1 CLINICAL CHEMISTRY 6th edition bishop
Page 568: Heart Failure (HF) and Causes
HF can result from disorders of the walls of the heart or from disorders of the great vessels
Most HF cases are due to left ventricular dysfunction
Common causes of HF include coronary artery disease, cardiomyopathies, inflammatory heart disease, valvular disease, and cardiac arrhythmias
HF is not equivalent to cardiomyopathy or left ventricular dysfunction, but these terms refer to possible reasons for the development of HF
Acute Coronary Syndromes (ACS)
ACS is a general term that describes a continuum of events including angina, reversible tissue injury, unstable angina, myocardial infarction (MI), and extensive tissue necrosis
Symptoms of ACS include chest pain, referred pain, nausea, vomiting, dyspnea, diaphoresis, and lightheadedness
Atherosclerosis is the major cause of ACS, characterized by the thickening and hardening of artery walls due to deposits of cholesterol-lipid-calcium plaque
Atherosclerosis is an inflammatory disorder with various mechanisms leading to cellular injury, such as bacterial infection, hyperlipidemia, diabetes mellitus, and proinflammatory cytokines
Atherosclerosis narrows the arteries and leads to plaque disruption and thrombus formation
Nine factors predispose individuals to atherosclerosis: age, sex, family history, dyslipidemia, smoking, hypertension, sedentary lifestyle, and diabetes mellitus
Premenopausal women have lower risk due to higher levels of high-density lipoprotein (HDL) cholesterol, but this difference disappears after menopause
Dyslipidemia, specifically elevated triglycerides and LDL cholesterol and reduced HDL cholesterol, is strongly associated with atherosclerosis
Lowering LDL cholesterol reduces the incidence of coronary artery disease and the progression of atherosclerosis
Atherosclerosis is often found in families, but it's difficult to distinguish genetic from lifestyle factors in predicting coronary artery disease
Smoking is strongly related to coronary artery disease in men, but the relationship is less defined in women
Diabetes is associated with an increased risk of coronary artery disease, especially in those with poorly controlled diabetes
Sedentary lifestyle and hypertension are risk factors for the development of atherosclerosis
Ischemia and its Effects on the Heart
Ischemia to the heart can result in three conditions: CHF, angina pectoris, and MI
Angina pectoris is chest pain due to coronary artery disease and is a symptom of ischemia
Stable angina occurs during moderate activity and subsides when the activity is removed
Unstable angina presents with pain and discomfort unpredictably
Not all chest pain is related to angina pectoris, as pain from heartburn can mimic angina pectoris pain
Page 569:
Angina has symptomatic and pathophysiologic differences
Stable angina: formed plaque enclosed in a fibrous cap
Unstable angina: plaque ruptures, blood clots form, and lumen of coronary vessel decreases
Stable angina goes away at rest, while unstable angina may worsen and cause permanent damage to heart muscle tissue
Unstable angina is extremely painful, does not respond well to standard treatment, and progresses rapidly towards AMI
Angina can be differentiated from AMI using diagnostic tests
Angina presents symptomatically with chest pain
Electrocardiographic or enzyme changes are not seen in angina unless it is prolonged or severe
Page 570:
Hypertension affects one in every three U.S. adults and its prevalence increases with age
Hypertension is defined as persistent systolic blood pressure of at least 140 mm Hg and/or diastolic pressure of at least 90 mm Hg
Hypertensive heart disease is caused by the direct or indirect effects of elevated blood pressure
Peripheral resistance is the most important factor that determines blood pressure and increased resistance results in heart disease
The relationship between blood pressure and risk for cardiovascular disease is independent of other risk factors
Prehypertension is a category that identifies individuals at increased risk for developing hypertension
Hypertension may be classified as normal, prehypertension, stage 1 hypertension, or stage 2 hypertension
Page 570 (continued):
Infectious agents can cause various heart diseases
Common heart diseases caused by infectious agents include rheumatic heart disease, infective endocarditis, and pericarditis
Rheumatic heart disease is a complication of rheumatic fever and is hypothesized to result from an autoimmune response
Rheumatic fever primarily affects children and young adults and is caused by group A β-hemolytic streptococci infection
Rheumatic fever is uncommon in the United States but remains a problem in developing countries
Rheumatic heart disease can lead to inflammation, valve insufficiency, heart failure, pericarditis, and death
The diagnosis of rheumatic heart disease is based on specific criteria
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Diagnosis of infective endocarditis requires presentation of major or minor criteria and evidence of recent streptococcal infection.
