (see b Surgery for endocarditis, p. 202), the patient may be disch arged and followed up in outpatient clinic. Patients should be advised of the need for endocarditis prophylaxis in the future (see b Endocarditis prophylaxis. p. 206). Patients with valvular damage following infection should be followed long term, and patient s with ventricular septal defects should be considered for closure. Viridans streptococci and Streptococcus bovis (penicillin sensitive) Benzylpenicillin only (4 weeks) Vancomycin or teicoplanin (4 weeks) Penicillin + aminoglyco side (2 weeks) Ceftriaxone 2 g (4 weeks) Group B, C, G streptococci, Strep. pyogenes , Strep. pneumoniae Penicillin (4 weeks) + aminoglycoside (2 weeks) Vancomycin (4 weeks) + aminoglycoside (2 we eks) Group A streptococci Penicillin (4 weeks) Vancomycin (4 weeks) Enterococci Penicillin + aminoglycoside (4 \200\2236 weeks) Vancomycin + aminoglycoside (4 \200\2236wee ks) \200 Extracardiac infection from septic emboli Penicillin (4 weeks) + aminoglycoside (2 weeks) Vancomycin (4 weeks) + aminoglycoside (2 we eks) Staphylococcus aureus and coagulase-negative staphylococci Left-sided endocarditis: Flucloxacillin (4 \200\2236 weeks) + aminoglycoside (2 weeks) If MRSA \200\224 vancomycin + rifampicin (6 weeks) aminoglycoside (2 weeks) Right-sided endocarditis: Flucloxacillin (2 weeks) + aminoglycoside (2 weeks) Cipro \202 oxacin (4 weeks) + rifampic in (3 weeks) If MRSA \200\224 vancomycin (4 weeks) + rifampicin (4 weeks) Fungi Amphotericin B IV to a total dose of 2.5 \200\2233 g STOPPING ENDOCARDITIS TREATMENT 197 Monitoring treatment Patients need careful clinical monitoring both during and for several months after the infection. Reappearance of features suggestive of IE must be investigated thoroughly to rule out recurrent infection or resistance to the treatment regime. Clinical features of progressive endocarditis \200 Signs of continued infection, persiste nt pyrexia, and the persistence of systemic symptoms Persistent fever may be due to drug resistance, concomitant infection (central line, urine, chest, septic emboli to lungs or abdomen), or allergy (?eosinophilia, ?leucopenia, ?proteinuria: common with penicillin but may be due to any antibiotic \200\224 consider changing or stopping antibiotics for 2 \200\2233 days) \200 Changes in any cardiac murmurs or signs of cardiac failure \200 The development of any new embolic phenomena \200 Inspect venous access s ites daily. Change peripheral cannulae every 3 \200\2234 days. Echocardiography \200 Regular (weekly) transthoracic echocardiograms may identify clinica lly silent, but progressive, valve destruction and development of intracardiac abscesses or veg etations. The tips of longstanding central lines may develop sterile \201 brinous \200\230fronds \200\231, which may be visible on TOE: change the line and send the tip for culture. \200\230Vegetations \200\231 need not be due to infection (see b Causes of \200\230vegetations \200\231 on ECHO, Culture-negative endocarditis, p. 199). ECG \200 Look speci \201 cally for AV block or conduction abnormalities suggesting intracardiac extension of the infection. A daily ECG must be performed. Microbiology \200 Repeated blood cultures (especially if there is continued fever) \200 Regular aminoglycoside and vancomycin levels (ensuring the absence of toxic levels and the presence of therapeutic levels). Gentamicin ototoxicity may develop wi th prolonged use even in the absence of toxic levels Back titration to ensure that minimum inhibitory and bactericidal concentrations are being achieved. Laboratory indices \200 Regular (daily) urinalysis \200 Regular U&Es and LFTs \200 Re gular CRP (ESR every 2 weeks) \200 FBC \200\224 rising hemoglobin (Hb) and falling white cell count (WCC) suggests successful treatment; watch for beta-lactam-associated neutropen ia Serum magnesium (if on gentamicin). 