RV infarction on ECG is seen in the setting of inferior MI and ST elevation in right-sided chest leads (V 3R \200\223V 4R ). Management \200 In either case, cardiac output will be improved by cautious plasma expansion. Give 100 \200\223200 mL of colloid over 10 minutes and reassess. \200 Repeat o nce if there is some improvement in blood pressure and the patient has not developed pulmonary oedema. Invasive haemodynamic monitoring with a PA catheter (Swan \200\223Ganz) is necessary to ens ure hypotension is not due to low left-sided \201 lling pressures. Aim to keep PCWP 12 \200\22315 mmHg. Start inotropes if BP remains low despite adequate \201 lling pressures. \200 Use IV ni trates and diuretics with caution, as venodilatation will compromise RV and LV \201 lling and exacerbate hypotension. See b p.272 for management of RV infarction. This page intentionally left blank 288 CHAPTER 5 Coronary artery disease Cardiogenic shock \200 Affects 5 \200\22320 % of patients, and up to 15 % of MI patients can present with cardiogenic shock. Management involves a complex interaction between many medical, surgical, and intensive car e teams, with multiple invasive and non- invasive measures. Despite signi \201 cant advanc es, prognosis remains poor. Therefore, the absolute wishes of the patient with regard to such an invasive strategy should be respected from the onset. Diagnosis A combination of clinical and physiological measures: \200 clinical: marked, pe rsistent ( > 30 min) hypotension with SBP<80 \200\22390 mmHg \200 physiological: low card iac index (<1.8 L/mm/m 2 ) with elevated LV \201 lling pressure (PCWP > 18 mmHg). Management \200 Complex and must be quick. \200 Correct reversible factors, including: arrhythmias and aim to restore sinus rhythm \200 acid \200\223base and electrolyte abnorm alities \200 ventilation abnormalities \200\224 intubate if necessary Rapid haemodynamic, echocardiographic, and angiographic evaluation: \200 haemodynamic: to ensure adequate monitoring and access, including central venous lines, Swan \200\223Ganz, arterial line insertion, urinary catheter echocardiographic: to assess ventricular systolic function and exclude mechanical lesions, which may need to dealed with, emergency cardiac surgery including mitr al regurgitation (NB: tall v waves on PCWP trace), VSD, and ventricular aneurysm/psuedoanue rysm. angiographic: with a view to PCI or CABG if appropriate \200 Aim to improve haemodynamic status achieving a SBP (cid:2) 90 mmHg guided by physical signs and LV \201 lling pressures. As a general guide: \200 PCWP<15 mmHg \200\224 cautious of IV \202 uids (colloids) in 100 \200\223200 mL aliquots PCWP > 15 mmHg \200\224 inotropic support diuretics (if pulmonary oedema). Inotropes should be avoided if at all possible in acutely ischaemic patients. The aim should be to rapidly restore/maximize coronary \202 ow and of \202 oad LV. Early revascularization is vital and has been shown to decrease mortality. IABP will p artially help achieve the aforementioned goals. If haemodynamic status does not improve post revascularization and IABP insertion, inotrope s should be used. The choice of agent can be dif \201 cult and should partly be guided by local protocols and expertise. Generally accepted choices depend on the clinical picture an d include: \200 if patient is hypotensive ( pulmonary oedema) \200\224 start with dopamine (up to 15 mcg/kg/min) and if ineffective substitute to adrenaline (epinephrine) an d/or noradrenaline (norepinephrine) CARDIOGENIC SHOCK 289 if the patient has adequate blood pressure ( pulmonary oedema) \200\224 dobutamine to increase cardiac output (starting at 2.5 \200\2235 mcg/kg/m in and increasing to 20 mcg/kg/min) titrating to HR and haemodynamics. Phosphodiesterase in hibitors can be used as an alternative. If hypotension and tachycardia complicate dobutamin e/ PDI inhibitor treatment, (nor)adrenaline can be added as a second agent to achieve desir ed haemodynamic effect. Use of diuretics, thrombolysis, GPIIb/IIIa antagonists, LMWH/UFH should follow normal princ iples, and is based on the clinical picture. 290 CHAPTER 5 Coronary artery disease Non-ST elevation myocardial infarction (NSTEMI)/unstable angina (UA) UA and NSTEMI are clos ely related conditions with similar clinical presen- tation, treatment, and pathogenesis bu t of varying severity. If there is bio- chemical evidence of myocardial damage, the conditi on is termed NSTEMI and, in the absence of damage, UA. Unlike patients with a STEMI, where diagnosis is generally made on presentation in the emer gency department, diagnosis of NSTEMI/UA may not be de \201 nitive on presentation and evo lves over the subsequent hours to days. Therefore, management of patients with NSTEMI/UA is a progression through a number of risk-strati \201 cation processes dependent on history, clinical features, and investigative results, which in turn