KULSOOM KULSOOM Biomarkers in Cardiovascular System Dr. Bibi Kulsoom http://www.123rf.com/photo_9342517_cartoon-doctor-in-white-coat-attending-a-patient.html KULSOOM KULSOOM KULSOOM KULSOOM KULSOOMBiomarkers Cardiovascular Cardio Blood Substances that • Lead to • Involved in process of • Released as a result of cardiovascular disease Vascular http://www.highlands.edu/academics/divisions/scipe/biology/labs/cartersville/2122/diagrams/heartdiagram3.jpg KULSOOM • Appearance of abnormal Detected substances and/OR • ed level of normal substances Sampling or measured in blood as a marker KULSOOM KULSOOM KULSOOM KULSOOM Cardiovascular Biomarkers: Serum Lipid Lipid profile: Normal Levels – LDL : < 100mg/dl TG VLDL – HDL: 40-60mg/dl – Total chol : <200mg/dl LDL LDL – Triglycerides: < 150 mg/dl Lipid profile: Abnormal HDL – LDL – HDL – Total cholesterol – Triacylglycerol KULSOOM Chol HDL Increased risk of CVS Disease HDL KULSOOM KULSOOM KULSOOM ProteinKULSOOM Biomarkers • Enzymes – Creatine Kinase • Other Proteins – Apolipoprotein A – Apolipoprotein B – Lactate Dehydrogenase – Troponin I – Aspartate Transaminase (AST) – Troponin T – Myoglobin – Homocysteine (amino acid) – C-reactive Protein – Fibrinogen – Amyloid A – Brain Natriuretic Factor – Atrial Natriuretic Factor KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Creatine (Phospho) Kinase (CK, CPK) • Tissue location & Isoenzymes : Three isoenzymes found o CK-MM (97%): found in skeletal muscles o CK-MB(2%): found in cardiac muscles o CK-BB(traces): found in brain cells  Function: ATP Creatine ADP Creatine kinase Creatine phosphate • Creatine phosphate quickly regenerates ATP in the tissues. • Arginine + Glycine + Methionine  Creatine. KULSOOM KULSOOM KULSOOM KULSOOM Creatine (Phospho) Kinase (CK, CPK) KULSOOM • Main conditions with raised levels of CK-MB is heart tissue damage(e.g. myocardial infarction (MI)). • A total CK level will reflect the presence of tissue damage but, specific isoenzyme (CK-MB) can identify the underlying cause or its location. • Normal levels of total CK =30 to 180 U/L (units per liter). • CK-MB fraction: 0-5% of CK, KULSOOM CK-MB activity: 0-15% KULSOOM KULSOOM KULSOOM KULSOOM Lactate Dehydrogenase • Tissue location & Isoenzyme: five isoezymes mainly distributed as follows: – LDH-1: heart muscle and red blood cells. – LDH-2: white blood cells. – LDH-3: lungs. – LDH-4: kidney, placenta, and pancreas. – LDH-5 : liver and skeletal muscle. KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Lactate Dehydrogenase  Function: NAD+ Lactate NADH Lactate dehydrogenase Pyruvate • Main conditions with abnormal levels: tissue damage (e.g. MI), cancers, kidney disease, and liver disease. LDH1 is raised in heart tissue damage. • Normal levels: 0-280 U/L KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Lactate Dehydrogenase • A total LDH level will reflect the presence of tissue damage but, by itself, it cannot be used to identify the underlying cause or its location. • LDH too has been superseded by the newer markers and should not be included in the ‘cardiac profile’. But LDH might be used as a marker of cardiac dysfunction where a troponin assay is not available. KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Aspartate Transaminase (AST) • One of the oldest markers of MI. • AST (+ CK and LDH) is still in use. • Levels can be elevated in liver diseases as well. • Little value as a marker of cardiac dysfunction and has been superseded by newer markers. KULSOOM KULSOOM KULSOOM KULSOOM Cardiovascular Biomarkers: KULSOOM Serum Apolipoproteins  Apolipoprotein A TG VLDL  Apolipoprotein B LDL LDL   Apolipoprotein A   Apolipoprotein B HDL Chol HDL Increased risk of cardiovascular Disease KULSOOM HDL KULSOOM KULSOOM KULSOOM KULSOOM Troponins Troponin Actin http://jolisfukyu.tokai-sc.jaea.go.jp/fukyu/tayu/ACT04E/04/0406.htm KULSOOM Tropomyosin I C T http://img.tfd.com/mk/S/X2604-S-10.png KULSOOM KULSOOM KULSOOM KULSOOM Troponins • Tissue location & types: cytoplasm of the muscle cells • Three types, which regulate muscle contraction. – Troponin C (TnC) binds to calcium ions to produce a conformational change in TnI – Troponin I (TnI) binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place. – Troponin T (TnT) binds to the tropomyosin strand