i 95 ECG: Additional points Figure 5.3 Where to place the chest leads V 1 : Right sternal edge, fourth intercostal space V 2 : Left sternal edge, fourth intercostal space V 3 : Half-way between V 2 and V 4 V 4 : The patient \200\231s apex beat All subsequent leads are in the same horizontal plane as V 4 V 5 : Anterior axillary line V 6 : Mid-axillary line (V 7 : Posterior axillary line) Finish 12-lead ECGs with a long rhythm strip in lead II. Disorders of ventricular conduction Bundle branch block ( see ECGs 1 and 2) Delayed conduct ion is evidenced by prolongation of QRS >0.12 sec. Abnormal conduction patterns lasting <0. 12 sec are incomplete blocks. The area that would have been reached by the blocked bundle d epolarizes slowly and late. Taking V 1 as an example, right ventricular depolarization is n ormally +ve and left ventricular depo- larization is normally \200\223ve. In RBBB, the following pattern is seen: QRS >0.12 sec, \200\234RSR \200\235 pattern in V 1 , dominant R in V 1 , inverted T waves in V 1 \200\223V 3 or V 4 , deep wide S wave in V 6 . Causes: Normal variant (isolated RBBB), pulmonary embolism, cor pulmonale. In LBBB, the following pattern is seen: QRS >0.12 sec, \200\234M \200\235 pattern in V 5 , no septal Q waves, inverted T waves in I, aVL, V 5 \200\223V 6 . Causes: IHD, hypertension, cardio-my opathy, idiopathic fibrosis. NB: If there is LBBB, no comment can be made on the ST segment or T wave. Bifascicular block is the combination of RBBB and left bundle hemi- block, mani fest as an axis deviation (e.g., LAD in the case of left anterior hemiblock). Trifascicular block is the combination of bifascicular block and first-degree heart block. Ventricular h ypertrophy There is no single marker of ventricular hyper- trophy: Electrical axis, voltage , and ST wave changes should all be taken into consideration. Relying on a single marker su ch as voltage may be unre- liable as a thin chest wall may result in large voltage, whereas a thick chest wall may mask it. Suspect LVH if the R wave in V 6 >25 mm or the sum of the S wave in V 1 and the R wave in V 6 is >35 mm (ECG 8, p. 136). Suspect RVH if dominant R wa ve in V 1 , T wave inversion in V 1 \200\223V 3 or V 4 , deep S wave in V 6 , RAD. Other c auses of dominant r wave in V1 : RBBB, posterior MI, some types of WPW syndrome (p. 124). C auses of low-voltage QRS complex : QRS <5 mm in all limb leads. Hypothyroidism, chronic obs tructive pulmonary disease (COPD), hema- tocrit ^ (intra-cardiac blood resistivity is relat ed to hematocrit), changes in chest wall impedance (e.g., in renal failure, subcutaneous em physema but not obesity), pulmonary embolism, bundle branch block, carcinoid heart disease, myocarditis, cardiac amyloid, Adriamycin cardiotoxicity, and other heart muscle diseases, pericardial effusion, pericarditis. 96 Figure 5.4 ECG 1: Left bundle branch block. Note the W pattern in V 1 and the M pattern in V 6 V 4 aVR V 1 I aVL 11 V 2 V 5 111 aVF V 3 V 6 11 e n i c i d e m Figure 5.5 ECG 2: Right bundle branch block. Note the M pattern in V 1 and the W pattern in V 5 V 4 aVR V 1 I r a l u c s a v o d r a C V 2 aVL 11 V 5 111 aVF V 3 V 6 i 11 Figure 5.6 ECG 3: Acute inferolateral myocardial infarc- tion. Note the marked ST elevation in the inferior leads (II, III, aVF), but also in V 5 and V 6 , indicating lateral involve - ment as well. There is also \200\234reciprocal change \200\235; i.e., ST-segment depress ion in leads I and aVL. The latter is often seen with a large myocardial infarction. 97 V4 aVR V1 I aVL V2 V5 11 111 aVF V3 V6 11 Figure 5.7 ECG 4: Acute anterior myocardial infarction. Note the marked ST segment elevatio n and evolving Q waves in leads V 1 \200\223V 4 . aVR V1 V4 I V5 aVL V2 11 111 aVF V3 V6 Figure 5.8 ECG 5: Complete heart block. Note the dis- sociation between the P waves and the QRS complexes. QRS complexes are relatively narrow, indicating that there is a ventricular rhythm originating from the conducting pathway. 98 aVR V1 V4 I aVL V2 V5 11 111 aVF V3 V6 11 e n i c i d e m Figure 5.9 ECG 6: Ventricular tachycardia. Note the broad complexes. aVR V1 V4 I r a l u c s a v o d r a C V5 aVL V2 11 i 111 aVF V3 V6 11 Figure 5.10 ECG 7: Dual-chamber pacemaker. Note the pacing spikes that occur before some of the P waves, and the QRS complexes. 