determine the choice and timin g of a number of medical and/or invasive treatment strategies. Fig. 5.16 is a summary of a recommended integrated care pathway illustrating a management p lan for diagnosis and risk-directed treatment of a patient with STEMI/UA. Clinical presentation There are three distinct presentations: \200 rest angina (angina wh en the patient is at rest) \200 new-onset severe angina \200 increasing angina (previou sly diagnosed angina which has become more frequent, longer in duration, or lower in threshold). General examination (as indicated for all ACS (see b Acute coronary syndromes, p. 254)) mus t beundertaken, in particular to rule out pulmo- nary oedema, and assess haemodynamic stabi lity, cardiac valve abnormali- ties, and diaphoresis. Integrated management plan We recommend that all patients follow a local integrated care pa thway on presentation. The various stages are broadly outlined below. See relevant pages fo r further information. Initial stabilization (see also b Acute coronary syndromes, p. 254): \200 transfer the pa tient to an area with continuous ECG monitoring and de \201 brillator facility strict bed rest. \200 give oxygen, aspirin 300 mg PO, SL nitrate, and mild sedation if required if pain persists give diamorphine 2.5 \200\2235 mg IV prn with metoclopramide 10 mg IV. General investigations : similar to STEMI patients (see b STEMI: diagnosis, p. 258) includi ng blood for FBC, biochemical pro \201 le, and markers of myocardial injury, lipid pro \201 le as well as CRP and thyroid function tests (TFTs) (if persistent tachycardia). Arran ge portable CXR (rule out LVF, mediastinal abnormalities). NSTEMI/UA 291 Con \201 rm diagnosis (see b NSTEMI/UA: diagnosis, p. 292). \200 Risk strati \201 catio n (see b NSTEMI/UA: risk strati \201 cation, p. 294) in order to determine appropriate med ical and invasive treatment strategies. High-risk patients should be admitted to CCU and lo w/ intermediate patients to monitored beds in step-down unit. Treatment is based on the patient \200\231s risk and includes: medical : \200\224 anti-ischaemic (see b NSTEMI/UA: medical management, p. 298) \200\224 antiplatelet (see b NSTEMI/UA: medical management, p. 298) \200\224 antithrombot ic (see b NSTEMI/UA: medical management, p. 298) invasive strategies (see b NSTEMI: invasive vs. non-invasive strategies, p. 301) Secondary prevention and discharge Symptoms suggestive of ACS Non-cardiac diagnosis Chronic stable angina NSTEMI/UA STEMI Admit ASA, clopidogrel, LMWH (UFH), GTN infusion, -blocker, statin Admit to CCU Reperfusion therapy Early risk stratification in emergency room see b Table 5.7, p. 295 Low risk Intermediate risk High risk Admit monitored bed. On-going symptoms? Admit to CCU IIb/IIIa inhibitors Early invasive strategy No late risk stratification Yes Treat as high risk Inpatient angiography High risk Low risk Outpatient angiography Fig. 5.16 NSTEMI/UA \200\224 integrated care pathway. Reproduced with permission from Ramr akha P, Moore K, and Sam A (2010). Oxford Handbook of Acute Medicine . 3rd edn. Oxford: Oxf ord University Press. 292 CHAPTER 5 Coronary artery disease NSTEMI/UA: diagnosis Diagnosis in NSTEMI/UA is an evolving process and may not be clear on presentation. A combination of history, serial changes in ECG, and biochemical markers of m yocardial injury (usually over a 24 \200\22348 hour period) determine the diagnosis. Once a patient has been designated a diagnosis of ACS with probable/possible NSTEMI/UA (see b Non -ST elevation myocardial infarction (NSTEMI)/unstable angina (UA), p. 290), they will requi re: \200 serial ECGs \200\224 changes can be transient and/or \201 xed, especially if a diagnosis of NSTEMI is made. See b STEMI: diagnosis, p. 258 for localization of ischaemic areas. \200 ST-segment depression of (cid:2) 0.05 mV is highly speci \201 c for myocard ial ischaemia (unless isolated in V 1 \200\223V 3 , suggesting a posterior STEMI). \200 T-wave inversion is sensitive but non-speci \201 c for acute ischaemia unless very deep ( (cid:2) 0.3 mV). rarely, Q waves may evolve or there may be transient/new LBBB. serial biochemical markers of cardiac injury are used to differentiate between NSTEMI and U A, as well as determine prognosis. We recommend levels at 6, 12, 24, and 48 hours after the last episode of pain. A positive biochemical marker (CK, CK-MB, or troponin) in the contex t of one or more of the aforementioned ECG changes is diagnostic of NSTEMI. If serial marke rs over a 24 \200\22372-hour period from the last episode of chest pain remain negative, UA is diagnosed: \200 cardiac troponin T and I \200\224 both are highly cardiac speci \201 c and sensitive, can detect \200\230microinfarction \200\231 in the presence of normal CK-MB, ar e not affected by skeletal muscle injury, and convey prognostic information (worse prognosi s if positive). Troponins can be raised in