Cardiovascular Diseases

Cardiovascular Diseases

Arrhythmias

Metabolic abnormalities should always be ruled out before performing Holter monitor studies or committing to long-term antiarrhythmic therapy (e.g., hypokalemia, hypomagnesemia, anemia, hypoxemia, hypo- or hyperthyroidism).

Arteriovenous Fistulas, Angiomatous, Congenital

Platelet count may be decreased.

Behçet's Syndrome

• (Systemic vasculitis involving arteries and veins characterized by triad of recurrent aphthous ulcers of mouth and genitalia, and relapsing panuveitis.)
• No definitive laboratory tests
• Laboratory findings due to involvement of various organ systems, e.g.,
• Large vessel occlusion (e.g., aneurysms, arthritis, meningitis) Skin lesions

Churg-Strauss Syndrome (Allergic Granulomatosis and Angiitis)

• Biopsy showing granulocytes around an arteriole and venule establishes the diagnosis.1
• ESR is high.
• WBC count is increased.
• Eosinophilia is usual and seems to correlate with disease activity.
• Serum IgE is often increased.
• p-ANCA is found in ≤60% of patients. c-ANCA is rare.

Cor Pulmonale

• Secondary polycythemia
• Increased blood CO when cor pulmonale is secondary to chest deformities or pulmonary emphysema
• Laboratory findings of the primary lung disease (e.g., chronic bronchitis and emphysema, multiple small pulmonary emboli, pulmonary schistosomiasis)

Coronary Heart Disease (CHD)

• Increased risk factors
• Increased serum total and LDL cholesterol, decreased HDL cholesterol and various ratios (see Chapter 12).
• Recent reports suggest that apo A-I and apo B may be better discriminators of CHD than cholesterol, and low ratio of apo A-I to apo B may be best predictor. (Variation in methodology and lack of interlaboratory standardization makes this difficult to evaluate at present.)

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• Atherogenic index (combination of ratio of LDL to HDL × apo B with ratio of apo B to apo A-I) =
• 
• Increased serum homocysteine >15.9 µmol/L (normal = 5-15 µmol/L) triples risk of AMI. Each increase of 5 µmol/L increases risk equivalent to increased cholesterol of 20 mg/dL. Increase may be due to vitamin B deficiency or genetic deficiency of methylene-tetrahydrofolate reductase enzyme. Increased in end-stage renal disease dialysis patients and in hypothyroidism, certain drug therapies (e.g., methotrexate [transient], phenytoin and carbamazepine [mild], theophylline, nitrous oxide), cigarette smoking.
• Low plasma vitamin B and folate levels are each independent risk factors for cor 717d36h onary artery disease.
• Increased serum triglyceride level is a risk factor but may not be independent of other factors.
• Clinical evidence of CHD or atherosclerosis in patient <age 40, family history of premature CHD, hypertension, male gender, smoking.
• Syndrome X: insulin resistance, low HDL level, high level of very low density lipoproteins (VLDLs) and triglycerides.
• Various abnormalities of blood clotting mechanisms (e.g., fibrinogen, factor VII, antithrombin III, phospholipid antibodies, protein C, protein S).
• Lipoprotein electrophoresis (see Table 13-6) shows a specific abnormal pattern in <2% of Americans (usually types II, IV). Chief purpose of test is to identify rare familial disorders (I, III, V) to anticipate problems in children.
• Lipoprotein electrophoresis may be indicated if serum triglyceride level is >300 mg/dL, fasting serum is lipemic, or hyperglycemia, significant glycosuria, impaired glucose tolerance, or increased serum uric acid (>8.5 mg/dL) is present.
• Perform laboratory tests to rule out diabetes mellitus, liver disease, nephrotic syndrome, dysproteinemias, hypothyroidism.

Endocarditis, Bacterial

• Blood culture is positive in 80-90% of patients. Streptococcus viridans causes 40-50% of cases; Staphylococcus aureus, 15-20%; Streptococcus pneumoniae, 5%; and Enterococcus, 5-10%. Other causes may be gram-negative bacteria (~10% of cases; e.g., Escherichia coli, Pseudomonas aeruginosa, Klebsiella, Proteus) and fungi (e.g., Candida, Histoplasma, Cryptococcus). Bartonella has been reported to cause 3% of cases, which may be culture negative.
• In drug addicts, S. aureus causes 50-60% of cases and ~80% of tricuspid infections; gram-negative bacteria cause 10-15% of cases; cases due to polymicrobial and unusual organisms appear to be increasing. ≤75% of patients may be HIV positive.
• Proper blood cultures require adequate volume of blood, at least five cultures taken during a period of several days with temperature of 101°F or more (preferably when highest), anaerobic as well as aerobic growth, variety of enriched media, prompt incubation, prolonged observation (growth is usual in 1-4 days but may require 2-3 wks). Beware of negative culture due to recent antibiotic therapy. Beware of transient bacteremia after dental procedures, tonsillectomy, etc., which does not represent bacterial endocarditis (in these cases, streptococci usually grow only in fluid media; in bacterial endocarditis, many colonies also occur on solid media). Blood culture is also negative in bacterial endocarditis due to Rickettsia burnetii, but phase 1 complement fixation test is positive.
• Positive blood cultures may be more difficult to obtain in prosthetic valve endocarditis (due to unusual and fastidious organisms), right-sided endocarditis, uremia, and long-standing endocarditis. A single positive culture must be interpreted with extreme caution. Aside from the exceptions noted in this paragraph, the diagnosis should be based on two or more cultures positive for the same organism.
• Serum bactericidal test measures ability of serial dilutions of patient's serum to sterilize a standardized inoculum of patient's infecting organisms; it is sometimes useful to demonstrate inadequate antibiotic levels or to avoid unnecessary drug toxicity.

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• Progressive normochromic normocytic anemia is a characteristic feature; in 10% of patients, Hb level is <7 gm/dL. Rarely there is a hemolytic anemia with a positive Coombs' test. Serum iron is decreased. Bone marrow contains abundant hemosiderin.
• WBC is normal in ~50% of patients and elevated ≤15,000/cu mm in the rest, with 65-86% neutrophils. Higher WBC indicates presence of a complication (e.g., cerebral, pulmonary). Occasionally leukopenia is present. Monocytosis may be pronounced. Large macrophages may occur in peripheral blood.
• Platelet count is usually normal, but occasionally it is decreased; rarely purpura occurs.
• Serum proteins are altered, with an increase in gamma globulin; therefore positive ESR and tests for cryoglobulins, RF, etc., are found. Often a direct correlation is seen between ESR and course and severity of disease.
• Hematuria (usually microscopic) occurs at some stage in many patients due to glomerulitis, renal infarct, or focal embolic GN.
• Albuminuria is almost invariably present, even without these complications. Renal insufficiency with azotemia and fixed specific gravity is infrequent now.
• Nephrotic syndrome is rare.
• CSF findings in various complications, meningitis, brain abscess
• Laboratory findings due to underlying or predisposing diseases or complications
• Rheumatic heart disease.
• Congenital heart disease.
• Infection of genitourinary system.
• Congestive heart failure.
• Bacterial endocarditis occurs in ≤4% of patients with prosthetic valves.
• Other.