99 aVR V1 V4 I aVL V2 V5 11 111 aVF V3 V6 Exercise ECG testing The patient undergoes a graduated treadmill exercise test with continu ous 12-lead ECG and BP monitoring. There are numerous treadmill protocols; the \200\234Bru ce protocol \200\235 is the most widely used. Indications: \212 \212 \212 To help confirm a suspected diagnosis of IHD To assess cardiac function and exercise tolera nce To develop prognosis following MI; often done predischarge (if +ve, worse outcome) \212 To evaluate response to treatment (drugs, angioplasty, coronary artery bypass grafting [CAB G]) To assess exercise-induced arrhythmias \212 Contraindications: \212 Unstable angina \212 Recent Q wave MI (<5 d) \212 Severe A S Uncontrolled arrhythmia, hypertension (systemic or pulmonary), or heart \212 failure Be cautious about arranging tests that will be hard to perform or interpret. These patients should have some type of imaging in addition to a stress test: \212 \212 \212 Stop the test if: \212 Complete heart block, LBBB Pacemaker patients Osteoarthritis, COPD, stroke, or other limita tions to exercise Chest pain or dyspnea occurs. You want to make sure that the patient has a maximal test and would consider not stopping for minor chest pain without ECG changes. The patient feels fa int, exhausted, or is in danger of falling. ST segment elevation/depression >2 mm is presen t(with or without chest pain). Atrial or ventricular arrhythmia (not just ectopy) is presen t. Fall in BP or excessive rise in BP (systolic >230 mm Hg)occurs. AV block or LBBB develop s. Maximal or 90% maximal heart rate for age is achieved. \212 \212 \212 \212 \212 \212 Interpreting the test: A +ve test only allows one to assess the pro bability that the patient has IHD. 75% of patients with significant coronary artery disease have a +ve test, but so do 5% of people with normal arteries (the false-positive rate is e ven higher in middle-aged women, e.g., 20%). The more +ve the result, the higher the predic tive accuracy. Down-sloping ST depression is much more significant than up-sloping; e.g., 1 mm J-point depression with down-sloping ST segment is 99% predictive of 2 \200\2233 vessel disease. Morbidity: 24 in 100,000. Mortality: 10 in 100,000. 100 Ambulatory ECG monitoring Continuous ECG monitoring for 24 h may be used to evaluate for pa roxys- mal arrhythmias. However, >70% of patients will not have symptoms during the period of monitoring. 20% will have a normal ECG during symptoms and only up to 10% will have an arrhythmia coinciding with symptoms. Give these patients an event recorder they can activat e themselves dur- ing a symptomatic episode. These episodes can then be transmitted via a t elephone for evaluation. Recorders may also be programmed to detect ST segment depression, either symptomatic (to prove angina), or to reveal \200\234silent \200\235 ischemia (predi ctive of reinfarction or death soon after MI). e n i c i d e m Figure 5.11 (a) r a l u c s a v o d r a C i Each complex is taken from sample ECGs (lead V 5 ) recorded at 1-min in- tervals during exe rcise ( top line ) and recovery ( bottom line ). At maximum ST depression, the ST segment i s almost horizontal. This is a positive exercise test. (b) 101 This is an exercise ECG in the same format. It is negative because al- though the J point i s depressed, the ensuing ST segment is steeply up sloping. Cardiac catheterization This involves the insertion of a catheter into the heart via the fe moral (or radial/brachial) artery or vein. The catheter is manipulated within the heart and great vessels to measure pressures. (See Tables 5.3 and 5.4.) Catheterization can also be used to: \212 \212 Sample blood to assess oxygen saturation Inject radiopaque contrast medium to image the ana tomy of the heart and flow in blood vessels Perform angioplasty ( stenting), valvuloplast y, and cardiac biopsies Perform intravascular ultrasound to quantify arterial narrowing \212 \212 During the procedure, ECG and arterial pressures are monitored continuously. In dications: \212Coronary artery disease: Diagnostic (assessment of coronary vessels and graft patency); therapeutic (angioplasty, stent insertion) \212Valve disease: Diagnostic (to assess severity); therapeutic valvuloplasty \212Congeni tal heart disease: Diagnostic (assessment of severity of lesions); therapeutic (balloon dilatation or septostomy) \212Other: Cardiomyopathy; pericardial disease; endomyocardial biopsy Preprocedure checks: \212 \212 Brief history/examination ( Investigations: Electrolytes, blood urea nitrogen (BUN)/creatin ine, CBC, prothrombin time (PT)/partial thromboplastin time (PTT), type and screen, ECG Obt ain consent for angiogram angioplasty stent depending on the indication of the proced ure; explain reason for procedure and possible complications (below). Obtain IV access. Pat ient should be nothing by mouth (NPO) for at least 6 h before the procedure. Patients shoul d take all their morning drugs (and premedication if needed). Withhold oral hypoglycemics a nd only give half dose of insulin. NB: Peripheral pulses, bruits, aneurysms) \212 \212 \212 \212 Postprocedure checks: \212 Pulse, BP, arterial puncture site (for bruising or swelling; false aneurysm), peripheral pu lses Investigations: CBC and PT/PTT (if suspected blood loss), ECG \212 Complications: \212Hemorrhage. Apply firm pressure for a long period of time (>10 mi n) over puncture site. If you suspect a false