non-atherosclerotic myocardial damage (cardiomyo pathy, myocarditis, pericarditis) and should therefore be interpreted in the context of the clinical picture. Both TnT and TnI rise within 3 hours of infarction. TnT may persist upto 10 \200\22314 days and TnI up to 7 \200\22310 days. Results must be interpreted with cauti on in patients with chronic renal failure. See Fig. 5.16 b Non-ST elevation myocardial infa rction (NSTEMI)/unstable angina (UA), p. 290 CK \200\224 levels do not always reach the diagnostic twice upper limit of normal and generally have little value in diagnosis of NSTEMI \200 CK-MB \200\224 has lo w sensitivity and speci \201 city; CK-MB isoforms improve sensitivity (CK-MB2 > 1 U/L or CK-MB2/CK-MB1 ratio > 1.5), but isoform assays are n ot widely available clinically myoglobin \200\224 is non-cardiac speci \201 c, but levels can be detected as early as 2 hours after onset of symptoms. A negative test is useful in ruling out myocardia l necrosis. continuous ECG monitoring can detect episodes of silent ischaemia and arrhythmia. Both have been shown to be more prolonged with NSTEMI than in UA. This page intentionally left blank 294 CHAPTER 5 Coronary artery disease NSTEMI/UA: risk strati \201 cation \200 NSTEMI/UA are a heterogeneous group of condition s with variable outcome. An assessment of risk for adverse outcome is vital to ensure formation of an adequ ate management plan. Risk strati \201 cation should begin on initial evaluation and continue throughout the hospital stay. At each stage, patients with a high chance of a poor outcome should be identi \201 ed and managed appropriately. We recommend at least two formal risk-strati \201 cation processes. Early risk strati \201 cation (Table 5.7 ) This should take place on presentation and form s part of the initial assessment used to make a diagnosis. It involves a combination of cli n- ical features, ECG changes, and biochemical markers of cardiac injury as demonstrated on b Non-ST elevation myocardial infarction (NSTEMI)/ unstable angina (UA), p. 290. Patients are divided into high risk and inter- mediate/low risk. \200 High-risk patients should be admitted to CCU, follow an early invasive strategy, and be managed with a combination of: \200 ASA, clopidogrel, LMWH (UFH), GP IIb /IIIa receptor inhibitors \200 anti-ischaemic therapy ( \201 rst line B-blocker, GTN) \200 early invasive strategy (inpatient catheterization and PCI within 48 hours of admission). Intermediate/low-risk patients should be admitted to a monitored bed on a step-down unit an d undergo a second inpatient risk strati \201 cation once their symptoms have settled, to determine the timing of invasive investigations. Initial management should include: \200 ASA, clopidogrel, LMWH (UFH). \200 anti-ischaemic therapy ( \201 rst line B-blocker, GTN ). \200 undergoing a late risk strati \201 cation in 48 \200\22372 hours from admission. Late risk strati \201 cation (see b NSTEMI/UA: late risk strati \201 cation, p. 296) Thi s involves a number of non-invasive tests to determine the optimal timing for invasive inve stigations in intermediate/low-risk patients. It is generally performed if there have been no further episodes of pain/ ischaemia at 24 \200\22348 hours after admission. \200 Inter mediate/low-risk patients who develop recurrent pain and/or ischaemic ECG changes at any po int during their admission, heart failure, or haemodynamic instability in the absence of a non-cardiac cause should be managed as a high-risk patient (GPIb/IIIa inhibitor and early i nvasive strategy). Table 5.7 is a summary of a recommended integrated care pathway combining diagnosis, risk strati \201 cation, and treatment. There are other risk-strati \201 cation assessment scores including Braunwald and TIMI. As recommended above, high-risk patients from these assessments should also follow an early invasive strategy, and intermediate/low-risk patients a more conservat ive strategy. Table. 5.7 Short-term risk of death non-fatal MI in patients with UA Feature High risk (at least 1 of the following features must be present) Intermediate risk (no high-risk feature but must have 1 of the following) Low risk (no high- or intermediate-risk feature) but may have any of the following features ) History Accelerating tempo of ischaemic symptoms in preceding 48 hours Prior MI, peripheral or cerebrovascular disease or CABG, prior aspirin use Character of pain Prolonged ongoing ( > 20 minutes) rest pain Prolonged ( > 20 minutes) rest angina now resolved, with moderate or high likelihood of CAD New-onset or progressive CCS class III or IV angina in the past 2 weeks without prolonged ( > 20 minutes) rest pain but with moderate or high likelihood of CAD Rest angina (<20 minutes) or relieved with rest or sublingual GTN N S T E M Age > 70 years Clinical \201 ndings Pulmonary oedema, most likely due to ischaemia New or worsening MR murmur S 3 or new/ worsening rales; hypotension, bradycardia, tachycard ia I / U A : R Age > 75 years I S K ECG Angina at rest with transient ST-segment changes > 0.05 mV T-wave inversions > 0.2 mV Normal or unchanged ECG during an episode of chest discomfort S T R A T Pathological Q waves Bundle-branch block, new or presumed new I F I C A T O N Sustained ventricular tachycardia Cardiac markers Elevated (e.g. TnT or Tnl > 0.1 ng/mL) Slightly elevated (e.g. TnT > 0.01 but <0.1 ng/mL Normal I Adapted from American College of Cardiology Practice Guidelines. 