Giant Cell Arteritis (GCA)

• (Systemic panarteritis of medium-sized elastic arteries)
• Biopsy of involved segment of temporal artery is diagnostic,1 but negative biopsy does not exclude GCA because of skip lesions. Therefore, surgeon should remove at least 20 mm of artery, paraffin sections of which must be examined at multiple levels. Biopsy findings remain positive for at least 7-14 days after onset of therapy.
• Classic triad of increased ESR (≥50 mm/hr),1 anemia, increased serum ALP is strongly suggestive of GCA.
• Mild to moderate normocytic normochromic anemia is present in 20-50% of cases and is rough indicator of degree of inflammation.
• ESR is markedly increased in virtually all patients (97%); average Westergren = 107. A normal ESR excludes the diagnosis when little clinical evidence exists for temporal arteritis. CRP test has equal sensitivity.
• Serum ALP is slightly increased in ~25% of patients.
• WBC is usually normal or slightly increased with shift to the left.
• Platelet count may be nonspecifically increased.
• Serum protein electrophoresis may show increased gamma globulins. Rouleaux may occur.
• Serum CK is normal.
• Laboratory findings reflect specific organ involvement.
• Kidney (e.g., GN).
• CNS (e.g., intracerebral artery involvement, which may cause increased CSF protein; stroke; mononeuritis of brachial plexus).
• Heart and great vessels (e.g., myocardial infarction, aortic dissection, Raynaud's disease).
• Mild liver function abnormalities in 20-35% of patients.
• SIADH.
• Microangiopathic hemolytic anemia.
• Polymyalgia rheumatica is presenting symptom in one-third of patients and ultimately develops in 50-90% of cases.

Heart Failure

• Renal changes:
• Slight albuminuria (<1 gm/day) is common.

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• Isolated RBCs and WBCs, hyaline, and (sometimes) granular casts.
• Urine is concentrated, with specific gravity >1.020.
• Phenolsulfonphthalein (PSP) excretion and urea clearance are usually depressed.
• Moderate azotemia (BUN usually <60 mg/dL) is evident with severe oliguria; may increase with vigorous diuresis. (Primary renal disease is indicated by proportionate increase in serum creatinine and low specific gravity of urine despite oliguria.)
• Oliguria is a characteristic feature of right-sided failure.
• ESR may be decreased because of decreased serum fibrinogen.
• Plasma volume is increased. Serum albumin and total protein are decreased, with increased gamma globulin. Hct is slightly decreased, but RBC mass may be increased.
• Plasma sodium and chloride tend to fall but may be normal before treatment. Urine sodium is decreased. Total body sodium is markedly increased and potassium is decreased. Plasma potassium is usually normal or slightly increased (because of shift from intracellular location); it may be somewhat reduced with hypochloremic alkalosis due to some diuretics.
• Liver function changes
• Laboratory findings due to underlying disease (e.g., rheumatic fever, viral myocarditis, bacterial endocarditis, chronic severe anemia, hypertension, hyperthyroidism, Hurler's syndrome).
• Acidosis (reduced blood pH) occurs when renal insufficiency is associated or CO retention exists due to pulmonary insufficiency, low plasma sodium, or ammonium chloride toxicity.
• Alkalosis (increased blood pH) occurs in uncomplicated heart failure itself, in hyperventilation, in alveolar-capillary block due to associated pulmonary fibrosis, after mercurial diuresis that causes hypochloremic alkalosis, or because of potassium depletion.
• Alkalosis (with normal or increased blood pH) showing increased plasma bicarbonate and moderately increased pCO after acute correction of respiratory acidosis is due to CO retention when there is chloride deficit and usually decreased potassium.

Hypertension

• (Present in 18% of adults in the United States)
• Systolic hypertension
• Hyperthyroidism
• Chronic anemia with hemoglobin <7 gm/dL
• Arteriovenous fistulas-advanced Paget's disease of bone; pulmonary arteriovenous varix
• Beriberi
• Diastolic hypertension
• Hypothyroidism
• Systolic and diastolic hypertension
• Essential (primary) hypertension (causes >90% of cases of hypertension).
• Secondary hypertension (causes <10% of cases of hypertension). Laboratory findings due to the primary disease. These conditions are often unsuspected and should always be ruled out, because many of them represent curable causes of hypertension.

Due To

• Endocrine diseases
• Adrenal
• Pheochromocytoma (<0.64% of cases of hypertension)
• Aldosteronism (<1% of cases of hypertension)
• Cushing's syndrome
• Congenital adrenal hyperplasia (CAH;)
• Pituitary disease
• Signs of hyperadrenal function
• Acromegaly
• Hyperthyroidism
• Hyperparathyroidism
• Renal diseases

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• Vascular (4% of cases of hypertension)
• Renal artery stenosis (usually due to atheromatous plaque in elderly patients and to fibromuscular hyperplasia in younger patients) (0.18% of cases of hypertension)
• Nephrosclerosis
• Embolism
• Arteriovenous fistula
• Aneurysm
• Aortitis or coarctation of aorta with renal ischemia
• Parenchymal
• Glomerulonephritis
• Pyelonephritis
• Polycystic kidneys
• Kimmelstiel-Wilson syndrome
• Amyloidosis
• Collagen diseases
• Renin-producing renal tumor (Wilms' tumor; renal hemangiopericytoma)
• Miscellaneous
• Urinary tract obstructions
• Central nervous system diseases
• Cerebrovascular accident
• Brain tumors
• Poliomyelitis
• Other
• Toxemia of pregnancy
• Polycythemia
• Acute porphyria
• Drugs, toxins
• Oral contraceptives, tricyclic antidepressants
• Lead, alcohol
• Licorice ingestion