198 CHAPTER 4 Infective endocarditis Culture-negative endocarditis \200 The commonest reason for persistently negative blood c ultures is prior antibiotic therapy and affects up to 15 % of patients with diagnosis of IE . If the clinical response to the antibiotics is good, these should be continued. For a persisting fever: withhold antibiotics if not already started \200 consider other investigations for a \200\230PUO \200\231 (pyrexia of unknown origin) if there the clinical suspicion of IE is high, it warrants further investigation repeated physical examination for any new signs \200 regular ECHO and TOE. \200\230Veget ations \200\231 need not be due to infection (see b p.199) repeated blood cultures, especially when the temperature is raised. Discuss with microbiology about prolonged culturing times (4 + weeks) and special c ulturing and subculturing techniques. Most HACEK group organisms can be detected Consider unusual causes of endocarditis: Q-fever (Coxiella burnetii) : complement \201 xation tests identify antibodies to phase 1 and 2 antigens. Phase 2 antigens are raised in the acute illness; pha se 1 antigens are raised in chronic illnesses such as endocarditis. Polymerase chain reacti on (PCR) can be performed on operative specimens. Treat with inde \201 nite (lifelong) ora l doxycycline co-trimoxazole, rifampicin, or quinolone \200 Chlamydia psittaci : commo nly there is a history of exposure to birds and there may be an associated atypical pneumonia. Diagnosis is con \201 rmed using complement \201 xation tests to detect raised antibody titres brucellosis : blood cultures may be positive, though organisms may take up to 8 weeks to grow. Serology usually con \201 rms the diagnosis fungi : Candida is the most common species and may be cultured. The detection of antibodies may be helpful, though levels may be raised in normal individuals. The detection of a risi ng titre is of more use. Other fungal infections (e.g. histoplasmosis, aspergillosis) are r are, but may be diagnosed with culture or serology, though these are commonly negative. Ant igen assays may be positive, or the organism may be isolated from biopsy material. Fungal I E is more common in patients with prosthetic valves, and IV drug users. Bulky vegetations a re common. Treatment is with amphotericin B \202 ucytosine. Prosthetic valves must be removed. Mortality is > 50 % . CULTURE-NEGATIVE ENDOCARDITIS 199 Causes of culture-negative endocarditis \200 Previous antibiotic therapy \200 Fastidiou s organism: nutritionally de \201 cient variants of Strep. viridans Brucella, Neisseria, Legionella, Nocardia Mycobacteria \200 The HACEK group of oropharyngeal \202 ora \200 Cell-wall-de \201 c ient bacteria and anaerobes Cell-dependent organism: Chlamydia , rickettsiae ( Coxiella ) Fungi Causes of \200\230vegetations \200\231 on ECHO \200 Infective endocarditis \200 Steril e thrombotic vegetations: Libman-Sacks endocarditis (SLE) \200 primary anti-phospholipid syndrome \200 marantic e ndocarditis (adenocarcinoma) Myxomatous degeneration of valve (commonly mitral) \200 Ruptured mitral chordae \200 Ex uberant rheumatic vegetations (Black Africans) \200 Thrombus ( \200\230pannus \200\231) o n a prosthetic valve \200 A stitch or residual calcium after valve replacement SLE = systemic lupus erythematosus. 200 CHAPTER 4 Infective endocarditis Prosthetic valve endocarditis Key facts \200 Devastating complication \200\224 frequentl y needs reoperative surgery \200 Conventionally divided into early (<2 months postoperati vely) and late ( > 2 months postoperatively). Early prosthetic valve endocarditis Incidence <1 % Causes: Most commonly due to staphylococci, Gram-negative bacilli, diphtheroids, or fungi. Generally infection has begun either preoperatively or in the immediate postoperative perio d Risks: Prior endocarditis, prolonged hospital stay Clinical features: Often a highly destructive, fulminant infection with parav- alvular leak , valve dehiscence, abscess formation, and rapid haemodynamic deterioration Treatment: Discuss with the surgeons early. Patients commonly require reoperation. Mortalit y is high (45 \200\22375 % ) Late prosthetic valve endocarditis Causes: The pathogenesis is different \200\224 two mech anisms: \200 abnormal \202 ow around the prosthetic valve ring produces micro thrombi and non-bacterial thrombotic vegetations (NBTV), which may be infected during trans ient bacteraemia. The source is commonly dental or urological sepsis, or from indwelling ve nous lines early infection with indolent organism (e.g. Strep. epidemidis ) that takes several months to manifest clinically. Common organisms are coagulase-negative staphylococci, Staph. aureus, Strep. viridans , or enterococci. Risks: Invasive procedures, dental sepsis \200\224 as for primary endocarditi s. Treatment: Frequently needs surgical intervention and this carries a high mortality, but le ss than for early PVE. It may be possible to sterilize infections on bioprostheses with IV anti- biotics only. Sur gery (see b Surgery for endocarditis, p. 202) may then be deferred. PROSTHETIC VALVE ENDOCARDITIS 201 Fig. 4.1 Mobile vegetation (V) attached to the lea \202 et (L) of a prosthetic aortic valv e in a man with infective endocarditis. Reproduced with permission from Tuna I \207, Harris on MR (2001). Images in clinical medicine. N Engl J Med 344 (4): 275. 