2 9 5 296 CHAPTER 5 Coronary artery disease NSTEMI/UA: late risk strati \201 cation \200 The highest risk of adverse outcome in pati ents who are designated as intermediate/low risk on presentation is during the early phase of admission. Therefore, it is important that the second risk-strati \201 cation process o ccurs within 24 \200\22348 hours of admission if the patient is stable. Late risk strati \201 cation is based on one of the following non-invasive investigations. A patient is regarded as being at high risk of adverse outcome if they ful \201 l one of t he features listed below. These patients should have inpatient cardiac catheterization. Exercise ECG test \200 Horizontal/down-sloping ST depression with: \200 onset at HR<120 bpm or <6.5 METS \200 magnitude of > 2.0 mm \200 post-exercise duration of changes > 6 min \200 depression in multiple leads re \202 ecting multiple coronary distributions Abnormal systolic BP response: sustained decrease of > 10 mmHg or \202 at BP response with abnormal ECG \200 Other: exercise induced ST-segment elevation \200 VT \200 Prolonged elevation of HR Stress radionuclide myocardial perfusion imaging \200 Abnormal tracer distribution in mor e than one territory \200 Cardiac enlargement LV imaging \200 Stress echocardiography: rest EF <35 % \200 wall motion score index of > 1 \200 Stress radionuclide ventriculogr aphy: rest EF <35 % \200 fall in EF > 10 % This page intentionally left blank 298 CHAPTER 5 Coronary artery disease NSTEMI/UA: medical management Anti-ischaemic therapy All patients should be treated with a combination of the below agents to ensure adequate symptom control and a favorable haemodyn amic status (SBP 100 \200\223110 mmHg, pulse rate 860). All patients should be treated with adequate analgesia, IV nitrates, B-blockers, and statins (if no contraindica- tions). Othe r agents can also be added depending on the clinical picture. \200 Analgesia : diamorphin e 2.5 \200\2235 mg IV (with metoclopramide 10 mg IV). Acts as an anxiolytic and reduces pai n and systolic blood pressure through venodilatation and reduction in sympathetic arteriola r constriction. Can result in hypotension (responsive to volume therapy) and respiratory de pression (reversal with naloxone 400 mcg to 2 mg IV). Nitrates : GTN infusion (50 mg in 50 mL 1 M saline at 1 \200\22310 mL/h) titrated to pain and keeping SBP > 100 mmHg. Tolerance to continuous infusion develops with in 24 hours, and the lowest ef \201 cacious dose should be used. Common side-effects are h eadache and hypotension, both of which are reversible on withdrawal of medication. Absolute contraindication is use of sildena \201 l (Viagra ) in the previous 24 hours. This can result in exaggerated and prolonged hypotension. B-blockers : should be started on presentation. Initially use a short-acting agent (e.g. me toprolol 12.5 \200\223100 mg PO tds), which, if tolerated, may be converted to a longer-act ing agent (e.g. atenolol 25 \200\223100 mg od). Rapid B-blockade may be achieved using shor t-acting IV agents such as metoprolol. Aim for HR of 750 \200\22360 bpm. \200 Mild LVF is not an absolute contraindication to B-blocker therapy. Pulmonary congestion may be seconda ry to ischaemic LV systolic dysfunction and/or reduced compliance. If there is overt heart failure, B-blockade is contraindicated and a calcium antagonist (amlodipine 5 \200\22310 mg od) can be used. By reducing heart rate and blood pressure, B-blockers reduce myocardial o xygen demand and thus angina. When either is used alone or in combination with nitrates and /or calcium antagonists, B-blockers are effective in reducing the frequency and duration of both symptomatic and silent ischaemic episodes. Calcium antagonists : diltiazem 60 \200\223360 mg PO, verapamil 40 \200\223120 mg PO tds). Aim to reduce HR and BP; these drugs are a useful adjunct to the three treatments above. Am lodipine/felodipine 5 \200\22310 mg PO od can be used with pulmonary oedema and in poor LV function. Calcium antagonists alone do not appear to reduce mortality or risk of MI in pati ents with UA. However, when combined with nitrates and/ or B-blockers, they are effective i n reducing symptomatic and silent ischaemic episodes, non-fatal MI, and need for revascular ization. \200 Statins (HMG-CoA reductase inhibitors) : high-dose statins (atorvastatin 80 mg od) have