• In children <18 yrs of age

Renal disease Cardiovascular disease (e.g., coarctation of aorta) Endocrine (e.g., mineralocorticoid excess, pheochromocytoma, hyperthyroidism, hypercalcemia) Miscellaneous (e.g., induced by traction, after GU tract surgery, associated with sleep apnea) Essential

• In neonates and young infants
• Most common
• Renal artery thrombosis after umbilical artery catheterization
• Coarctation of aorta
• Congenital renal disease
• Renal artery stenosis
• Less common
• Bronchopulmonary dysplasia
• Patent ductus arteriosus
• Intraventricular hemorrhage
• Laboratory findings indicating the functional renal status (e.g., urinalysis, BUN, creatinine, uric acid, serum electrolytes, PSP, creatinine clearance, radioisotope scan of kidneys, renal biopsy). The higher the uric acid in uncomplicated essential hypertension, the less the renal blood flow and the higher the renal vascular resistance.
• Laboratory findings due to complications of hypertension (e.g., congestive heart failure, uremia, cerebral hemorrhage, myocardial infarction)
• Laboratory findings due to administration of some antihypertensive drugs
• Oral diuretics (e.g., benzothiadiazines)
• Increased incidence of hyperuricemia (to 65-75% of hypertensive patients from incidence of 25-35% in untreated hypertensive patients)
• Hypokalemia
• Hyperglycemia or aggravation of preexisting diabetes mellitus

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• Less commonly, bone marrow depression, aggravation of renal or hepatic insufficiency by electrolyte imbalance, cholestatic hepatitis, toxic pancreatitis
• Hydralazine
• Long-term dosage of >200 mg/day may produce syndrome not distinguishable from SLE. Usually regresses after drug is discontinued. Antinuclear antibody may be found in ≤50% of asymptomatic patients.
• Methyldopa
• ≤20% of patients may have positive results on direct Coombs' test, but relatively few have hemolytic anemia. When drug is discontinued, Coombs' test may remain positive for months but anemia usually reverses promptly. Abnormal liver function tests indicate hepatocellular damage without jaundice associated with febrile influenza-like syndrome. RA and SLE tests may occasionally be positive (see Chapter 17). Rarely, granulocytopenia or thrombocytopenia may occur.
• Monoamine oxidase inhibitors (e.g., pargyline hydrochloride)
• Wide range of toxic reactions, most serious of which are
• Blood dyscrasias
• Hepatocellular necrosis
• Diazoxide
• Sodium and fluid retention
• Hyperglycemia (usually mild and manageable by insulin or oral hypoglycemic agents)
• When hypertension is associated with decreased serum potassium, rule out
• Primary aldosteronism
• Pseudoaldosteronism (due to excessive ingestion of licorice)
• Secondary aldosteronism (e.g., malignant hypertension)
• Hypokalemia due to diuretic administration
• Potassium loss due to renal disease
• Cushing's syndrome

Kawasaki Syndrome (Mucocutaneous Lymph Node Syndrome)

• (Variant of childhood polyarteritis of unknown etiology, with high incidence of cardiac complications; diagnosis is based on clinical criteria)
• Diagnosis is confirmed by histologic examination of coronary artery (same as in poly- arteritis nodosa).
• Laboratory changes due to acute myocardial infarction
• Acute phase reactants are increased (e.g., ESR, CRP, alpha-1-antitrypsin); usually return to normal after 6-8 wks.
• Leukocytosis (20,000-30,000/cu mm) with shift to left during first week; lymphocytosis thereafter; peaks at end of second week; this is a hallmark of the illness.
• Anemia occurs in ~50% of patients; reaches nadir about end of second week; improves during recovery.
• CSF shows increased mononuclear cells with normal protein and sugar.
• Increased mononuclear cells in urine; dipstick negative.
• Increased WBC(predominantly PMNs) in joint fluid in patients with arthritis.

Löffler's Parietal Fibroplastic Endocarditis

• Eosinophilia ≤70%; may be absent at first but appears sooner or later.
• WBC frequently increased.
• Laboratory findings due to frequent
• Mural thrombi in heart and embolization of spleen and lung
• Mitral and tricuspid regurgitation

Myocardial Contusion

• (90% due to motor vehicle accident)
• Increased serum CK-MB (>3%) alone in 15% of cases; combined with ECG changes in 20% of cases; ECG changes alone in 65% of cases
• Increased serum cardiac troponin I (cTnI) implies some myocardial necrosis and differentiates increased CK-MB due to skeletal muscle damage. Specificity = 90% but

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sensitivity = only 30% and positive predictive value = only 16%. Cardiac troponin T (cTnT) may be increased due to muscle necrosis.

Myocardial Infarction, Acute (AMI)

• See Figs. 5-1 and and Tables 5-1, and .
• Includes the whole spectrum of acute coronary syndromes, from silent ischemia, unstable angina, and "non-Q wave" infarction, to typical AMI.

Diagnostic Criteria for AMI

• Two of the following three findings:
• History of ischemic chest discomfort for ≥30 mins
• Characteristic evolution of ECG changes

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• Typical rise and fall of cardiac enzymes. Blood should be drawn promptly after onset of symptoms. Repeat determinations should be made at appropriate intervals (e.g., 4, 8, and 12 hrs) and also if symptoms recur or new signs or symptoms develop. Changes may indicate extension or additional myocardial infarction (MI) or other complications (e.g., pulmonary infarction).

Use of Laboratory Determinations

• For diagnosis when ECG changes are nondiagnostic (occurs in ~50% of AMI patients) on admission to emergency room (e.g., masked by bundle branch block or Wolff-Parkinson-White syndrome) or may not reveal intramural or posterior or lateral infarcts. False-positive ECG occurs in >10-20% of cases.
• For differential diagnosis of chest pain.
• To follow the course of the patient with AMI.
• To estimate prognosis (e.g., marked elevation of serum enzyme [4-5× normal] correlates with increased incidence of ventricular arrhythmia, shock, and heart failure, and with higher mortality).
• For noninvasive assessment of coronary reperfusion after thrombolytic therapy.
• Utility of each enzyme depends on time of specimen's collection after onset of AMI
• Combination of markers (e.g., serum myoglobin, CK-MB, cTn) and (ratios of) serial changes are most effective because of uncertainty as to actual duration of myocardial damage.