Major criteria: Carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules.
Minor criteria: Fever, arthralgia, previous rheumatic fever or rheumatic heart disease, acute phase reactants, prolonged P-R interval on ECG.
Evidence of streptococcal infection: Increased anti-streptolysin O or other streptococcal antibodies, positive throat culture for group A -hemolytic streptococci, positive rapid direct group A streptococci carbohydrate antigen test, recent scarlet fever.
Infective endocarditis is an infection of the endocardial surface of the heart caused by microorganisms and fungi.
Common bacterial causes: Streptococci and staphylococci.
Organism attaches to the endocardium, invades the valves, and forms vegetations that interfere with valve function.
Clinical presentation: Acute (sudden onset of spiking fevers, chills, drowsiness) or subacute (vague and insidious with low-grade fevers, fatigue, anorexia, splenomegaly).
Treatable if identified early.
Pericarditis is inflammation of the pericardium, the membrane surrounding the heart.
Causes: Infections (bacteria, viral or fungi), autoimmune disorders, other diseases.
Accumulation of pericardial fluid is hallmark sign.
Different types of fluid indicate different causes: Purulent exudates (bacterial infections), clear serous fluids (viral infections), serofibrinous exudate (severe damage as in rheumatic heart disease).
Laboratory Diagnosis of Myocardial Infarction:
Myocardial infarction is myocardial necrosis due to prolonged ischemia.
Categorized by size of infarct: microscopic, small, moderate, large.
Size categories based on percentage of left ventricular myocardium affected.
Diagnosis based on laboratory findings.
Jones Criteria for the Diagnosis of Rheumatic Heart Disease:
Major criteria: Carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules.
Minor criteria: Fever, arthralgia, previous rheumatic fever or rheumatic heart disease, acute phase reactants, prolonged P-R interval on ECG.
Evidence of streptococcal infection required for diagnosis.
Various tests and indicators used to confirm streptococcal infection.
Page 572: Definition and Diagnosis of Myocardial Infarction (MI)
MI can be defined pathologically as acute, healing, or healed
Acute MI is characterized by the presence of polymorphonuclear leukocytes
Healing MI is characterized by the presence of mononuclear cells and fibroblasts without polymorphonuclear leukocytes
Healed MI is characterized by scar tissue without cellular infiltration, usually takes 5-6 weeks
Diagnosis of MI is based on clinical symptoms, ECG changes, and rise and/or fall of highly sensitive biochemical markers
Criteria for the diagnosis of MI include:
Rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit, and evidence of myocardial ischemia, and at least one of the following:
Symptoms of ischemia
ECG changes (new ST-T changes or new left bundle-branch block [LBBB])
Development of pathologic Q waves in the ECG
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood
For percutaneous coronary interventions (PCIs) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile of upper reference limit are indicative of periprocedural myocardial necrosis
For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile of the upper reference limit are indicative of periprocedural myocardial necrosis
Pathologic findings of an AMI
Page 550: Case Study 25-3
An 83-year-old man with severe coronary artery disease, diffuse small vessel disease, and significant stenosis distal to a vein graft from previous CABG surgery
Admitted after routine office visit with symptoms of pedal edema, jugular vein distention, and heart sound abnormalities
Laboratory data on admission:
Urea nitrogen: 53 mg/dL (normal range: 6-24 mg/dL)
Creatinine: 2.2 mg/dL (normal range: 0.5-1.4 mg/dL)