been shown to reduce mortality and recurrent MI NSTEMI/UA: MEDICAL MANAGEMENT 299 in the acute setting. The role of statins in primary and secondary prevention of cardiovasc ular events is well documented. ACE-Is : unlike patients with STEMI, where early introduction of an ACE-I has signi \201 cant prognostic bene \201 ts, speci \201 c trials in the NSTEMI/ UA setting are lacking. However, there is good evidence that patients with both low and high risk of cardiovascular disease will bene \201 t from long-term ACE inhibition (HOPE (Heart Outcomes Prevention Evaluation) and EUROPA (European Trial on Reduction of cardiac Events with Perindopril in Stable Coronary Artery Disease) trials). Antiplatelet therapy All patients should be given aspirin and clopidogrel (unless there are contraindications) \200\224 GPIb/IIIa antagonists to high-risk patients only. \200 Aspi rin : (75 \200\223300 mg PO) should be administered immediately in the emergency department and continued inde \201 nitely (unless there are contraindications). It has been shown to consistently reduce mortality and recurrent ischaemic events in many trials. In patients w ith aspirin hypersensitivity or major GI intolerance, clopidogrel 75 mg od should be used. Thienopyridines : clopidogrel (75 mg od) should be given on admission to all patients with proven NSTEMI/UA, regardless of risk, and continued for at least 1 mon th and ideally for 9 months. Clopidogrel should be withheld for 5 \200\2237 days in patient s requiring CABG, to reduce haemorrhagic complications. Clopidogrel is preferred over ticlo pidine because of its rapid onset of action and better safety pro \201 le. \200 Glycopro tein IIb/IIIa antagonists : there are multiple short- and long- acting commercially availab le molecules. These agents should be used in conjunction with aspirin, clopidogrel, and LMW H (or UFH). Epti \201 batide and tiro \201 ban should be used in high-risk patients with ongoing ischaemia and elevated troponin in whom an early invasive management strategy is no t planned/available (<24 hours). In patients with an early invasive strategy, all GPIIb/III a antagonists can be used. Infusion is generally continued for 12 hours post-PCI. Taken as a group, these agents protect NSTEMI/UA patients from death and non-fatal MI during the acu te phase of their presentation and 24 hours post intervention. See box on b p.300 for doses and administration regime. Antithrombotic therapy All patients should be given a LMWH (UFH). \200 Low molecular weig ht heparins (LMWH) have been shown to be as good as, or superior to, UFH in short-term redu ction of death, MI, and revascularization in patients with NSTEMI/UA. They should be used i n conjunction with aspirin and clopidogrel in all patients on presentation and continued fo r 2 \200\2235 days after the last episode of pain and ischaemic ECG changes. Other advantag es over UFH include subcutaneous administration, lack of monitoring, reduced resistance, an d thrombocytopenia. The box on b p.300 lists the doses of various agents in use for NSTEMI/ UA. 300 CHAPTER 5 Coronary artery disease Unfractionated heparin (UFH): multiple trials have demonstrated reduction of risk of death and MI in patients with UA/NSTEMI. UFH should be started on pres entation as an alternative to LMWH in conjunction with aspirin and clopidogrel. Infusion sh ould be continued for 2 \200\2235 days subsequent to the last episode of pain and/or ischae mic ECG changes. An initial bolus of 60 \200\22370 U/kg (maximum 5000 U) should be followed by an infusion of 12 \200\22315 U/kg/h (81000 U/h). The infusion rate should be altered to achieve an aPTT value of 1.5 \200\2232.0 times control. Coagulation should be checked init ially every 6 hours, followed by once every 24 hours after two consistent values have been obtained. Thrombolysis There is no evidence to suggest that combing thrombolytic agents with aspirin, LMWH and conventional anti-ischaemic therapy is of bene \201 t. In the TIMI IIIB trial, t he rt-PA group had a worse outcome at 6 weeks, and the risk of bleeding was also greater wi th the thrombolyis group. Doses of LMWH IIb/IIIa antagonists licensed for NSTEMI/UA \200 LMWH Dalteparin : 120 U/kg bd (max 10 000 U twice daily) \200 Enoxaparin : 1 mg/kg bd (100 U/k g twice daily) GPIIb/IIIa antagonists Abciximab (ReoPro ) \200\224 bolus 250 mcg/kg over 1 minute followed by IV infusion 125 ng/kg/min Tiro \201 ban (Aggrastat ) \200\224 400 ng/kg/min for 30 minutes followed by IV infusion 100 ng/kg/min Epti \201 batide ( Integrilin ) \200\224 bolus 180 mcg/kg followed by IV infusion 2 mcg/kg/min NSTEMI/UA: DISCHARGE AND SECONDARY PREVENTION 301 NSTEMI/UA: invasive versus non- invasive strategies The current evidence supports early ang iography and revascularization in patients who present with either high-risk features or in termediate/ low-risk features with ongoing symptoms. Furthermore, low- and