Serum Total Creatine Kinase (CK)

• Use
• Replaced by serum cTn, CK-MB, myoglobin in various combinations.
• May allow early diagnosis because increased levels appear 3-6 hrs after onset and persist≤48 hrs.
• Sensitive indicator because of large amplitude of change (6-12× normal).
• Interpretation
• Serial total CK has sensitivity of 98% early in course of MI but false-positive rate of 15% due to many causes of increased CK.
• Returns to normal by third day; a poorer prognosis is suggested if the increase lasts more than 3-4 days. Reinfarction is indicated by an elevated level after the fifth day after previous return to normal.

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• Useful in differential diagnosis of chest pain due to diseases often associated with MI or difficult to distinguish from MI.

Serial Serum CK-MB Concentrations

• Use
• Present gold standard for diagnosis within 24 hrs of onset of symptoms.
• Detect reinfarction or extension of MI after 72 hrs.
• Document reperfusion after thrombolytic therapy.
• Interpretation
• . In AMI, CK-MB usually is evident at 4-8 hrs, peaks at 15-24 hrs (mean peak = 16× normal), with sensitivity and specificity each >97% within the first 48 hrs. By 72 hrs, two-thirds of patients still show some increase in CK-MB. More frequent sampling (every 6 hrs) is more likely to identify a peak value. False-negative results may be due to sampling timing (e.g., only once in 24 hrs or sampling <4 hrs or >72 hrs after AMI).
• . Diagnosis of AMI is usually confirmed by 8-12 hrs, and sampling beyond 24 hrs is usually not needed except to detect early reinfarction (especially in patients receiving thrombolytic therapy).
• . Diagnosis of AMI should not be based on only a single enzyme value. One criterion for AMI is serial CK-MB measurements 4 hrs apart that show ≥50% increase with at least one sample greater than upper reference value.

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• . In ~5% of AMI patients (especially in older age groups) a peak CK-MB may be the only abnormality, with total CK and CK-MB still within reference ranges. This is because normal serum total CK values decline with decreased muscle mass (e.g., with age and sedentary or bedridden status).
•  . Rapid return to normal makes CK-MB a poor marker >72 hrs after symptoms.
•  . Increased CK-MB with normal total CK may indicate non-Q wave AMI.
•  . MB index (CK-MB/total CK) should be calculated; normal <2.5. For example, with extreme skeletal muscle injury (e.g., trauma, perioperative condition), total CK may be >4000 U/L and CK-MB may be ≤40 U/L.
•  . CK-MB should be reported in units as well as percentage, because if injury of both cardiac and skeletal muscle (e.g., perioperative AMI) is present, CK-MB percentage may not appear increased.
•  . CK-MB mass immunoassays (preferred method) at 0, 3, and 6 hrs can measure small but significant serial changes that may still be within the normal range. CK-MB mass ≥10 µg/L indicates AMI. Serum CK-MB can now be measured directly in the emergency room with or without total CK, cTn, and myoglobin.
•  . Thrombolytic therapy should be given within 4-6 hrs of the acute event, at which time CK-MB may not yet be increased. CK-MB, cTn, and myoglobin measured initially and at 60 and/or 90 mins after thrombolytic therapy can document failed reperfusion.

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60 min 90 min Sensitivity Specificity Sensitivity Specificity CK-MB cTnT Myoglobin Numbers in parentheses are ratios of marker values after thrombolytic therapy to pretreatment values.

CK and CK-MB May Also Be Increased In

• Diagnostic value of CK-MB and total CK are diminished after cardiac surgery. A diagnosis of AMI cannot be made until >12-24 hrs after cardiac surgery; typically AMI patients have higher peak values of CK, CK-MB, and myoglobin; patients without AMI have earlier peaks that return to base values more rapidly.
• Increases common after angioplasty of coronary arteries; may indicate reperfusion.
• Cardiac trauma and contusions, electrical injury, and inflammatory myocarditis may produce enzyme changes that cannot be distinguished from those due to AMI. CK-MB and total CK can be increased with long-term exercise and in chronic disease.
• No significant increase after pacemaker implantation or electrical cardioversion.
• If CK-MB is >20% or persists >48-72 hrs, consider atypical CK-MB.
• Other causes of CK and CK-MB changes are noted.
• In one protocol the criteria for AMI are an increasing (above reference range) and then decreasing CK total and CK-MB in serial specimens drawn on admission and at 8- or 12-hr intervals; this is considered almost pathognomonic in patients in whom AMI is strongly suspected; no blood need be collected after 48 hrs in patients with uneventful course.
• CK-MB in pericardial fluid may be helpful for postmortem diagnosis of AMI.

Increased Serum Cardiac Troponins T and I

• Use
• Increased cTn implies some myocardial necrosis (e.g., anoxia, contusion, inflammation) even without ECG changes.
• Replace LD testing for late diagnosis of AMI. May replace CK-MB as gold standard.
• Risk stratification in patients with chest pain. Sensitive marker for minor myocardial injury in unstable angina without AMI. Patients with chest pain, normal CK-MB, nondiagnostic ECG, and detectable cTn have greater risk of later coronary events.
• Diagnosis of perioperative AMI when CK-MB may be increased by skeletal muscle injury.
• Serial measurements to assess reperfusion after thrombolytic therapy. Peak cTn after reperfusion is related to infarct size.
• Serial values may be indicator of cardiac allograft rejection.
• Interpretation
• . cTn is about as sensitive as CK-MB during first 48 hrs after AMI; sensitivity = 33% from 0 to 2 hrs, 50% from 2 to 4 hrs, 75% from 4 to 8 hrs, and approaches 100% from 8 hrs after onset of chest pain. >85% concordance with CK-MB. Specificity approaches 100%. High sensitivity for 6 days; may remain increased for ~7-10 days.
•  . With rapid ELISA for cTnT, AMI was present in
• 1% of cases with cTnT <0.1 µg/L
• 28% of cases with cTnT 0.1-0.19 µg/L
• 88% of cases with cTnT 0.2-0.29 µg/L
• 100% of cases with cTnT >4.0 µg/L3

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•  . cTnT may be increased in some patients with skeletal muscle injury, myotonic dystrophy, and chronic renal failure. cTnI is not increased by skeletal muscle injury, which makes it more highly specific for myocardial injury; may be detected in some patients with renal failure.
•  . Normal values exclude myocardial necrosis in patients with increased CK of skeletal muscle origin (e.g., after arduous physical exercise).
•  . Not increased by uncomplicated coronary angioplasty or electrical cardioversion.
•  . Not increased by pulmonary or orthopedic surgery.
•  . Long duration of increase provides a longer diagnostic window than with CK-MB but may make it difficult to recognize reinfarction.
•  . cTnI increases ~4-6 hrs after AMI and remains increased for ≤7 days. Rapid (20 mins) test kit using whole blood is now available.