202 CHAPTER 4 Infective endocarditis Surgery for endocarditis Discuss early with the regional cardiothoracic center: immediate i ntervention may be appropriate. \200 Surgical intervention may be necessary, either durin g active infection or later because of the degree of valve destruction. Optimal timing depe nds on a number of factors: \200 haemodynamic tolerance of the lesion \200 outcome of t he infection \200 presence of complications. The choice of antimicrobial therapy should be modi \201 ed depending on microbiological re sults from intraoperative specimens. Samples should be sent for culture, staining, immunolo gical testing, and PCR, depending on the suspected organism. The duration of antimicrobial treatment is dependent on the clinical picture: \200 culture-negative operative specimens: 2 \200\2233 weeks for valve infection and 3 \200\2234 weeks for abscess. culture-positive operative specimens: 3 \200\2234 weeks for valve infection and 4 \200\2236 weeks for abscess. Timing is dictated by the clinical picture. American College of Cardiology/American Heart Association (ACC/AHA) indications for surgery are listed in Table 4.2. In patients with neurological injury, surgery should be delayed to avoid intracranial hemorrhage if cardiac function permits (embolic infarct \200\224 delay 10 \200\22314 days , hemorrhage 21 \200\22328 days and when ruptured mycotic aneurysms have been repaired). Timing of surgery (see Table 4.2) \200 If the patient is haemodynamically stable, surgery may be delayed until after the antibiotic course is completed. The \201 nal management depends on the va lve affected, the degree of destruction, and its effect on ventricular function. Severe aor tic and mitral regurgitation usually require surgery; tricuspid regurgitation, if well tole rated, is managed medically. Decompensation (severe congestive cardiac failure or low cardiac output syndrome with functional renal failure) may respond to surgery, but the mortality is high. \200\230Metastable \200\231 patients who have been successfully treated after an episode o f acute decompensation should be considered for early operation after 2 \200\2233 weeks \200\231 antibiotic therapy. The onset of complications listed opposite is an indication for early surgery Outcome of infection \200 Persistence or relapse of infection (clinical and laboratory in dices) despite appropriate antibiotics at an adequate dose may be due either to a resistant organi sm or to an abscess (paravalvular, extracardiac). Consider valve replacement if no extracar diac focus is found. The organism may in \202 uence the decision: consider early surgery for fungal endocarditis or prosthetic endocarditis with E. coli or S. aureus. SURGERY FOR ENDOCARDITIS 203 The presence of complications \200 High-degree AV block \200 Perforation of interventri cular septum \200 Rupture of sinus of Valsalva aneurysm into right ventricle (RV) \200 Intracardiac abscess \200 Prosthetic endocarditis, especially associated with an unstable prosthesis Surgical options \200 The presence of annular abscess makes surgery technically more challenging. Mitral and tricuspid endocarditis: competent valve repair (rater than replacement) is the b est solution, minimizing prosthetic material, maximizing freedom from reoperation. It may b e technically challenging. Aortic valve: annular abscess may require root replacement \200 Additional risk of operat ive mortality associated with endocarditis is 2 \200\2235 % , with signi \201 cant additio nal risk if the patient presents in cardiogenic shock or after prolonged hospital stay. 204 CHAPTER 4 Infective endocarditis Table 4.2 Indications and timing of surgery in left-sided native valve infective endocardit is Timing a Recommendations: Indications for surgery A. Heart failure Emergency Aortic or mitral IE with severe acute regurgitation or valve obstruction causing refractory pulmonary oedema or cardiogenic shock Emergency Aortic or mitral IE with \201 stula into a cardiac chamber or pericardium causing refract ory pulmonary oedema or shock Urgent Aortic or mitral IE with severe acute regurgitation or valve obstruction and persisting hea rt failure or echocardiographic signs of poor haemodynamic tolerance (early