Total protein: 5.8 g/dL (normal range: 6.0-8.3 g/dL)
Albumin: 3.2 g/dL (normal range: 3.5-5.3 g/dL)
Glucose: 312 mg/dL (normal range: 60-110 mg/dL)
Calcium: 4.1 mEq/L (normal range: 4.3-5.3 mEq/L)
Phosphorus: 2.4 mg/dL (normal range: 2.5-4.5 mg/dL)
Total CK: 134 U/L (normal range: 54-186 U/L)
CK-MB: 4 ng/L (normal range: 0-5 ng/L)
% CK-MB: 3% (normal range: >6%)
Myoglobin: 62 µg/L (normal range: >70 µg/L)
Troponin T: 0.2 µg/L (normal range: 0-0.1 µg/L)
Page 573: Introduction to Cardiac Markers
LDH ratio replaced by CK and CK-MB as diagnostic markers for myocardial necrosis
Cardiac troponins I and T currently preferred biomarkers for myocardial necrosis
Combination of cardiac markers recommended due to lack of ideal single diagnostic test
Ideal cardiac marker features:
High specificity for myocardial damage in the presence of skeletal muscle injury
High sensitivity to detect minor heart damage
Capability to differentiate reversible from irreversible cardiac damage
Ability to be used as a monitor of prognosis and therapy
Rapid, easy-to-perform, and cost-effective quantitative assays
Absent or not detectable in patients without myocardial damage
Page 573: Current guidelines for diagnosing AMI
National Academy of Clinical Biochemistry recommends using two biochemical markers to diagnose AMI
Marker increased early after symptom onset (within 6 hours)
Definitive marker with high sensitivity and specificity for myocardial damage (increases within 6-9 hours after symptoms and remains abnormal for several days)
Page 573-574: Enzymes used to detect myocardial damage
Enzymes previously used but not recommended for routine use: AST, LDH, and LDH isoenzyme determinations
Enzymes currently in clinical use: CK and CK-MB
Total CK measurement not recommended due to large skeletal muscle distribution and lack of specificity
CK is a cytosolic enzyme involved in muscle metabolism
CK has three cytosolic isoenzymes: CK-MM (CK-3), CK-MB (CK-2), and CK-BB (CK-1)
CK-MB most specific for myocardium, valuable tool for MI diagnosis
CK-MB rises within 4-6 hours after chest pain onset, peaks at 12-24 hours, returns to normal levels within 2-3 days
CK-MB mass assays replace CK-MB activity assays, detect increased serum CK-MB earlier
Relative index (CK-MB mass assay/total CK * 100) used as indicator of MI, relative index >3 indicative of AMI
Page 574: Cardiac Proteins
Proteins monitored in cases of AMI: myoglobin, cardiac troponins, cardiac myosin light chains
Myoglobin present in cardiac and skeletal muscle, rises early after damage
Lack of specificity, but useful for early release from damaged muscle
Page 574: Biomarkers for Assessment of Myocardial Necrosis
Myoglobin is not cardiac specific, but if concentrations remain within the reference range 8 hours after the onset of chest pain, AMI can essentially be ruled out.
Troponins (TnT, TnI, TnC) are preferred biomarkers for assessment of myocardial necrosis.
Troponins rise 4-10 hours after the onset of symptoms, peak at 12-48 hours, and remain elevated for 4-10 days.
Sustained elevation of troponins serves as definitive markers for AMI.
Blood samples for troponins should be drawn at presentation, at 6-9 hours, and again at 12-24 hours if earlier measurements were not elevated and clinical suspicion of MI is high.
TnT measurements are useful in patients who do not seek medical attention in the 2-3 day window when CK-MB is elevated.
Cardiac TnT begins to rise within a few hours after the onset of chest pain, peaks at 2 days, and can remain elevated for 7-10 days.
Cardiac TnI increases above the reference range between 4 and 6 hours after chest pain onset, peaks at 12-18 hours, and returns to within reference limits in about 6 days.
An ultrasensitive TnI assay (TnI-Ultra) has been developed for earlier identification of AMI and implementation of treatment.