Comparative Sensitivity Time after symptom onset in AMI Rapid cTnI CK-MB mass CK-MB activity    3.5±2.7 hrs    4 hrs later Unstable angina

Serum Myoglobin

• Use
• Earliest marker for AMI
• Interpretation
• Increased within 1-3 hrs in >85% of AMI patients, peaks in ~8-12 hrs (may peak within 1 hr) to ~10× upper reference limit, and becomes normal in ~24-36 hrs or less; reperfusion causes peak 4-6 hrs earlier.
• May precede release of CK-MB by 2-5 hrs.
• Sensitivity >95% within 6 hrs of onset of symptoms.
• Myoglobinuria often occurs.
• Disadvantages
• Two or three blood samples should be drawn at ~1-hr intervals (myoglobin may be released in multiple short bursts).
• Wide normal range (6-90 ng/mL).
• Low specificity for AMI (may also be increased in renal failure, shock, open heart surgery, and skeletal muscle damage or exhaustive exercise, or in patients and carriers of progressive muscular dystrophy, but not by cardioversion, cardiac catheterization, or congestive heart failure). Values are usually much higher in patients with uremia and muscle trauma than in those with AMI.

CK Isoforms

• CK-MB and CK-MM are sequentially converted in the serum by a carboxypeptidase (CK-MM MM-3 MM-2 MM-1; CK-MB MB-2 MB-1).
• Interpretation
• . CK-MM and CK-MB isoforms parallel CK-MB but rise and peak earlier. MB-2/MB-1 and MM-3/MM-1 isoform ratios appear to be the most useful, but methodology for rapid turnaround time is not widely available. Because serum MM-3 is normally so low, its release from damaged cardiac muscle is readily evident.

• Diagnostic MM isoform changes are independent of amount of tissue damage, whereas total CK activity depends on infarct size.
• MM-3/MM-1 isoform ratio shows a large change because MM-1 is continually cleared from the blood. Ratio is ~1.3 in controls but >14 in AMI patients (1.0 is a useful cutoff value).
• MB-2 >1.0 U/L and MB-2/MB-1 ratio >1.5 (normal ratio = 1) is specific for AMI within 4-8 hrs of infarct. Ratio is >1.5 within 2-4 hrs in >50% of cases, within 4-6 hrs in 92%, and by 8 hrs in 100%. MB-2/MB-1 ratio ≤1.0 by 4-6 hrs or normal CK-MB by 10 hrs rules out AMI in 95% of cases.
• MM-3 and MM-3/MM-1 ratio also increase 2 hrs after intense brief exercise and in marathon runners.

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• CK-MB subforms may also be increased in severe skeletal muscle damage (e.g., rhabdomyolysis) and muscular dystrophy.
• Isoform ratios return to normal by 24 hrs in most patients.

Glycogen Phosphorylase BB

• Use
• More sensitive early marker for AMI and unstable angina within 4 hrs after onset of pain than is CK-MB, cTnT, or myoglobin
• Sensitive marker of perioperative myocardial injury in coronary artery bypass surgery

Interpretation

• Returns to normal within 24-36 hrs.
• Not widely available. Additional studies are needed.
• Also being investigated are serum cardiac myosin heavy and light chains, fatty acid-binding protein, alpha-actin, calcitonin gene-related peptide.

Serum Lactate Dehydrogenase (LD)

• Use
• Replaced by cTn.
• Prolonged elevation lasting 10-14 days was formerly used for late diagnosis.
• Interpretation
• Increases in 10-12 hrs, peaks in 48-72 hrs (~3× normal).
• Increased CK-MB and LD-1/LD-2 ratio >1 ("flipped" LD) both within 48 hrs (not necessarily at the same time) is virtually diagnostic of AMI.
• Increased total LD with flipped LD may also occur in acute renal infarction, hemolysis (e.g., hemolytic anemia, pernicious anemia, prosthetic heart valves), some muscle disorders (e.g., polymyositis, muscular dystrophies, rhabdomyolysis), pregnancy, some neoplasms (e.g., small cell of lung, prostate, testicular germ cell); LD >2000 U suggests a poorer prognosis.

Serum Aspartate Aminotransferase (AST)

• Use
• Replaced by other enzymes in diagnosis of AMI.
• Interpretation
• AST is increased in >95% of the patients when blood is drawn at the appropriate time.
• Increase appears within 6-8 hrs, peaks in 24 hrs; level usually returns to normal in 4-6 days.
• Peak level is usually ~200 U (5× normal). Value >300 U and a more prolonged increase suggest a poorer prognosis.
• Reinfarction is indicated by a rise that follows a return to normal.
• Serum ALT is usually not increased unless there is liver damage due to congestive heart failure, drug therapy, etc.
• Serum ALP (from vascular endothelium) is increased during reparative phase (4-10 days after onset). Serum GGT is also increased.
• Leukocytosis is almost invariable; commonly detected by second day but may occur as early as 2 hrs. WBC is usually 12,000-15,000; ≤20,000 is not rare; sometimes it is very high. Usually 75-90% PMNs with only a slight shift to the left. Leukocytosis is likely to develop before fever.
• ESR is increased, usually by second or third day (may begin within a few hrs); peak rate is in 4-5 days, persists for 2-6 mos. ESR is sometimes more sensitive than WBC, as increase may occur before fever and persists after temperature and WBC have returned to normal. Degree of ESR increase does not correlate with severity or prognosis.
• CRP is usually normal in unstable angina patients who have a normal cTnT (<0.1 µg/L). Peak CRP correlates with peak CK-MB.
• Blood lactate is increased; sensitivity = 55%, specificity = 96% in patients presenting with acute chest pain.
• Glycosuria and hyperglycemia occur in ≤50% of patients.
• Glucose tolerance is decreased.
• Laboratory findings due to underlying coronary heart disease.
• Laboratory findings due to sequelae (e.g., congestive heart failure).