mitral closure or pulmonary hypertension) Aortic or mitral IE with severe regurgitation and no HF Elective B. Uncontrolled infection Locally uncontrolled infection (abscess, false aneurysm, \201 stula, enlarging vegetation ) Urgent Persisting fever and positive blood cultures > 7 \200\22310 days Urgent Infection caused by fungi or multiresistant organisms Urgent/elective C. Prevention of embolism Urgent Aortic or mitral IE with large vegetations ( > 10 mm) following one or more embolic episode s despite appropriate antibiotic therapy Urgent Aortic or mitral IE with large vegetations ( > 10 mm) and other predictors of complicated c ourse (heart failure, persistent infection, abscess) Isolated very large vegetations ( > 15mm) b Urgent a Emergency surgery: surgery performed within 24 h, urgent surgery: within a few days, elec tive surgery: after at least 1 or 2 weeks of antibiotic therapy. b Surgery may be preferred if a procedure preserving the native valve is feasible. Reproduced from Guidelines on the Prevention, Diagnosis, and Treatment of Infective Endocar ditis (new version 2009). The Task Force on the Prevention, Diagnosis, and Treatment of Inf ective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J 30 : 2369 \200 \223413. Y http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/ g uidelines-IE-FT.pdf This page intentionally left blank 206 CHAPTER 4 Infective endocarditis Endocarditis prophylaxis Key facts \200 ACC/AHA guidelines on endocarditis prophylaxis we re updated in 2008 to re \202 ect consensus opinion that routine antibiotic prophylaxis is not indicated in the majority of what were previously considered at-risk patients for procedures such as dental work, endoscopy, etc. Although reducing antibiotic use might provide important population bene \201 t in the form of reducing evolution-resistant species, in view of the risk:ben \201 t ratio at the individual level, many clinicians continue to prescribe prophylaxis acc ording to earlier guidelines (see Tables 4.3 and 4.4 ) b Presentation of endocarditis, Table 4.1, p. 195 shows cardiac conditions at risk of IE. High and moderate risk requires prophylaxis; \200\230low \200 \231 risk does not. The regimen may be modi \201 ed, depending on the \200\230degree of risk \200\231 (both patient and procedure related) as shown in the box below. Table 4.3 Recommendations for prophylaxis of infective endocarditis in highest-risk patient s according to the type of procedure at risk Recommendations: prophylaxis A. Dental procedures: Antibiotic prophylaxis should only be considered for dental procedures requiring manipulati on of the gingival or periapical region of the teeth or perforation of the oral mucosa Antibiotic prophylaxis is not recommended for local anesthetic injections in non-infected t issue, removal of sutures, dental X-rays, placement or adjustment of removable prosthodonti c or orthodontic appliances or braces. Prophylaxis is also not recommended following the sh edding of deciduous teeth or trauma to the lips and oral mucosa B. Respiratory tract procedures a : Antibiotic prophylaxis is not recommended for respiratory tract procedures, including bronc hoscopy or laryngoscopy, transnasal or endotracheal intubation C. Gastrointestional or urogenital procedures a : Antibiotic prophylaxis is not recommended for gastroscopy, colonoscopy, cystoscopy, or tran soesophageal echocardiography D. Skin and soft tissue a : Antibiotic prophylaxis is not recommended for any procedure a For management when infections are present, please refer to the text. Reproduced from Guidelines on the prevention, diagnosis, and treatment of infective endocar ditis (new version 2009). The Task Force on the Prevention, Diagnosis, and Treatment of Inf ective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J 30 : 2369 \200 \223413. Y http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/ g uidelines-IE-FT.pdf ENDOCARDITIS PROPHYLAXIS 207 Table 4.4 Antibiotic prophylaxis Minimal regimen 1 h before 6 h after No penicillin allergy Amoxicillin 3 g PO No 2nd dose Allergy to penicillin Clindamycin 300 \200\223600 mg PO No 2nd dose Flexible modi \201 cations depending on the \200\230degree of risk \200\231 Additional doses after procedure \200 Additional aminoglycosides \200 Parenteral admini stration Maximal regimen 1 h before 6 h after Amoxicillin 2 g IV 1 \200\2231.5 g PO + No penicillin allergy Gentamicin 1.5 mg/kg IM/IV No 2nd dose Vancomycin 1 g IV over 1 h 1 g IV at 12 h + Allergy