aneurysm, diagnostic ultrasound is required. Some require ultrasound-guided or surgical repair. \212Contrast reaction. This is usually mild with modern contrast agents. \212Loss of peri pheral pulse. May be due to dissection, thrombosis, distal embolus, or arterial spasm; occu rs in <1% of brachial catheterizations, rare with femoral catheterization. \212Angina. May occur during or after cardiac catheterization; usually responds to subling ual nitroglycerin (NTG); if not, give analgesia and IV nitrates. \212Arrhythmias. Usually transient; manage along standard lines and remove 102 all catheters from the heart. \212Pericardial tamponade. Rare, but should be suspected if the patient becomes hypotensive and/or anuric. \212Infection. Postcatheter fever is usually due to a contrast reaction. If it per- sists for >24 h, take blood cultures before giving antibiotics. Mortality: <1 in 1,000 patients, in most centers. Intracardiac electrophysiology This cathe ter technique can determine types and origins of arrhythmias and locate (and ablate) aberra nt pathways (e.g., causing atrial flutter or VT). Arrhythmias may be induced and the effect iveness of control by drugs assessed. e n i c i d e m Table 5.3 Normal values for intracardiac pres sures and saturations Location Pressure (mm Hg) Saturation (%) Mean Range Inferior vena cava Superior vena cava Right atrium Right ventricle Systolic End-diastolic P ulmonary artery 76 70 74 74 r a l u c s a v o d r a C 4 0 \200\2238 25 4 15 \200\22330 0 \200\2238 i 74 Systolic Diastolic Mean 25 10 15 a v 15 \200\22330 5 \200\22315 10 \200\22320 3 \200\22312 3 \200\22315 Pulmonary artery Wedge pressure 74 Left ventricle Systolic End-diastolic 110 8 80 \200\223140 5 \200\22312 98 Aorta Systolic Diastolic Mean Brachial 110 70 85 80 \200\223140 60 \200\22390 70 \200\223105 98 103 Systolic Diastolic Mean 120 72 83 90 \200\223140 60 \200\22390 70 \200\223105 98 Table 5.4 Gradients across stenotic valves Valve Normal gradient (mm Hg) 0 0 5 \200\22310 Stenotic gradient (mm Hg) Moderate 30 \200\22350 5 \200\22315 Mild <30 <5 Severe >50 >15 Aortic Mitral Prosthetic Figure 5.12 Diagram of coronary circulation Ascending aorta Left main stem Circumflex coronary artery Right coronary artery Diagonal branches (of the LAD) Left anterior descending artery Posterior descending artery Septal branches (of the LAD) Reproduced from Myerson SG, Choudhury RP, Mitchell ARJ (eds.). Emergencies in Cardiology . New York: Oxford University Press, 2006. By permission of the publisher. Echocardiography This noninvasive technique uses the differing ability of various structure s within the heart to reflect ultrasound waves. It not only demonstrates anatomy but also p rovides a continuous display of the functioning heart throughout its cycle. There are vario us types of scans: M-mode (motion mode): Scans are displayed to produce a permanent single- dimension (time) image. Two-dimensional (real-time): A 2-D, fan-shaped image of a segment o f the heart is produced on the screen, which may be \200\234frozen \200\235 and hard-copie d. Several views are possible; the four most common are: Long axis, short axis, four-chambe r, and subcostal. 2-D echocardiography is good for visu- alizing ventricular function, cong enital heart disease, LV aneurysm, mural thrombus, left atrial (LA) myxoma, and septal defe cts. Doppler and color-flow echocardiography: Different colored jets illustrate flow and gr adients across valves and septal defects (p. 148). Transesophageal echocardiography (tee) c an be more sensitive than transt- horacic echocardiography (TTE) because the transducer is nearer to the heart and the images are not limited by lung or fat interference. Indications : Diagnosis of aortic dissections; assessment of prosthetic valves; finding of cardiac sour ce of emboli and endocarditis. Contraindicated in esophageal disease or cervical spine inst ability. Stress echocardiography: Used to evaluate ventricular function, ejection frac- tio n, myocardial thickening, and regional wall motion pre- and postexercise. Dobutamine may be used if the patient cannot exercise. Inexpensive and as sensitive and specific as a thalli um scan (p. 107). 