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Myocarditis, Viral

(Routine autopsy incidence of 1.2-3.5%)

Due To

• Coxsackievirus B (causes most cases in United States) and coxsackievirus A, echovirus, poliomyelitis, influenza A and B, cytomegalovirus (CMV), EBV, adenovirus, rubeola, mumps, rubella, variola, vaccinia, varicella-zoster virus (VZV), rabies, lymphocytic choriomeningitis, chikungunya, dengue, yellow fever
• Serologic tests for viral antigen, IgM antibody, or changed titer using acute and convalescent paired sera
• Endomyocardial biopsy of right ventricular muscle showing >5 lymphocytes/HPF and degeneration of muscle fibers has become major diagnostic tool to establish diagnosis of myocarditis and rules out other lesions (e.g., sarcoidosis).
• Increased serum markers of myocardial damage is common only in early stages
• cTn sensitivity = 53%, specificity = 93%
• CK-MB and CK total <10% sensitivity
• Increased acute phase reactants (e.g., ESR, CRP, mild to moderate leukocytosis)

Myxoma of Left Atrium

• Anemia that is hemolytic in type and mechanical in origin (due to local turbulence of blood) should be sought and may be severe. Bizarre poikilocytes may be seen in blood smear. Reticulocyte count may be increased. Other findings may reflect effects of hemolysis or compensatory erythroid hyperplasia. The anemia is recognized in ~50% of patients with this tumor. Increased serum LD reflects hemolysis.
• Serum gamma globulin is increased in ~50% of patients. IgG may be increased.
• Increased ESR is a reflection of abnormal serum proteins.
• Platelet count may be decreased (possibly the cause here also is mechanical) with resultant findings due to thrombocytopenia.
• Negative blood cultures differentiate this tumor from bacterial endocarditis.
• Occasionally WBC is increased, and CRP may be positive.
• Laboratory findings due to complications
• Emboli to various organs (increased AST may reflect many small emboli to striated muscle)
• Congestive heart failure
• These findings are reported much less frequently in myxoma of the right atrium, which is more likely to be accompanied by secondary polycythemia than by anemia.

Pericardial Effusion, Chronic

• See Table 6-2 on body fluids.
• Laboratory findings due to underlying disease (e.g., TB, myxedema, metastatic tumor, uremia, SLE). Rarely due to severe anemia, scleroderma, polyarteritis nodosa, Wegener's granulomatosis, RA, irradiation therapy, mycotic or viral infections, primary tumor of heart, African endomyocardial fibrosis, idiopathic causes.

Pericarditis, Acute

Laboratory Findings Due to Primary Disease

• Active rheumatic fever (40% of patients)
• Bacterial infection (20% of patients)
• Other infections (e.g., viral [especially coxsackievirus B], rickettsial, parasitic, mycobacterial, fungal)
• Viruses are most common infectious causes.
• Uremia (11% of patients)
• Benign nonspecific pericarditis (10% of patients)
• Neoplasms (3.5% of patients)
• Collagen disease (e.g., SLE, polyarteritis nodosa) (2% of patients)
• Acute myocardial infarction, postcardiac injury syndrome

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• Trauma
• Myxedema
• Others (e.g., hypersensitivity, unknown origin or in association with various syndromes)
• WBC is usually increased in proportion to fever; normal or low in viral disease and tuberculous pericarditis; markedly increased in suppurative bacterial pericarditis
• Examination of aspirated pericardial fluid (see Table 6-1)

Phlebothrombosis

• Tests indicate recent extensive clotting of any origin (e.g., postoperative status).
• D-dimer test (see Pulmonary Embolism and Infarction).
• Staphylococcal clumping test measures breakdown products of fibrin in serum; these indicate the presence of a clot that has begun to dissolve. Sensitivity = 88%, specificity = 66% using venography as gold standard.
• Serial dilution protamine sulfate test measures the presence of a fibrin monomer that is one of the polymerization products of fibrinogen. It is less sensitive than the staphylococcal clumping test but indicates clotting earlier.
• Laboratory findings of pulmonary infarction should be sought as evidence of embolization.

Polyarteritis Nodosa

• Tissue biopsy is basis for diagnosis
• Findings on biopsy of small or medium-sized artery.
• Findings in random skin and muscle biopsy are confirmatory in 25% of patients; most useful when taken from area of tenderness; if no symptoms are present, pectoralis major is the most useful site.
• Testicular biopsy is useful when local symptoms are present.
• Lymph node and liver biopsies are usually not helpful.
• Renal biopsy is not specific; often shows glomerular disease.
• Increased BUN or creatinine; uremia occurs in 15% of patients.
• Hepatitis B surface antigen (HBsAg) is present in 20-40% of adult patients.
• p-ANCA is positive in 70% of patients; rarely reflects disease activity.
• Increased WBC (≤40,000/cu mm) and PMNs. A rise in eosinophils takes place in 25% of patients and is sometimes very marked; it usually occurs in patients with pulmonary manifestations.
• ESR and CRP are increased.
• Mild anemia is frequent; it may be hemolytic anemia with positive Coombs' test.
• Urine is frequently abnormal.
• Albuminuria (60% of patients)
• Hematuria (40% of patients)
• "Telescoping" of sediment (variety of cellular and noncellular casts)
• Serum globulins are increased.
• Abnormal serum proteins occasionally occur. Biological false-positive test for syphilis, circulating anticoagulants, cryoglobulins, macroglobulins, etc., occurs.
• Laboratory findings due to organ involvement by arteritis may be present (e.g., GU, pulmonary, GI, neurologic in >75% of patients).

Prosthetic Heart Valves

• Complications
• Hemolysis-increased serum LD, decreased haptoglobin, reticulocytosis are usual. Severe hemolytic anemia is uncommon and suggests leakage due to partial dehiscence of valve or infection.
• Prosthetic valve infection
• Early (<60 days after valve replacement)-usually due to Staphylococcus epidermidis, S. aureus, gram-negative bacteria, diphtheroids, fungi; occasionally due to Mycobacteria and Legionella. 30-80% mortality.
• Late (>60 days postoperatively)-usually due to streptococci. S. epidermidis is common up to 12 mos after surgery. 20-40% mortality.
• . Blood culture positive in >90% of patients unless received antibiotic therapy, infection involves fastidious organism (e.g., HACEK [Haemophilus-Actinobacillus-Cardiobacterium-Eikenella-Kingella]),

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or identification requires special technique (e.g., Rickettsia, fungi, mycobacteria, Legionella).