to penicillin Gentamicin 1.5 mg/kg IM/IV No 2nd dose 208 CHAPTER 4 Infective endocarditis Outpatient review Be very wary about discharging patients from routine follow-up. General considerations Valvular heart disease tends to worsen with time. Consequently, long - term follow up is the norm rather than the exception. Very minor lesions (e.g. mild mitra l, aortic, or tricuspid regurgitation) with no symptoms are relatively benign and do not ne ed regular review. Symptoms review Has there been any progression since last review (NB : can be insidious and patients often don \200\231t notice \200\224 ask about speci \201 c activities and wheth er they can still do them as well as before). Are there any new symptoms (particularly ches t pain, dyspnoea, palpitations, syncope)? Are there any symptoms to suggest endocarditis (f evers, weight loss, malaise, joint, or back pains)? When did they last visit the dentist an d are they aware of need for prophylaxis? Ask about medications (what are they on, have the re been any additions or dose changes? If so, why?). Review antico- agulation and antiplate let therapy: is there an indication, is compliance adequate? Examination Look for peripheral stigmata of endocarditis (see b Chapter 5), record the rate and character of pulse and blood pressure (BP). Assess jugular venous pressure (JVP) and a pex beat and then auscultate precordium and remember to listen to lung bases and to check f or pedal oedema. Investigation Always review current ECG, TTE ( CXR) and compare with previous results to look for progression of condition. Consider hemoglobin/hae- matocrit and lactate dehydroge nase in patients with a prosthetic valve. Speci \201 c conditions With all conditions, patients should be advised to seek earlier re view if symptoms change in the intervening period. Mitral stenosis: If mild with no symptoms, can be reviewed every 2 years. Moderate to sever e (or with symptoms) should be seen at least annually. Mitral regurgitation (MR): Patients with asymptomatic mild MR can be reassured and discharg ed. Moderate to severe MR or with symptoms should be seen at least annually. If LV dimensio ns start to enlarge or ejection fraction (EF) declines, consider referral for surgery. Aortic stenosis (AS): Asymptomatic patients with mild AS should be seen every 2 \200\2233 y ears. Anything greater than moderate AS or with symptoms should be seen annually. Mild AS: ECHO every 3 \200\2235 years; moderate AS: ECHO every 1 \200\2232 years. In severe AS or pa tients with moderate AS and symptoms, work-up for aortic valve replacement (AVR) should be commenced. OUTPATIENT REVIEW 209 Aortic regurgitation (AR): Asymptomatic patients with mild AR can be reassured and discharg ed. Patients with symptoms or moderate AR should be seen at least annually. If LV starts to dilate or severe AR, refer for consideration of AVR. Prosthetic valves: See annually. After > 8 years, review patients with bioprostheses every 6 months (iincidence of valve failure). If new valvular dysfunction is detected, then inves tigate promptly (often requiring admission), as this can dramatically worsen very rapidly. Once regurgitation is detected, close follow-up with 2D and Doppler echocardiography every 3 to 6 months is indicated. This page intentionally left blank 211 Chapter 5 Coronary artery disease Atherosclerosis: STEMI: complications 276 Ventricular septal defect pathophysiology 212 post-MI 278 Development of Acute mitral regurgitation atherosclerotic plaques 214 post-MI 280 Epidemiology 216 Assessment of Pseudoaneurysm and atherosclerotic risk 218 free-wall rupture 281 Cocaine-induced MI 282 Ventricular tachyarrhythmias Risk factors for coronary artery disease 220 Hypertension 226 Treatment of high blood post-MI 284 Atrial tachyarrhythmias pressure 228 post-MI 284 Combining antihypertensive Bradyarrhythmias and drugs 230 indications for pacing 285 Bradyarrhythmias post-MI 285 Hypotension and shock Lipid management in atherosclerosis 232 Lipid-lowering therapy 236 When to treat lipids 238 Diabetes and post-MI 286 Cardiogenic shock 288 Non-ST elevation myocardial atherosclerosis 240 The metabolic syndrome infarction (NSTEMI)/ unstable angina (UA) 290 NSTEMI/UA: diagnosis 292 NSTEMI/UA: risk and insulin resistance 244 Metabolic syndrome: management 248 Angina pectoris 250 Acute coronary strati \201 cation 294 NSTEMI/UA: late risk strati \201 cation 296 NSTEMI/UA: medical man agement 298 syndromes 254 ST elevation myocardial infarction (STEMI) 