inter- mediate-r isk patients who settle on medical therapy should undergo symp- tom-limited non-invasive st ress testing to identify a cohort of patients with an increased risk of adverse outcome. Th is second group will also bene \201 t from an early invasive management. Patients managed with an early conservative strategy tend to have an increased need for ant i-anginal therapy and rehospitalization for angina, and many undergo coronary angiography w ithin a year. The following groups are recommended to bene \201 t from an early invasive strategy (inpatient cardiac catheterization and PCI): \200 patients with high-ri sk features of NSTEMI/UA: recurrent angina/ischaemic ECG changes despite optimal medical therapy elevated troponin \200 new/presumed new ST-segment depression \200 chest pain with clin ical features of heart failure (pulmonary oedema, new/worsening MR, S 3 gallop) haemodynamic instability \200 sustained VT poor LV systolic function (EF <40 % ) \200 patients allocated to low/medium risk in whom subsequent non- invasive testing demonstrates high-risk features PCI in the previous 6 months \200 previous CABG \200 patients with other co-morbidities (e.g. malignancy, liver failure, renal disease), in whom the risks of revascularization are not likely to outweigh the bene \201 ts. NSTEMI/UA: discharge and secondary prevention \200 The length of hospital stay will be de termined by symptoms and the rate of progression through the NSTEMI/UA pathway. Generally, patients are hospitalized for 3 \200\2237 days. Secondary prevention remains of paramount importance and is similar in principle to STEMI patients. 302 CHAPTER 5 Coronary artery disease Genetics of coronary artery disease: introduction A number of studies (e.g. Framingham) hav e established family history as an independent risk factor for coronary artery disease (CAD ). Approximately 50 % of susceptibility to CAD is believed to be genetic; a Swedish twin st udy showed 57 % and 38 % hereditability of fatal coronary events in males and females respe ctively. 1 In addition, premature CAD is known to show greater hereditability than that occ urring later in life. The majority of cases of CAD result from complex interactions between genetic and environ- mental risk factors, with only a relatively small proportion secondar y to well-de \201 ned monogenic disorders. 1 Zdravkovik S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, De Faire U. (2002). Heredit ability of death from coronary heart disease: a 36 year follow-up of 20,966 Swedish twins. J Intern Med 252 : 247 \200\22354. This page intentionally left blank 304 CHAPTER 5 Coronary artery disease Monogenic causes of coronary artery disease These are rare diseases characterized by Mendel ian inheritance (see Table 5.8 for examples). The most commonly identi \201 ed monogenic c ause for CAD is familial hypercholesterolaemia (FH), an autosomal co-dominant condi- tion t hat is present in 5 \200\22310 % of patients who develop CAD before the age of 55 years. FH is caused by mutations affecting the LDL receptor, apolipoprotein B, and PCSK9 (proprotein convertase subtilisin/kexin type 9); these mutations cause elevated plasma LDL-C and accel erated atherosclerosis, with subsequent premature CAD. Homozygotes (fre- quency 1:1 000 000 ) have no functional LDL receptors and suffer very premature CAD; the majority will die bef ore the age of 30 years, in the absence of treatment. The population prevalence of heterozy gous FH is estimated at 1:500, but may be much higher in some populations (e.g. Afrikaners and French Canadians), secondary to \200\230founder \200\231 effects. Many of those affect ed by FH remain undiagnosed. Guidelines for the diagnosis and management of FH were published by the National Institute for Health and Clinical Excellence (NICE) in 2008. 1 A clinical diagnosis of FH should be s uspected in adults who have markedly elevated total cholesterol ( > 7.5 mmol/L), particular ly if there is a positive family or personal history of premature CAD. Clinical diagnosis o f de \201 nite or possible FH should be based on the Simon Broome criteria, as outlined op posite; patients diagnosed with FH should be referred to a specialist lipid clinic for DNA testing and cascade testing of relatives. Those diagnosed with homozygous FH, or with sympt oms and/or signs of CAD should be referred urgently to a cardiologist. First-line treatment is with statins, aiming for a (cid:2) 50 % reduction in LDL-C, although dual treatment wit h a statin and ezetimibe may be required to meet this target. Fibrates, bile acid sequestra nts, and nicotinic acid may be initiated by a specialist in FH if initial treatment is cont raindicated, is not tolerated, or is ineffective. 