• Surgery is indicated if blood culture is positive after 5 days of appropriate antimicrobial therapy or infection is recurrent. Infection with organisms other than Streptococcus usually require valve replacement.
• Complications of anticoagulant therapy

Rheumatic Fever, Acute5

• Increased serum cTn implies some myocardial necrosis due to myocarditis.
• Laboratory confirmation of preceding group A streptococcal infection
• Increased titer of antistreptococcal antibodies
• Positive throat culture for group A Streptococcus and recent scarlet fever
• Serologic tests-see below
• Serologic titers: one of the following is elevated in 95% of patients with acute rheumatic fever; if all are normal, a diagnosis of rheumatic fever is less likely.
• ASOT increase indicates recent group A Streptococcus pharyngitis within the last 2 mos. Increased titer develops only after the second week and reaches a peak in 4-6 wks. Increasing titer is more significant than a single determination. Titer is usually >250 U; more significant if >400-500 U. A normal titer helps to rule out clinically doubtful rheumatic fever. Sometimes ASOT is not increased even when other titers are increased. Height of titer is not related to severity; rate of fall is not related to course of disease.
• Anti-DNase B assay should also be performed because >15% of patients with acute rheumatic fever do not have an increased ASOT. This assay is superior to ASOT in detecting antibodies after group A streptococcal skin infections and is less prone to false-positive reactions; longer period of reactivity is helpful in patients with isolated chorea or carditis, who may have a long latent period before manifesting rheumatic fever during which ASOT may have returned to normal.
• Antihyaluronidase titer of 1000-1500 U follows recent group A streptococcal disease and ≤4000 U with rheumatic fever. Average titer is higher in early rheumatic fever than in subsiding or inactive rheumatic fever or nonrheumatic streptococcal disease or nonstreptococcal infections. Antihyaluronidase titer is increased as often as ASOT and antifibrinolysin titer.
• Antifibrinolysin (antistreptokinase) titer is increased in rheumatic fever and in recent hemolytic streptococcus infections.
• Acute phase reactants (ESR, CRP, increased WBC) are minor manifestations.
• ESR increase is a sensitive test of rheumatic activity; ESR returns to normal after adequate treatment with ACTH or salicylates. It may remain increased after WBC becomes normal. It is said to become normal with onset of congestive heart failure even in the presence of rheumatic activity. It is normal in uncomplicated chorea alone.
• CRP parallels ESR.
• WBC may be normal but usually is increased (10,000-16,000/cu mm) with shift to the left; increase may persist for weeks after fever subsides. Count may decrease with salicylate and ACTH therapy.
• Serum proteins are altered, with decreased serum albumin and increased alpha and gamma globulins. (Streptococcus group A infections do not increase alpha globulin.) Fibrinogen is increased.
• Anemia (Hb usually 8-12 gm/dL) is common; gradually improves as activity subsides; microcytic type. Anemia may be related to increased plasma volume that occurs in early phase of acute rheumatic fever.
• Urine: A slight febrile albuminuria is present. Often mild abnormality of protein, casts, RBCs, WBCs indicates mild focal nephritis. Concomitant GN appears in ≤2.5% of cases.

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• Blood cultures are usually negative. Occasional positive culture is found in 5% of patients (bacteria usually grow only in fluid media, not on solid media), in contrast to bacterial endocarditis.
• Throat culture is often negative for group A streptococci.
• Serum AST may be increased, but ALT is normal unless the patient has cardiac failure with liver damage.
• Determine clinical activity-follow ESR, CRP, and WBC. Return to normal should be seen in 6-12 wks in 80-90% of patients; it may take ≤6 mos. Normal findings do not prove inactivity if patient is receiving hormone therapy. When therapy is stopped after findings have been suppressed for 6-8 wks, a mild rebound may be seen for 2-3 days followed by a return to normal. Relapse after cessation of therapy occurs within 1-8 wks.

Shock

• Leukocytosis is common, especially with hemorrhage. Leukopenia may be present when shock is severe, as in gram-negative bacteremia. Circulating eosinophils are decreased.
• Hemoconcentration (e.g., dehydration, burns) or hemodilution (e.g., hemorrhage, crush injuries, and skeletal trauma) takes place.
• Acidosis appears when shock is well developed, with increased blood lactate, low serum sodium, low CO -combining power with decreased alkaline reserve.
• Blood pH is usually relatively normal but may be decreased. BUN and creatinine may be increased.
• Serum potassium may be increased.
• Hyperglycemia occurs early.
• Urine examination
• Volume: Normovolemic patients have output ≥50 mL/hr; cause should be investigated if <25-30 mL/hr. In hypovolemia, normal kidney may lower 24-hr urine output to 300-400 mL.
• Specific gravity: >1.020 with low urine output suggests patient is fluid depleted. <1.010 with low urine output suggests renal insufficiency. Specific gravity depends on weight rather than concentration of solutes; therefore it is more affected than osmolarity by high-molecular-weight substances such as urea, albumin, and glucose.
• Osmolarity: Hypovolemia is suggested by high urine osmolarity and urine-plasma osmolarity ratio of ≥1:2. Renal failure is suggested by low urine osmolarity with oliguria and urine/plasma osmolarity ratio of ≤1:1.

Systemic Capillary Leak Syndrome6

• (Very rare recurring idiopathic disorder in adults with sudden transient extravasation of <70% of plasma; very high morbidity and mortality; hypotension is part of triad)
• Hemoconcentration (e.g., leukocytosis; Hb may be ~25 gm/dL)
• Hypoalbuminemia
• Monoclonal gammopathy (especially IgG with kappa or lambda light chain) without evidence of multiple myeloma is often present. Some patients may progress to multiple myeloma.
• Laboratory findings due to complications (e.g., rhabdomyolysis, acute tubular necrosis, pleural/pericardial effusion)

Takayasu's Syndrome (Arteritis)

• Increased ESR in ~75% of cases during active disease but normal in only one-half during remission
• WBC usually normal
• Serum proteins abnormal with increased gamma globulins (mostly composed of IgM)
• Female patients have a continuous high level of urinary total estrogens (rather than the usual rise during luteal phase after a low excretion during follicular phase).
• Laboratory tests not useful for diagnosis or to guide management.
• Diagnosis is established by characteristic arteriographic changes or histologic examination.

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Thromboangiitis Obliterans (Buerger's Disease)

• (Vascular inflammation and occlusion of intermediate-sized arteries and veins of extremities)
• Laboratory tests are usually normal.