104 Uses of echocardiography Quantification of global rv and lv function: Echo is useful for de tecting focal and global wall motion abnormalities, LV aneurysm, mural thrombus, and LVH (e cho is 5 \200\22310 times more sensitive than the ECG in detecting this). The size of the v entricle can also be assessed. Estimating right-heart hemodynamics: Doppler studies of pulm onary artery flow allow evaluation of RV function and pressures. Valve disease: Measurement of pressure gradients and valve orifice areas in stenotic lesions. Detecting valvular regu rgitation. Evaluating function of prosthetic valves is another role. Congenital heart disea se: Establishing the presence of lesions and determin- ing their functional significance. E ndocarditis: Vegetations may not be seen if <2 mm in size. TTE with color Doppler is best f or aortic regurgitation (AR). TTE is useful for visualizing mitral valve vegetations, leafl et perforation, or looking for an aortic root abscess. Pericardial effusion is best diagnos ed by echo. Fluid may first accumulate between the posterior pericardium and the left ventr icle, then anterior to both ventricles and anterior and lateral to the right atrium. There may be paradoxical septal motion. HOCM (p. 144): Echo features include asymmetrical septal hypertrophy, small LV cavity, dilated left atrium, and systolic anterior motion of the mitr al valve. e n i c i d e m r a l u c s a v o d r a C i 105 Figure 5.13 106 Normal M-mode echocardiogram (RV, right ventricle; LV, left ventricle; AO, aorta; AV, aorti c valve; LA, left atrium; MV, mitral valve; PW, posterior wall of LV; IVS, interventricular septum). After Hall R. Med International 17 774. Nuclear cardiology and other cardiac scans Myocardial perfusion imaging A noninvasive metho d of assessing regional myocardial blood flow and the cellular integrity of myocytes. The t echnique uses radionuclide tracers, which cross the myocyte membrane and are trapped intrac ellularly. Thallium-201 , a K + analog, is the most widely used agent. It is distributed vi a regional myocardial blood flow and requires cellular integrity for uptake. Newer techneti um-99 -based agents are similar to thallium-201 but have improved imaging characteristics a nd can also be used to assess myocardial perfusion and LV performance in the same study. My ocardial territories supplied by unobstructed coronary vessels have nor- mal perfusion, whe reas regions supplied by stenosed coronary vessels have poorer relative perfusion, a differ ence that is accentuated by exercise. For this reason, exercise tests are used in conjuncti on with radionuclide imag- ing to identify areas at risk of ischemia/infarction. Exercise s cans are com- pared with resting views. Reperfusion (ischemia) or fixed defects (infarct) c an be seen, and the coronary artery involved is reliably predicted. Drugs (e.g., adenosine and dipyridamole) can also be used to induce perfusion dif- ferences between normal and und erperfused tissues in patients who can \200\231t exercise. Myocardial perfusion imaging has also been used in patients presenting with acute MI (to determine the amount of myocardium salvaged by throm- bolysis) and in diagnosing acute chest pain in those without classical ECG changes (to define the presence of significant perfusion defects). e n i c i d e m r a l u c s a v o d r a C i 107 Positron emission tomography (PET) Severely underperfused tissues, such as those supplied b y a critically stenotic coronary artery, switch from fatty acid metabolism to glycolytic me tabolism. Such altered cellular biochemistry may be imaged by PET using 18 F-labeled deoxyg lucose (FDG), which identifies glycolytically active tissue that is viable. This phenomenon , called hibernating myocardium, occurs in up to 40% of fixed defects seen on thallium-201 scans. Computed tomography (CT) allows only limited assessment of cardiac structures. It ca n help evaluate cardiac disease (e.g., constrictive pericarditis). CT is also part of first -line assessment for abnormalities of the ascending and descending aorta, especially in aor tic dissection, and for detecting pul- monary emboli. Ultra-fast CT is now shown to reliabl y evaluate for lesions of coronary arteries and assist with evaluating congenital anomalies . Magnetic resonance imaging (MRI) is used in assessing congenital heart disease, infiltrat ing disease of the myocardium, intracardiac structures, and the great vessels. Its advantag es over CT are the lack of exposure to radia- tion, the wide field of view and high-image r esolution, the ability to orient images in multiple planes, and the ability to gate or trig ger the MRI scanner, according to the cardiac cycle, thus allowing stop-frame imaging of th e heart and great vessels. Spin-echo MRI has a high sensitivity for detecting false lumina and intra-mural flaps in aortic dissection compared with CT. Its main limitation, compared with TEE (p. 105) and CT, is its inability to image significantly unstable patients. Additi onally, significant artifact occurs in patients who have implantable devices, and some pati ents \200\231 devices will be altered by the magnet. New uses of MRI include myocardial pho sphorus-31 NMR spectroscopy ( 31 P-NMR), which may demonstrate ischemia in the not-uncommon problem of women with chest pain but normal coronary angiograms. ( \200\234Syndrome X \200 \235 denotes this type of uncertain chest pain.) 31 P-NMR may suggest abnor- mal dilator re sponses of the microvasculature to stress. Figure 5.14 Technetium perfusion scan showing perfusion defect in the left ventricle anteri or and lateral walls at stress which is reversible (difference between stress and rest imag es). 