1 NICE (2008). Clinical Guidelines and Evidence Review for Familial Hypercholesterolaemia: the identi \201 cation and management of adults and children with familial hypercholestero laemia . London: National Collaborating Center for Primary Care and Royal College of Genera l Practitioners. MONOGENIC CAUSES OF CORONARY ARTERY DISEASE 305 Table 5.8 Examples of monogenic disorders causing coronary artery disease Condition Genes Clinical effects Familial hypercholesterolaemia LDLR , PCSK9 , APO-B Raised plasma total and LDL cholesterol, tendon xanthomata Sitosterolaemia ABCG5 , ABCG8 Raised plasma phytosterols, tendon xanthomata, haemolysis Tangier disease ABCA1 Reduced plasma HDL cholesterol, enlarged yellow tonsils, hepatosplenomegaly Homocystinuria CBS Raised urinary homocysteine, delayed development, Marfan-like physique, thromboembolic even ts LDLR = low density lipoprotein receptor, PCSK9 = proprotein convertase subtilisin/kexin typ e 9, APO-B = apolipoprotein B, ABCG5/8 = ATP binding cassette proteins, type G, ABCA1 = ATP binding cassette transporter 1, CBS = cystathionine beta-synthase Simon Broome criteria for diagnosis of FH in adults (after exclusion of secondary causes of hyperlipidaemia) De \201 nite FH \200 Total cholesterol > 7.5 mmol/L (LDL > 4.9 mmol/L) , pretreatment (or highest on treatment), and presence of tendon xanthomas in the patient or 1st- or 2nd-d egree relative or \200 evidence of a mutation in the LDL receptor, apolipoprotein B, or PCSK9 Possible FH \200 Total cholesterol > 7.5 mmol/L (LDL > 4.9 mmol/L) pretreatment (or highest on treatment). and one of the following: \200 family history of MI (< 50 years in 2nd-degree relative or <60 years in 1st-degree relative) family history of raised cholesterol ( > 7.5 mmol/L in adult 1st- or 2nd- degree relative; > 6.7 mmol/L in child or sibling aged <16 years) 306 CHAPTER 5 Coronary artery disease Genes conferring increased risk of coronary artery disease (polygenic CAD) Evidence suggest s that CAD in most patients results from a combination of genetic predisposition and enviro nmental risk factors. In particular, pre- mature CAD is thought to arise in individuals wit h a genetic predisposi- tion who are then exposed to a high-risk environment. However, with the exception of the monogenic disorders described above, attempts to iden- tify the genes responsible for conferring an increased risk of CAD have met with only limited success. At herosclerosis is a complex process, involving interactions between a number of physiologica l pathways, including lipo- protein metabolism, in \202 ammation, maintenance of endotheli al integrity, and coagulation. Genetic polymorphisms affecting any of these pathways may th erefore contribute towards an increased risk of CAD. In addition, well-established risk fac tors for CAD such as hypertension, diabetes, and obesity are also polygenic traits and will interact with other susceptibility genes and environmental risk factors (e.g. smoking) in the development of atherosclerosis. Historically, \200\230candidate gene \200\231 studies have been used in an attempt to iden tify risk factor genes for CAD; candidate genes are selected based on their role within one of the physiological pathways responsible for atherosclerosis. One of the genes most succe ssfully identi \201 ed from such studies is apolipoprotein E, of which there are 3 alleles : APOE2 , APOE3 , and APOE4 . APOE3 is the most common allele in European populations; the APOE2 and APOE4 alleles are associated with reduced and elevated plasma LDL-C respectively. A meta-analysis of 121 studies in which coronary outcomes were evaluated showed an odds ra tio for CAD of 0.80 in carriers of the APOE2 allele, and 1.06 in carriers of the APOE4 alle le, compared to individuals who were homozygous for APOE3 . 1 Individuals carrying the APOE 4 allele and who also smoke may show a particularly elevated risk for CAD, 2 although this remains controversial. Additional genes that have been implicated include those for lipoprotein lipase, thrombospo ndin, prothrombin, endothelial nitric oxide synthase (eNOS), myocyte enhancer factor 2A (ME F2A), and 5-lipoxygenase activation protein (FLAP). However, inconsistent results have been obtained for a number of these genes. More recently, following sequencing of the human gen ome, a number of independent genome-wide association studies have identi \201 ed a single locus on chromosome 9p21 as being associated with an increased risk of CAD 3 . A cluster of genes involved in control of the cell cycle have been identi \201 ed in this region; sinc e cellular proliferation is an essential step in the development of the atherosclerotic pla que, this may provide a mechanism for the role of this locus in the development of CAD. 1 Bennet AM, Di Angelantonio E, Ye Z, et al. (2007). Association of apolipoprotein E genoty pes with lipid levels and coronary risk. JAMA 298 : 1300 \200\22311. 2 Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, Miller GJ (2001). Apolipoprotein E4 and coronary heart diseas e in middle-aged men who smoke: a prospective study. Lancet . 