256 NSTEMI/UA: invasive versus non-invasive strategies 301 STEMI: diagnosis 258 STEMI: general measures 262 STEMI: reperfusion therapy (thrombolysis) 264 STEMI: reperfusion by primary PCI 268 NSTEMI/UA: discharge and secondary prevention 301 Genetics of coronary artery disease: introduction 302 Monogenic causes of coronary Surgery for acute STEMI 269 STEMI: additional measures 270 Right ventricular infarction 272 artery disease 304 Genes conferring increased risk of coronary artery disease (polygenic CAD) 306 STEMI: predischarge risk strati \201 cation 274 Genetic testing for coronary artery disease 307 212 CHAPTER 5 Coronary artery disease Atherosclerosis: pathophysiology Atherosclerosis is a disease of the large and medium-sized arteries. The term atherosclerosis is derived from Latin and means gruel-like ( \200\230at hero \200\231) hardening ( \200\230sclerosis \200\231) of the arteries. The disease is char acter- ized by a gradual build up of fatty plaques within the arterial wall, which eventual ly results in a signi \201 cant reduction of the vessel lumen, impairing blood \202 ow t o the distal tissues. These plaques may also cause acute coronary syndromes by becoming uns table and triggering coronary thrombosis. Pathophysiology The atherogenic process is characterized by: \200 dysfunction of the endo thelial lining of the vessel \200 in \202 ammation of the vascular wall \200 build up of lipids, cholesterol, and in \202 ammatory cells in the vessel wall \200 accumulation of cellular debris within the intima and subintimal layers of the vessel. These processes result in plaque formation, and remodeling of the arte- rial wall. The unde rlying mechanisms are uncertain, but the most widely accepted theory is the \200\230respon se-to-injury \200\231 hypothesis de \201 ned by Ross in the 1970s. Endothelial dysfunction The initiating trigger of this disease process appears to be injury of arterial endothelial cells from exposure to stimuli including: \200 tobacco toxins \200 oxidized low-density lipoprotein (LDL) \200 advanced glycation end-products \200 elevated homocysteine \200 infectious agents. Endothelial cell injury initiates a cascade of events resulting in cellular dysfunction (see Fig. 5.1 ). The hallmark of endothelial d ysfunction is a change in the balance of production of endothelium-derived vasoactive molec ules: \200 reduced bioavailability of endothelial nitric oxide (NO), an important vasodilator, anti-thrombotic, and antiproliferative agent increased generation of potent vasoconstrictor agents endothelin-1 and angiotensin-II, promoting cell migration and growth dysfunctional endothelial cells express adhesion molecules and secrete chemokines, promoting cell migration and adhesion local thrombotic balance is altered as levels of plasminogen activator inhibitor (PAI) and tissue factor are increased tissue plasminogen activator (t-PA) and thrombomodulin are reduced \200 low NO release re sults in increased platelet activation and adhesion. ATHEROSCLEROSIS: PATHOPHYSIOLOGY 213 Hypolipidaemia Smoking Diet Type 2 diabetes mellitus Genetic factors Cytokines/inflammation Hypertension Endothelial dysfunction and activation Reactive oxygen species Aging Expression of adhesion molecules and recurrence of circulatory monocytes Decreased NO production Platelet adhesion Impaired fibrinolysis ( \206\223t-PA, \206\223PAI-1) Atherosclerosis Plaque activation and rupture Thrombosis Acute coronary syndrome/CVA Fig. 5.1 Endothelial dysfunction is the underlying process in atherosclerosis, from lesion initiation and progression, through to acute cardiovascular events. Endothelial dysfunction is caused by a variety of genetic factors (and aging), as well as environmental factors th at can be modi \201 ed. CVA = cerebrovascular accident. 214 CHAPTER 5 Coronary artery disease Development of atherosclerotic plaques Endothelial dysfunction creates a local milieu, whic h facilitates the initiation and development of the atherogenic process (see Fig. 5.2). \200 Circulating leucocytes, predominantly monocytes, are attracted and bind to activated endothelial cells, followed by migration into the subendothelial layer, where they transfor m into macrophages. They act as local \200\230scavenger \200\231 cells with the capacity to take up modi \201 ed LDL cholesterol (LDL-C), ultimately becoming the characteristic \200\230foam cells \200\231 of established atherosclerosis. The earliest lesions are known as \200\230fatty streaks \200\231, which