108 Hyperlipidemia Cholesterol is a major risk factor for coronary heart disease (CHD) and, due to the efficacy of current medications, is very treatable. The decision to treat hyperchol esterolemia should be based on multiple factors. The Adult Treatment Panel III (ATP III) ha s established clinical guidelines for choles- terol testing and management (http://www.nhlb i.nih.gov/guidelines/choles- terol/atp3_rpt.htm). See Table 5.5 for a list of primary hyper lipidemias. \212 First, determine if the patient has CHD or its equivalent (DM, symptom- atic carotid artery disease, peripheral vascular disease, or an abdominal aortic aneurysm). Second, determine if the patient has other risk factors for CHD (smoking, BP ^ , family history, HDL <40 mg/d L, or age: Male >45, female >55). Third, decide to treat based on LDL level and their risk for CHD using the Framingham risk calculator (http://hin.nhlbi.nih.gov/atpiii/calculator. a sp?usertype=prof). \212 \212 Trial evidence that treating hypercholesterolemia is worthwhile \200\234 \212 4S \200\235 study . Secondary prevention trial (patients with IHD) using simvas- tatin \211 20 mg/d PO in 4,444 men aged 35 \200\22370 (cholesterol 212 \200\223309 mg/dL). Number needed to tr eat (NNT) to prevent 1 fatal MI was 25 (over 6 yrs) and 14 for nonfatal events. \212WOSCOPS . Primary prevention trial in Scotland with more than 6,500 men (cholesterol > 155 mg/dL), pravastatin 40 mg/24 h PO. NNT to pre- vent 1 fatal MI was 142 (over 5 yrs) and for all cardiac events was 55. \212CARE study . Secondary prevention trial with pravastat in 40 mg/24 h PO in 4,159 people, post-MI, with \200\234normal \200\235 cholesterol (avera ge 209 mg/dL). NNT for fatalities was 91 (over 5 yrs), and for nonfatal MI was 38. e n i c i d e m \212HEART PROTECTION STUDY . Secondary prevention trial with 40 mg sim- vastatin to patien ts irrespective of cholesterol. NNT for death was 55. No evidence of \200\234threshold of cholesterol \200\235 for benefit. 33% of the patients had an LDL <113 mg/dL and still demon strated reduction in mortality and cardiovascular events. r a l u c s a v o d r a C Who to screen \212 \212 \212 \212 Management \212 \212 i CHD or elevated risk (e.g., DM, BP ^ ) Family history of hyperlipidemia or CHD before 65 yr s Xanthoma or xanthelasma Corneal arcus before 50 yrs old Exclude familial or second-degree hyperlipidemias; treat as appropriate. Lifestyle advice. Aim for BMI of 20 \200\22325. Diet with <10% of calories from saturated fats and plenty of fiber. Exercise. \212 Treat those with known CHD. If \212 0 or 1 risk factors , treat at LDL >160. If \211 2 risk factors and MI risk <20%, treat at LDL >130 mg/dL. If CHD or >20 % MI risk, treat at LDL >100 mg/dL. Statins are first choice; they decrease cholesterol syn thesis in the liver (e.g., simvastatin 10 \200\22340 mg PO at night). CI: Porphyria, LFT ^ . se: Myositis (stop if CK ^ by \211 10-fold. If any muscle aches, check CK; risk is 1/10 0,000 treatment yrs); abdominal pain; LFT ^ (stop if AST 100U/L). Second-line therapy: Fi brates, such as bezafibrate (useful in familial mixed hyperlipidemias); cholesterol absorpt ion inhibitors of ezetimibe (useful in combination with a statin to enhance cholesterol red uction); anion exchange resins, such as cholestyramine; and nicotinic acid (HDL ^ ; LDL ; SE: Severe flushes; aspirin 325 mg half-hour pre-dose helps this). \212 Hypertriglycerid emia responds best to fibrates, nicotinic acid, or fish oil. Familial or primary hyperlipid emias Increased risk of CHD . Lipids travel in blood packaged with proteins as lipoproteins . There are four classes: Chylomicrons (mainly triglyceride); LDL (mainly cholesterol, the lipid correlating most strongly with CHD); very-low-density lipoprotein (VLDL; mainly trigl yceride); HDL (mainly phospholipid, correlating inversely with CHD). See Table 5.5. Seconda ry hyperlipidemias A result of DM, alcohol abuse, T4 ; renal failure, nephrosis, and cho lestasis. Xanthomata These yellowish lipid deposits may be eruptive (itchy nod- ules in cro ps in hypertriglyceridemia), tuberous (yellow plaques on elbows and knees), planar (also ca lled palmar; orange-colored streaks in palmar creases that are virtually diagnostic of remn ant hyperlipidemia), or deposits in tendons, eyelids (xanthelasmata), or cornea (arcus). \212 109 \212 1 1 0 Table 5.5 Primary hyperlipidemias Familial hyperchylomicronemia (lipoprotein lipase deficiency or apoCII deficiency) I Chol <250 Trig 900 \200\2231,300 Chylomicrons ^ Eruptive xanthomata, lipemia retinalis, hepatosplenomegaly (HSM) Familial hypecholesterolemia ii (LDL receptor defects) Chol 300 \200\223600 Trig <200 Chol 300 \200\223600 Trig <200 Chol >300 Trig <200 Chol 250 \200\223400 Trig 200 \200\2231,000 LDL ^ Tendon xanthoma, corneal arcus, xanthelasma Familial defective apoprotein B-100 IIa LDL ^ Tendon xanthoma, arcus, xanthelasma Polygenic hyper-cholesterolemia IIa LDL ^ The most common 1 lipidemia xanthelasma; corneal arcus Familial combined hyperlipidemia IIb, IV or V LDL ^ , VLDL ^ HDL ^ Next most common 1 lipidemia xanthelasma; arcus Dysbetalipoproteine-mia Chol 350 \200\223550 Trig 800 \200\2231,200 Chol 290 \200\223450 Trig 250 \200\223550 Trig 850 \200\2232,500; chylomicrons IDL ^ HDL LDL VLDL ^ Palmar striae; tubero-eruptive xanthoma (remnant particle disease) III Familial hypertriglyceridemia IV Type V hyperlipoproteinemia Eruptive xanthoma; lipemia retinalis; HSM Chol = plasma cholesterol (mg/dL) Trig = plasma triglyceride (mg/dL); colored numerals = wh o phenotype 1 HDL abnormalities: Hyperalphalipoproteinemia: HDL ^ chol >80 Hypoalphalipoproteinemia ( Tangiers \200\231s disease): HDL chol <35 1 Primary LDL abnormalities: Abetalipoproteinemia: Trig <30, Chol <50, missing LDL, VLDL and chylomicrons, and fat malabsorption, retinopathy, and acanthocytosis Hypobetalipoprotei nemia: Chol <60, LDL , HDL ; longevity ^ Atherosclerosis and statins Think of atheroma as the slow accumulation of snow on a mountai n. Nothing much happens until one day an avalanche devastates the commu- nity below. The sn ow is lipid and lipid-laden macrophages; the mountain is an arterial wall; the avalanche is plaque rupture; and the community below is, all too often, myocardium or CNS neurons. The devastation is infarc- tion. In assessing risk of thrombi, remember Rudolph Virchow \200 \231s (1821 \200\2231902) triad of changes in the vessel wall, changes in blood flow, and c hanges to the blood constituents. Plaque biology Atheroma is the result of cycles of vascul ar wall injury and repair, leading to the accumulation of T lymphocytes, which produce grow th factors, cytokines, and chemoattractants. LDL gains access by a process called transcyto sis , where it undergoes modification by macrophage-derived oxida- tive free radicals \200 \224a process enhanced by smoking tobacco and hypertension. Rupture of atheromatous plaque triggers most acute coronary events. These plaques have a core of lipid-laden macrophages a nd a fibrous cap. Many factors predispose to plaque formation; e.g., genetics, sex ( \231 \202 ), BP, smoking, and DM. Plaques are not static, dead things. They can regress or accum ulate, or become inflamed (e.g., in unstable angina). The balance between LDL efflux and in flux is alterable (e.g., by diet or antilipid drugs). Neither is the vessel wall a nonparti cipatory audience to these great events. A sclerotic arterial wall comprises areas of chron ic inflammation, with monocytes, mac- rophages, and T lymphocytes \200\224with smooth muscl e proliferation and elabo- ration of extracellular matrix. These macrophages make cholester ol and also produce enzymes (e.g., interstitial collagenase, gelatinase, and stromelysin), which have been implicated in digesting the plaque cap. The thinner the cap, and the fewer smooth muscle cells involved, the more unstable the plaque and the more likely it is to rup ture. Endothelial cells also release a number of anti- and proatherogenic molecules, includ ing nitric oxide and endothelin-1. Normal endothelial function is lost early in the process of atherosclerosis with a shift to the production of proatherogenic molecules. After plaqu e rupture, what happens to fibrinogen and passing platelets partly determines the extent of the impending catastrophe. Hypercholesterolemia (if present) is associated with hypercoagu lable blood and enhanced platelet reactivity at sites of vascular damage. Disease preventio n What can we do about plaques? First, try to pre- vent them: Eat a healthy diet (p. 203), encourage some exercise, discour- age smoking; treat high BP and DM. Once a plaque is there , it can be bypassed, ablated (physically removed or compressed), or stented (with a metal stent). Angioplasty splits the plaque, causing an injury response: Elastic recoil \206\222 thrombus formation \206\222 inflammation \206\222 smooth muscle pro- liferation \206 \222 arterial remodeling. An alternative to this drastic change is to give a statin, even i f the cholesterol is \200\234normal \200\235 since the whole process described above is fa vorably influenced by statins. Statins inhibit the enzyme HMG-COA reductase, which is respo nsible for the de novo synthesis of cholesterol in the liver. This leads to an increase in LDL receptor expres- sion by hepatocytes and, ultimately, reduced circulating LDL cholester ol. In the past, reducing LDL to <100 was the goal but recent data suggest that even lower levels may be beneficial. Besides this, statins have other favorable effects: \212 \212 \212 \212 \212 \212 e n i c i d e m r a l u c s a v o d r a C i 111 Thrombotic state