358 : 115 \200\22319. 3 McPhe rson R, Pertsemlidis A, Kavaslar N, et al. (2007). A common allele on chromosome 9 associat ed with coronary heart disease. Science 316 : 1488 \200\22391. GENETIC TESTING FOR CORONARY ARTERY DISEASE 307 Genetic testing for coronary artery disease In patients where a monogenic cause of CAD is d iagnosed on clinical assessment, it is desirable to perform genetic testing to identify the mutation(s) responsible and allow relatives to be screened. A number of methods are now av ailable for identifying the mutations responsible for causing FH, and the current NICE guid elines recommend that genetic testing is offered to all patients with a clinical diagnosis of FH; current methods can detect the FH-causing mutation in 70 \200\22380 % of patients wi th a de \201 nite diagnosis of FH based on the Simon Broome criteria. Unfortunately, the a vailable techniques are not 100 % sensitive; therefore the absence of an identi \201 ed mu tation does not exclude a diagnosis of FH. Once a mutation is identi \201 ed, NICE guideli nes recommend cascade testing for the mutation in 1st-, 2nd-, and, if possible, 3rd-degree relatives. Appropriate primary prevention with cholesterol-lowering drugs can then be insti tuted to reduce the risk of CAD; this results in a 48 % reduction in coronary heart disease mortality. 1 Unfortunately, genetic testing is not yet available for the majority of patients, in whom C AD results from the interactions between polygenic susceptibility and a high-risk environme nt. However, evidence suggests that those patients who carry (cid:2) 7 \200\230risk \200 \231 alleles (from a group of 10 identi \201 ed candidate genes) have an increased odds ra tio (4.51) for CAD when compared to those carrying 3 \200\2234 \200\230risk \200\231 allel es. 2 Any future genetic test for such patients will need to incorporate a number of polymo rphisms in a range of genes, and be assessed in the context of environmental risk factors, if it is to be used for clinical risk strati \201 cation. 1 Neil A, Cooper J, Betteridge J, et al. (2008). Reductions in all-cause, cancer, and coron ary mor- tality in statin-treated patients with heterozygous familial hypercholesterolaemia : a prospective registry study. Eur Heart J 29 : 2625 \200\22333. 2 Drenos F, Whittaker JC, Humphries SE (2007). The use of meta analysis risk estimates for candi- date genes in comb ination to predict coronary heart disease risk. Ann Hum Genet 71 : 611 \200\22319. This page intentionally left blank 309 Chapter 6 Cardiac catheterization and intervention Radiation protection in the catheterization laboratory 310 Vascular access: the femoral art ery 312 Vascular access: the radial artery 314 Vascular access site management 316 Coronary angiography 318 Interpreting the coronary angiogram 320 Angiographic study of grafts 322 C omplications of angiography 324 Right-heart catheterization 326 Cardiac output and left ven tricular function 328 Cardiac catheterization in valve disease 329 Intravascular ultrasound 330 Angioplasty and coronary stenting 332 Restenosis following percutaneous transluminal coronary angioplasty (PTCA) 334 Drug-eluting stents 336 Stent thrombosis 338 Physiological assessment of coronary \202 ow 340 Primary angioplasty for STEMI 342 Primary angioplasty: procedure 344 Invasive assessme nt of vulnerable plaque 346 Complex coronary angioplasty 348 Angioplasty in multivessel dis ease 354 SYNTAX score 355 Left main stem angioplasty 356 Adjunctive therapy for angioplasty and stenting 358 Embolic protection devices 360 Special techniques 362 Mitral valvuloplast y 364 310 CHAPTER 6 Cardiac catheterization & intervention Radiation protection in the catheterization laboratory All practitioners delivering ionizin g radiation during medical procedures must attend a radiation protection course (IRMER, Ion izing Radiation Medical Exposure Regulations 2000). Furthermore, staff working in the cathe terization laboratory should be issued with radiation-monitoring badges, for the body and n eck, which should always be worn while in the lab. These badges should be checked monthly t o assess doses of radiation received by individual members of staff. No unnecessary staff s hould be within the catheterization lab during a procedure, and all staff that need to be i n the lab should be as far from the tube as practical. Minimizing patient dose \200 Minimize screening time and minimize acquisition time. \200 Keep the distance between the X-ray tube and image intensi \201 er to a minimum. Use collimation and cones to minimize the irradiated area. \200 Use lower magni \201 cat ions when possible. \200 Use the lowest number of frames/second to allow adequate imaging . \200 For prolonged procedures, the intensi \201 er should be moved regularly, a few degrees, to try to minimize the possibility of skin burns.