forming a complex. KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM I & T Troponin • TnT & TnI are specific (different) for skeletal & heart muscle. They are measured in the blood to differentiate between unstable angina and myocardial infarction (heart attack) in patients with chest pain KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Myoglobin • A protein which stores oxygen inside muscle tissue (cardiac, skeletal & smooth). • is the earliest biological marker of myocardial necrosis. • This is now replaced by troponin, the more specific one. • has the advantage of responding very rapidly, rising and falling earlier than CKMB or troponin. • Raised in muscle damage (e.g. MI, skeletal muscle damage). • Normal levels in blood: < 80 ng/mL. KULSOOM http://www.nap.edu/books/0309064066/xhtml/images/img00013.jpg KULSOOM KULSOOM KULSOOM Biomarkers ReleasedKULSOOM in Blood after Myocardial Infarction Myoglobin Total CK LDH CK-MB Troponin I http://1.bp.blogspot.com/-ORQRvT9GZGM/Th7e0di7WhI/AAAAAAAAoKw/Ex7Cv5eba30/s1600/CardiacEnzymes.jpg KULSOOM KULSOOM KULSOOM KULSOOM Biomarkers ReleasedKULSOOM in Blood after Myocardial Infarction Troponin T Troponin I Myoglobin KULSOOM CK-MB & Total CK http://www.revespcardiol.org/sites/default/files/elsevier/images/255/255v56n07/grande/255v56n07-13049677tab04.gif KULSOOM KULSOOM KULSOOM Biomarkers ReleasedKULSOOM in Blood after Myocardial Infarction KULSOOM http://www.vetmed.vt.edu/education/Curriculum/VM8304/vet%20pathology/CASES/ISCHEMIA%202006/CARDIAC%20ENZYMES.jpg KULSOOM KULSOOM KULSOOM Biomarkers ReleasedKULSOOM in Blood after Myocardial Infarction KULSOOM MARKER DETECTION PEAK DISAPPEARANCE Myoglobin 1–4h 6 – 7h 24h CK-MB mass 3 – 12 h 12 – 18 h 2– 3 days Total CK 4–8h 12 – 24 h 2– 3 days cTnT 4–9h 12 – 48 h 5 – 7 days cTnI 4–9h 12 – 24 h 5 – 7 days LDH 24-48 hrs 48-72 hrs 10-14 days KULSOOM KULSOOM KULSOOM MetabolismKULSOOM of Homocysteine THF Methyl THF Serine Methionine ATP Pi + PPi B12 Homocysteine S-Adenosylmethionine Adenosine Methyl acceptor B6 S-Adenosylhomocysteine Methylated product Cystathionine -ketobutyrate B6 Cysteine THF = Tetrahydrofolate KULSOOM KULSOOM KULSOOM KULSOOM Elevated Homocysteine Levels Increase the Risk for KULSOOM Cardiovascular Disease 1 Homocysteine injures the arterial wall and fatty substances accumulate. Circulating monocytes rush to the site of injury causing inflammation. http://www.laddmcnamara.net/wp-content/uploads/2012/03/Homocysteine-Damage-Ladd-McNamara.jpg 2 3 Arterial wall cells proliferate in an effort to heal the lesion, leading to plaque formation. The normal levels of homocysteine should be less than 10 micromoles/L. KULSOOM KULSOOM KULSOOM KULSOOM C-reactive Protein (CRP), Fibrinogen & Amyloid A protein KULSOOM •  C-reactive protein •  Fibrinogen •  Amyloid A protein Activation certain genes Inflammation in any part of the body IL-6 Increased risk of cardiovascular Disease •  C-reactive protein •  Fibrinogen •  Amyloid A protein Inflammation in atherosclerotic plaque • Markers of inflammation • Favor more inflammation • More coagulobility KULSOOM KULSOOM KULSOOM KULSOOM C-reactive Protein (CRP), Fibrinogen & Amyloid A protein KULSOOM CRP is a protein present in the blood (secreted by liver) that shows the presence of inflammation in the body. Atherosclerosis is an inflammatory process. CRP can be a marker of atherosclerosis and myocardial infarction. Fibrinogen is a protein present in the blood that shows the predisposition to thrombus formation. Atherosclerosis can rupture and lead to thrombus formation which is the collection of fibrin meshwork of and platelets aggregation. Hence it can be a marker of myocardial infarction. Amyloid A a protein in the blood secreted by liver in response to the presence of inflammation in the body. Amyloid A can be a marker of atherosclerosis. KULSOOM KULSOOM KULSOOM KULSOOM KULSOOM Atrial & Brain Natriuretic Peptide(ANP) • Atrial natriuretic peptide (ANP): Secreted by atrial muscles in response to atrial distention due to any cause. Normal levels: 3 + 0.3 p mol/L • Brain natriuretic peptide(BNP): Secreted by ventricular muscles stretching. Normal values of BNP: <50 pg/ml BNP: >100 pg/ml suggests congestive heart failure. KULSOOM http://www.ncbi.nlm.nih.gov/pubmed/8630708 KULSOOM