Thrombophlebitis, Septic

• Laboratory findings due to associated septicemia
• Increased WBC (often >20,000/cu mm) with marked shift to left and toxic changes in neutrophils.
• DIC may be present.
• Respiratory alkalosis due to ventilation-perfusion abnormalities with hypoxia. Significant acidosis indicates shock.
• Azotemia.
• Positive blood culture (S. aureus is most frequent organism; others are Klebsiella, Pseudomonas aeruginosa, enterococci, Candida).
• Laboratory findings due to complications (e.g., septic pulmonary infarction)
• Laboratory findings due to underlying disease

Transplant Rejection (Acute) of Heart

• Endocardial biopsy to determine acute rejection and follow effects of therapy has no substitute.
• Increasing ESR and WBC
• Increased isoenzyme LD-1 as amount (>100 IU) and percentage (35%) of total LD during first 4 wks after surgery
• These findings are reversed with effective immunosuppressive therapy. Total LD continues to be increased even when LD-1 becomes normal.
• Chronic rejection is accelerated coronary artery atherosclerosis.

Valvular Heart Disease

• Laboratory findings due to associated or underlying or predisposing disease (e.g., syphilis, rheumatic fever, carcinoid syndrome, genetic disease of mucopolysaccharide metabolism, congenital defects)
• Laboratory findings due to complications (e.g., heart failure, bacterial endocarditis, embolic phenomena)

Vasculitis, Classification

By Etiology

• Primary
• Polyarteritis nodosa
• Wegener's granulomatosis
• Giant cell arteritis
• Hypersensitivity vasculitis
• Secondary
• Infections
• Bacteria (e.g., septicemia due to Gonococcus or Staphylococcus)
• Mycobacteria
• Viruses (e.g., CMV, HBV)
• Rickettsia (e.g., Rocky Mountain spotted fever)
• Spirochetes (e.g., syphilis, Lyme disease)
• Associated with malignancy (e.g., multiple myeloma, lymphomas)
• Connective tissue diseases
• RA
• SLE
• Sjögren's syndrome
• Diseases that may simulate vasculitis (e.g., ergotamine toxicity, cholesterol embolization, atrial myxoma)

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By Size of Involved Vessel (Noninfectious Vasculitis)

• Large vessel
• Takayasu's arteritis
• Giant cell (temporal) arteritis
• Medium-sized vessel
• Polyarteritis nodosa
• Kawasaki's disease
• Primary granulomatous CNS vasculitis
• Small vessel
• ANCA-associated vasculitis
• Wegener's granulomatosis
• Churg-Strauss syndrome
• Drug induced
• Microscopic polyangiitis
• Immune complex-type vasculitis
• Henoch-Schönlein purpura
• Cryoglobulinemia
• Rheumatoid vasculitis
• SLE
• Sjögren's syndrome
• Goodpasture's syndrome
• Behçet's disease
• Drug induced
• Serum sickness
• Paraneoplastic vasculitis (lymphoproliferative, myeloproliferative, carcinoma)
• Inflammatory bowel disease

Wegener's Granulomatosis7

• (Necrotizing granulomatous vasculitis affecting respiratory tract; disseminated form shows renal involvement)
• Diagnosis is established by biopsy of affected tissue with cultures and special stains that exclude mycobacterial and fungal infection.

Antineutrophil Cytoplasmic Antibodies (ANCA)

• Use
• Aid in diagnosis and classification of various vasculitis-associated and autoimmune disorders.
• Interpretation
• c-ANCA (anti-proteinase 3; coarse diffuse cytoplasmic pattern) is highly specific (>90%) for active Wegener's granulomatosis. Sensitivity >90% in systemic vasculitic phase ~65% in predominantly granulomatous disease of respiratory tract, ~30% during complete remission. Height of ELISA titer does not correlate with disease activity; high titer may persist during remission for years. Also occasionally found in other vasculitides (polyarteritis nodosa, microscopic polyangiitis [e.g., lung, idiopathic crescentic and pauci-immune GN], Churg-Strauss vasculitis).
• p-ANCA (against various proteins [e.g., myeloperoxidase, elastase, lysozyme], perinuclear pattern) occurs only with fixation in alcohol, not formalin. Positive result should be confirmed by ELISA. Has poor specificity and 20-60% sensitivity in a variety of autoimmune diseases (microscopic polyangiitis, Churg-Strauss vasculitis, SLE, inflammatory bowel disease, Goodpasture's syndrome, Sjögren's syndrome, idiopathic GN, chronic infection). However, pulmonary small vessel vasculitis is strongly linked with myeloperoxidase antibodies.
• Both p-ANCA and c-ANCA may be found in non-immune mediated polyarteritis and other vasculitides.
• Atypical pattern (neither c-ANCA or p-ANCA; unknown target antigens) has poor specificity and unknown sensitivity in various conditions (e.g., HIV infection, endocarditis, cystic fibrosis, Felty's syndrome, Kawasaki syndrome, ulcerative colitis, Crohn's disease).

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• Laboratory findings reflecting specific organ involvement
• Kidneys-renal disease in ~80% of cases. Hematuria (>5 RBCs/HPF), proteinuria, azotemia. Nephrosis or chronic nephritis may occur. Most patients develop renal insufficiency. Biopsy most frequently shows focal necrotizing GN with crescent formation; coarse granular pattern with immunofluorescent staining. Biopsy is important to define extent of disease.
• CNS.
• Respiratory tract.
• Heart.
• Nonspecific laboratory findings
• Normochromic anemia, thrombocytosis, and mild leukocytosis occur in 30-40% of patients; eosinophilia may occur but is not a feature. Leukopenia or thrombocytopenia occur only during cytotoxic therapy.
• ESR is increased in 90% of cases, often to very high levels; CRP level correlates with disease activity even better than ESR.
• Serum globulins (IgG and IgA) are increased in up to 50% of cases.
• Serum C3 and C4 complement levels may be increased.
• RF may be present in low titer in two-thirds of cases.
• ANA is negative.
• Laboratory findings due to secondary infection (usually staphylococcal) of sinus, mucosal, pulmonary lesions.
• Laboratory findings due to therapy (e.g., bladder cancer and sterility due to cyclophosphamide therapy).

REFERENCES

1. Included in American College of Rheumatology 1990 criteria for classification of vasculitis. Arthritis Rheum .

2. Stewart JT, et al. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol .

3. Gerhardt W, et al. An improved rapid troponin T test with a decreased detection limit: a multicentre study of the analytical and clinical performance in suspected myocardial damage. Scand J Clin Lab Invest .

4. Heeschen C, et al. Analytical performance and clinical application of new rapid bedside assay for the detection of serum cardiac troponin I. Clin Chem .

5. Special Writing Group, Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Guidelines for the diagnosis of rheumatic fever: Jones Criteria, 1992 update. JAMA .

6. Tahirkheli NK, Greipp PR. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. Ann Intern Med .

7. Included in American College of Rheumatology 1990 criteria for classification of vasculitis. Arthritis Rheum .