Suppress inflammation (c-reactive protein [CRP] ) Plaque stabilizati on Restoration of normal endothelial function Reduction in cholesterol synthesis by within- vessel macrophages Reduction of within-vessel macrophage proliferation and migration Other cardiovascular drugs Antiplatelet drugs Aspirin irreversibly acetylates cyclo-oxygena se, pre- venting production of thromboxane A 2 , thereby inhibiting platelet aggre- gation. It is commonly used in low doses (e.g., 81 mg) for secondary prevention following MI, tran sient ischemic attack (TIA)/stroke, and for patients with angina or peripheral vascular dis ease. May have a role in pri- mary prevention. ADP receptor antagonists (e.g., clopidogrel) also block platelet aggregation, but may cause less gastric irritation. They have a role i n patients intolerant of aspirin and in post-coronary stent insertion. \222 -blockers Bloc k -adrenoceptors, thus antagonizing the sympathetic nervous system. Blocking 1 -recep tors is negatively inotropic and chro- notropic and delays AV conduction, and blocking 2 -receptors induces peripheral vasoconstriction and bronchoconstriction. Drugs vary in thei r 1 / 2 selectivity (e.g., propranolol is nonselective, and bisoprolol relatively 1 selective), but this does not seem to alter their clinical efficacy. Uses: Angina, hypert ension, antidysrhythmic, post MI (mortality ), heart failure (with caution). CI: Asthma/ COPD, heart block. Caution: Peripheral vascular disease, heart failure, DM. SE : Lethargy, impotence, depression , nightmares, headache. Diuretics Loop diuretics (e.g., furosemide ) used in heart failure and hyper- tension to inhibit the Na/K/2Cl co-transporter. Thiazides are used in hyper- tension to inhibit Na/Cl co-transporter. SE: Loop dehydration, K + , Ca 2+ , ototoxic; thiazides: K + , Ca 2+ ^ , Mg 2+ ,urate ^ (+/ \210\222 gout), im potence. Vasodilators are used in heart failure, IHD, and hypertension. Nitrates preferenti ally dilate veins and the large arteries, reducing filling pressure (preload), while hydral azine primarily dilates the resistance vessels thus lowering BP (afterload). Prazosin (an -blocker) dilates arteries and veins. Calcium antagonists These reduce cell entry of Ca 2 + via voltage-sensitive channels on smooth muscle cells, thereby promoting coronary and per iph- eral vasodilatation and reducing myocardial oxygen consumption. Pharmacology: Effects of specific Ca 2+ antagonists vary because they have different effects on the L-Ca 2+ -type channels. The dihydropyridines (e.g., nifedipine and amlodipine) are mainly peripheral vas odilators (they also dilate coronary arteries) and can cause a reflex tachycardia, so are o ften used with a -blocker. They are used mainly in hypertension and angina. Verapamil an d diltiazem ( nondihydropyridines ) also slow conduction at the atrioventricular and sinoat rial nodes and may be used to treat hypertension, angina, and dysrhythmias. Don \200\231t g ive verapamil with -blockers (risk of bradycardia LVF). SE : Flushes, headache, edema (diuretic unresponsive), LV function, gingival hypertrophy. CI: Heart block. Digoxin Bl ocks the Na + /K + pump. It is used to slow the pulse in fast AF (p. 123; aim for <100). As it is a weak +ve inotrope, its role in heart failure in sinus rhythm may be best reserved if the patient is symptomatic despite optimal ACE-inhibitor and -blocker therapy. For HF there is no benefit with mortality (but admissions for worsening CHF are decreased by 25% ). Elderly people and people with renal insufficiency are at increased risk of toxicity: Us e lower doses. Check plasma levels >6 h post-dose. Typical dose : 0.25 mg/d, 0.125 mg (or r enal function ). Toxicity risk is increased if K + , Mg 2+ , or Ca 2+ ^ . t appr oximately 36 h. If on digoxin, use less energy in cardioversion (start with 5J). SE: Any ar rhythmia (supraventricular tachycardia SVT with AV block is suggestive), nausea, reduced ap petite, yellow vision, confusion, gynecomastia. In toxicity, stop digoxin, check K + , trea t arrhythmias, consider Digibind by IVI (p. 789). CI: HOCM, WPW syndrome (p. 124). ACE-in hibitors (p. 131), nitrates (p. 117), antihypertensives (p. 134). 