consist predominantly of lipid-accumulating macrophages and foam cells. \200 These lesions may de velop into \201 brous plaques, as a consequence of further lipid accumulation accompanied by local migration, proliferation, and \201 brous transformation of smooth muscle cells. These cells are responsible for the deposition of extracellular connective tissue matrix, leading to formation of a \201 brous cap, which overlies a cent ral core, consisting of foam cells, extracellular lipid, necrotic cellular debris, and a mi xture 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-beta (TGF-B), and insulin-like growth factor (IGF) from endothelial cells, macropha ges, and activated platelets. Further growth of the plaque initially causes outward remodeling of the vessel wall, minimizing the impact on the cross-sectional area of the lumen and the ves sel \200\231s ability to deliver blood. Progressive plaque accumulation results in luminal narrowing, and ultimately vessel obstruction. Lesion initiation and progression tends to occur more predictably at certain locations of t he vascular system. \200 Blood \202 ow through arteries causes local generation of \202 uid \200\230shear- stress \200\231, which in \202 uences the biology of the underlying endothelial cells. High laminar shear (from blood \202 owing quickly through a straight vessel) favors the g eneration of NO, which helps maintain the functional integrity of the vessel. In contrast, low shear, or \200\230differential \200\231 shear caused by turbulent \202 ow, causes dysfunction of the underlying endothelial cells, which facilitates initiation an d progression of atheroma. This helps explain why plaques are found more commonly at sites of vessel branching or curv ature, which experience more dramatic and abrupt changes and irregularities of direction an d velocity of blood \202 ow. These shear-stress-mediated effects are most marked in vessels that carry a high (basal) bl ood \202 ow, such as the coronary, carotid, renal, and ilio-femoral arteries, in which th e majority of clinically important atherosclerotic lesions develop. DEVELOPMENT OF ATHEROSCLEROTIC PLAQUES 215 Normal Fatty streak Atheroma Ulcerated plaque/ rupture and occlusive thrombosis smooth muscle Occlusive thrombus Endothelium Lumen restricted Lumen Lipid Smooth muscle and collagen cap over lipid core Ulceration/rupture with platelet and thrombosis aggregation Growth by lipid Time From 4th decade Acute syndromes (ACS/MI, sudden death) From 3rd decade Angina From 1st decade No symptoms Fig. 5.2 Cellular interactions in the development and progression of atherosclerosis. VSMC, vascular smooth muscle cells. ACS = acute coronary syndrome; MI = myocardial infarction. R eproduced with permission from Weissberg PL (2003). Atherogenesis: current understanding of the causes of atheroma. Heart 83 : 247 \200\22352. 216 CHAPTER 5 Coronary artery disease Epidemiology Cardiovascular disease is the most common cause of death in the UK, responsibl e for 238 000 deaths in 2002 or 39 % of all deaths. Coronary artery disease (CAD) results i n over 117 000 deaths a year in the UK. Advances in prevention and treatment of this diseas e have led to a fall in the death rate since the late 1970s, but the UK incidence of CAD re mains amongst the highest in the world. The cost of health care alone is estimated at over 1.7 billion a year, and the total economic cost is far greater. Regional variation There is considerable variation in mortality from CAD across the UK. Dea th rates are higher in Scotland than the South of England, in manual workers than in non-ma nual workers, and in certain ethnic groups. There are several important risk factors that a re associated with CAD and other atherosclerotic disease (see b Risk factors for coronary a rtery disease, p. 220), which together account for the majority of the CAD burden in the UK . Although identi \201 cation and treatment of individuals with these risk factors has the potential to reduce signi \201 cantly the burden of CAD, the incidence of and death rate from MI remain high. The vulnerable plaque Erosion or denudation of the endothelial layer, or rupture of the ove rlying \201 brous cap of the plaque may expose the highly thrombogenic lipid-rich core of the plaque to circulating blood. \200 Collagen, tissue factor, and other factors activat e platelets and trigger the coagulation cascade. This leads to acute thrombosis, which may rapidly occlude the vessel. \200 This results i n MI