Markers of Inflammation and Coagulation Disorders
Inflammation plays a role in atherogenesis, atherosclerotic plaque formation, and acute coronary syndrome.
Proposed markers of inflammation include high-sensitivity C-reactive protein (hsCRP), pregnancy-associated plasma protein A (PAPP-A), and lipoprotein-associated phospholipase A2 (Lp-PLA2).
hsCRP is the most extensively studied marker of inflammation.
It is an acute-phase protein produced by the liver in response to injury, infection, and inflammation.
Elevated baseline levels of hsCRP are correlated with higher risk of future cardiovascular morbidity and mortality.
Each standard deviation increase in baseline hsCRP is associated with a 45% increase in relative risk of nonfatal MI or sudden cardiac death over 2 years of follow-up.
hsCRP also demonstrates prognostic capacity in those without a diagnosis of vascular disease.
Page 575: Biomarkers for Cardiovascular Disease
Inflammation markers, such as high-sensitivity C-reactive protein (hs-CRP), can predict the long-term risk for future cardiovascular events.
Treatment to reduce inflammation can be given to patients at risk.
Pregnancy-Associated Plasma Protein A (PAPP-A) is a zinc-binding protein found in high serum concentrations in pregnant women.
PAPP-A is associated with the progression of atherosclerosis and plaque instability.
More data is needed to confirm its role as a marker of unstable atherosclerotic plaques.
Lipoprotein-Associated Phospholipase A2 (LP-PLA2) is an enzyme associated with small, dense LDL cholesterol particles.
Elevated LP-PLA2 values are associated with increased risk for heart disease and stroke.
When analyzed with CRP, it further increases the risk for cardiovascular disease.
Natriuretic peptides (NPs), such as B-type natriuretic peptide (BNP) and its prohormone fragment NT-proBNP, play a role in the regulation of cardiovascular homeostasis.
BNP and NT-proBNP are released in response to ventricular stretch or stress and are increased in diseases characterized by expanded fluid volume and reduced renal clearance.
BNP and NT-proBNP are useful in diagnosing heart failure (HF) and have prognostic value in patients with acute coronary syndromes (ACSs).
BNP concentrations below 20 pmol/L are unlikely to indicate HF, while concentrations above this level have a high probability of HF.
BNP may also be relevant in determining the prognosis of patients with CHF or recent AMI.
Page 576: Patient-Focused Cardiac Tests
Early diagnosis of patients with AMI leads to less cardiac tissue damage, fewer complications, reduced hospital length of stay, and faster recovery.
90% of patients admitted to the hospital require biochemical testing to confirm or exclude AMI.
Cardiac marker results should be available within 1 hour of sampling according to the National Academy of Clinical Biochemistry Standards of Laboratory Practice.
Point-of-care (POC) testing for cardiac markers is a strategy to reduce turnaround time.
Medical and technical issues must be addressed when considering POC cardiac testing.
Qualitative and quantitative test systems are available, as well as systems that produce a panel of cardiac marker results or discrete, single-analyte results.
Collaboration between laboratorians and clinicians is necessary to determine which cardiac markers are offered at their institution.
Determining diagnostic cutoff values for AMI on POC results and correlating those results with those performed in the clinical laboratory at a later time are concerns.
POC cardiac marker testing is classified as moderately complex testing under the Clinical Laboratory Improvement Amendments Act (CLIA), requiring more stringent regulatory guidelines and greater oversight by the laboratory.
Role of Laboratory in Monitoring Heart Disease
The laboratory's role in monitoring heart function involves measuring the effects of the heart on other organs such as the lungs, liver, and kidney.
Arterial blood gases are used to determine the respiratory acidosis and elevated carbon dioxide levels often seen in patients with heart disease.
Patients with edema will develop electrolyte and osmolality changes as a result of fluid retention and ionic redistribution.
Serum electrolyte determinations, including sodium, potassium, chloride, and calcium, are important to monitor diuretic and drug therapy in patients with heart disease.
Elevations of AST, ALT, ALP, and GGT are often seen in patients with chronic right ventricular failure, suggesting liver congestion and damage.