112 Acute coronary syndrome Definitions Acute coronary syndrome (ACS) includes unstable angina and evolving MI, which share a common underlying pathology \200\224plaque rupture, thrombos is, and inflammation. However, ACS may rarely be due to emboli or coronary spasm in normal coronary arteries or vasculitis (p. 416). Usually divided into ACS with ST-segment elevatio n or new-onset LBBB \200\224what most of us mean by acute MI \200\224and ACS without ST-seg ment elevation \200\224the ECG may show ST-depression, T-wave inversion, nonspecific chang es, or be normal (includes non-Q wave or subendocardial MI). The degree of irreversible myo cyte death varies, and significant necrosis can occur without ST-elevation. Cardiac troponi ns (T and I) are the most sensi- tive and specific markers of myocardial necrosis and have become the test of choice in patients with ACS (see below). Risk factors Nonmodifiable: Age , \231\202 sex, family history of IHD (MI in first-degree relative <55 yrs). Modifiable: S moking, hypertension, DM, hyperlipidemia, obesity, sedentary lifestyle. Controversial risk factors include stress, type A personality, LVH, apoprotein A ^ , fibrinogen ^ , hyperinsul ine- mia, homocysteine levels ^ , ACE genotype, and cocaine use. Diagnosis is based on the presence of at least two out of three of: Typical history, ECG changes, and cardiac enzyme rise (World Health Organization [WHO] criteria). Symptoms Acute central chest pain, lasting >20 min, often associated with nausea, diaphoresis, dyspnea, palpitations. May present wit hout chest pain ( \200\234silent \200\235 infarct) or with atypical chest pain (e.g., in el derly or diabetic patients). In such patients, presentations may include syncope, pulmonary edema, epigastric pain and vomiting, postoperative hypotension or oliguria, acute confusio nal state, stroke, diabetic hyperglycemic states. Signs Distress, anxiety, pallor, sweatine ss, pulse or ^ , BP ^ or , fourth heart sound. There may be signs of heart failure (J VP ^ , third heart sound, and bibasilar crackles) or a pansystolic murmur (papillary muscle dysfunc- tion/rupture; ventral septal defect [VSD]). A low-grade fever may be pres- ent. L ater, a pericardial friction rub or peripheral edema may develop. Tests ECG: Classically, h yperacute (tall) T waves, ST elevation or new LBBB occur within hours of acute Q wave (tran smural infarction). T wave inversion and the development of pathological Q waves follow ove r hours to days (p. 95). In other ACS : ST-depression, T-wave inversion, nonspecific change s, or normal. In 20% of MIS, the ECG may be normal initially. CXR: Look for cardiomegaly, p ulmonary edema, or a widened mediastinum (?aortic dissection). Don \200\231t routinely dela y treatment while waiting for a CXR. Blood: CBC, electrolytes, renal function, glucose ^ , lipids , cardiac enzymes ^ (CK, troponin); CK is found in myocardial and skeletal muscle . It is raised in MI, after trauma (falls, seizures) or prolonged exercise, and in myositis , hypothermia, and hypothyroidism. Check CK-MB isoenzyme levels if there is doubt as to the source (normal CK-MB/CK ratio <5%). Troponin T bet- ter reflects myocardial damage (peaks at 12 \200\22324 h; elevated for >1 wk). If normal \211 6 h after onset of pain, and ECG normal, risk of missing MI is tiny (0.3%). Peak post-MI levels also help risk stratificatio n. Differential diagnosis (p. 90) Angina, pericarditis, myocarditis, aortic dis- section, p ulmonary embolism, and esophageal reflux/spasm Management See emergencies (p. 749). The man agement of ACS with and without ST-segment elevation varies. Likewise, if there is no ST-el evation, and symptoms settle without a rise in cardiac troponin, then no myocardial damage has occurred, the prognosis is good, and patients can be discharged. e n i c i d e m r a l u c s a v o d r a C i 113 Therefore, the two key questions are: Is there ST-segment elevation? And, is there a rise i n troponin? Mortality 50% of deaths occur within 2 h of onset of symptom. Figure 5.15 Enzyme changes following acute MI Cardiac enzymes \227 50 Trop CK CK \200\223MB AST LDH Trop Creatine kinase CK cardiac isoenzyme Aspartate transaminase Lactate dehydrogenase Cardiac t roponin CK \227 5 l e v e CK \200\223MB \227 4 l e m y z n e m u r e S \227 3 LDH \227 2 AST \227 1 0 1 2 3 4 6 5 Days 7 8 9 10 114 Figure 5.16 Sequential ECG changes following acute MI Management of ACS Prehospital Arrange emergency ambulance. Aspirin 325 mg chewed (if no abs olute CI) and NTG sublingual. Analgesia, such as morphine 5 \200\22310 mg IV (not IM becaus e of risk of bleeding with thrombolysis). Ask if the patient took a PDE 5 inhibitor (silden afil, vardenafil, tadalafil) since nitrates are contraindicated in that situation. In the h ospital O 2 , morphine, aspirin (p. 751). Then the key question for subsequent management o f ACS is whether there is ST-segment elevation (includes new-onset LBBB or a true posterior MI). ST-segment elevation \212Primary angioplasty or thrombolysis, if no contraindication \212 \222 -blocker , e.g., atenolol 5 mg iv, unless contraindicated \212ACE-inhibitor : Consider starting ace-inhibitor (e.g., lisinopril 2.5 mg) in all normotensive patients with in 24 h of acute MI, especially if there is clinical evidence of heart failure or echo evid ence of LV dysfunction. ACS without st-segment elevation \212 \222 -blocker , e.g., atenolol 5 mg iv, unless contr aindicated \212Low-molecular-weight heparin (LMWH) (e.g., enoxaparin) \212Nitrates , unle ss contraindication (usually given IV) \212 e n i c i d e m