of this vascular territory, usually characterized by ST-segment elevation on the electrocardiogram (ECG). Coronary thrombosis is a dynamic process in vivo , and may be reversed, at least in part, by activation of t-PA and proteins C and S of the intrinsic ant ithrombotic/ \201 brinolytic system. Acute, subtotal occlusion of the vessel typically causes acute symptomatic deterioration and non-ST-segment elevation MI (NSTEMI) or unstable angina. Atheromatous plaques that have a thin \201 brous cap and a large necrotic lipid core, and contain a high proportion of in \202 ammatory cells and mediators, and are particularly p redisposed to destabilization or rupture, with consequent thrombosis. Conversely, plaques with a smaller lipid pool, thicker \201 brous caps, and less in \202 ammatory activity are more stable and less prone to rupture. \200 Several studies have s hown that well over half of all MIs are caused by acute destabilization of plaques that wer e previously not obstructing \202 ow in the vessel, suggesting that the likelihood of an acute coronary event is more closely related to the stability of the plaque rather than the severity of the stenosis. This page intentionally left blank 218 CHAPTER 5 Coronary artery disease Assessment of atherosclerotic risk Identi \201 cation and treatment of risk factors is ess ential for the prevention of atherosclerotic disease in both individuals and society. When multiple risk factors such as dyslipidaemia, high blood pressure, and smoking co-exist, the cardiovascular risk is greatly increased, suggesting a synergistic interaction between the se factors. Global risk assessment Risk-assessment scoring systems are derived from large prospective p op- ulation cohorts, most commonly the Framingham study. These systems allow calculation of the \200\230absolute risk \200\231 of having a cardiovascular event (i.e. the probability of having a heart attack or stroke) within the next 10 years. Current UK practice recommen ds use of the Joint British Societies risk-assessment tables (see Fig. 5.3) or a computer p rogram. Other commonly used methods include: \200 the Framingham risk-scoring system \200 the Shef \201 eld tables \200 the European SCORE charts. Subjects with stable angi na have a 10-year event rate of approximately 20 % ; therefore, subjects without clinical d isease that have a predicted 10-year likelihood of suffering a cardiovascular event of (cid :2)20 % are con- sidered to be at \200\230high risk \200\231 and are candidates for aggres sive risk-factor management. Individuals with low-intermediate risk \200\224 scoring systems typically underes- timate the true risk in: \200 young subjects with multiple risk factors \200 subjects with a f amily history of premature cardiovascular disease \200 certain ethnic groups including in dividuals of South Asian racial origin living in the UK. Identi \201 cation of subjects with intermediate (10 \200\22320 % ) conventional risk scor es that are actually at \200\230high \200\231 risk remains a major challenge, as these ind ividuals are also likely to bene \201 t from preventive therapy. Adjunctive risk-assessment techniques may improve risk-assessment accuracy but are not curr ently used in routine clinical practice: \200 C-reactive protein (CRP) levels \200 ultr asound assessment of carotid arterial intima \200\223media thickness \200 detection of co ronary artery calci \201 cation with computed tomography (CT) scanning. Calculation of risk is unnecessary in subjects who already have clinical atherosclerotic disease, as secondary prevention measures are mandatory in these individual s. Similarly, risk calculation is not required for subjects with diabetes mellitus, whose risk approaches that of subjects with established atherosclerosis. ASSESSMENT OF ATHEROSCLEROTIC RISK 219 Fig. 5.3 Reproduced with permission from 2004 Joint British Societies Risk Prediction Table s. The University of Manchester. CVD = cardiovascular disease. 220 CHAPTER 5 Coronary artery disease Risk factors for coronary artery disease Age The UK population is aging: \200 between 197 1 and 2002, the percentage of older people (aged 65 years and over) in the UK, increased fr om 13 % to 16 % , and is projected to rise to 23 % in the next 25 years aging is a major risk factor for atherosclerotic disease, due to the degenerative process associated with aging per se , together with the cumulative impact of the worsening risk-factor pro \201 le that develops with increasing age