Cardiac & Skeletal Muscle Disease & Muscle Biomarkers PDF

CARDIAC & SKELETAL MUSCLE DISEASE, and MUSCLE BIOMARKERS Dr. Halil Resmi 17-18/12/2024  MUSCLE ANATOMY AND FUNCTION There are three groups of muscle: – Skeletal – Cardiac – Smooth Skeletal muscle consist of unbranched, cylindirical muscle cells that arranged in...

CARDIAC & SKELETAL MUSCLE DISEASE, and MUSCLE BIOMARKERS Dr. Halil Resmi 17-18/12/2024  MUSCLE ANATOMY AND FUNCTION There are three groups of muscle: – Skeletal – Cardiac – Smooth Skeletal muscle consist of unbranched, cylindirical muscle cells that arranged in parallel bundles, Cells contains fibers that run the whole lenght of the muscle. Skeletal muscle The contraction of these fibers are initiated by nerve impulses and therefore termed neurogenic. Skeletal muscle can also be divided into two types; – Fast-twitch – Slow-twitch which differ in their biochemical nature. Cardiac muscle Cardiac muscle is found exclusively in the heart and like skeletal muscle, it contains actin and myosin flaments.  Contraction of muscle flaments leads to the pumping of the blood from atria and ventricle. Cardiac muscle control is involunterily, it therefore is termed myogenic. Smooth muscle Smooth muscle composed of elongated, nonstriated cells with a single, centrally located nucleus. SMC is not under voluntary control, it is also called involuntary muscles, They are found in wall of tube or sac like structure, such as blood vessel, the wall of uterus, the wall of bladder and intestines. PATHOLOGICAL CONDITIONS  Cardiac Disorders Ischemic Heart Disease Ischemia is a condition in which an organ has an inadequate blood supply for maintaining its essential functions. The most common cause is atherosclerosis. In atherosclerosis, cholesterol is deposited in arterial wall that feed myocardium and occlude the artery.  Ischemic diseases range from unstable angina (associated with reversible myocardial cell injury) to frank myocardial infarction (with large areas of necrosis).  Acute Coronary Syndrome (ACS) Acute coronary syndrome (ACS) is a term for a group of conditions that suddenly block or severely reduce blood flow to the heart muscle. This can damage the heart muscle. Heart attack and unstable angina are both types of ACS.  Congestive Heart Failure (CHF) CHF is a disease that is related to decreased capability to pump blood. CHF represents a spectrum disease from left ventricular dysfunction (LVD) to end-stage overt CHF, An important therapy for CHF is treatment with angiotensin-converting enzyme (ACE) inhibitors.  Cardiomyopathy Cardiomyopathy is characterized by inadequate muscle contraction caused by direct damage to myocardium cells and typical results in heart failure. Cardiomyopathy usually manifests as an enlargement in all four chambers of the heart and as cardiac failure.  Skeletal Muscle Disorders Diseases of muscle are charcterized by motor function such as muscular weakess. The three major categories of muscle disorders, according to the part of the motor affected; – Neurogenic muscular atrophies, – Muscle fiber disorders (myopathies), – Disturbances of the neuromuscular junctions.  Disorders of Muscle Fibers: Muscular Dystrophies Muscular dystrophy is a general name for a group of genetic chronic disease of muscle, General characteristics include progressive weakness and degeneration of skeletal muscle with no evidence of neural degeneration. These genetic disease have different inheritance patterns, The age of onset, the course of disease, and its effects on different fiber types differ among the individual disease. Disorders of Muscle Fibers: Muscular Dystrophies Pseudohypertrophic muscular dystrophy (or Duchenne’s muscular dystrophy-DMD) is the most common type, Most people with DMD have a deletion in dystrophin gene, and a defective dystrophin protein, Serum CK enzyme is greatly elevated, even before symptoms develop, No effective treatment is available for DMD, but the disease is a prime candidate for gene therapy. CHANGES OF ANALYTES IN DISEASE  Myocardiocyte Biomarkers When cardiac myocytes become necrotic, they lose membrane integrity and intracellulary components pass into blood circulation. Eventually, these molecules are detectable in the peripheral circulation, These molecules are collectively known as cardiac biomarkers. Cardiac Biomarkers The ideal cardiac marker of MI should be abundant in myocytes and low in blood, released early after injury and absent in nonmyocardial tissues. There should be a direct relation between the plasma level of the cardiac marker and the effect of myocardial injury. Cardiac Biomarkers The marker should persistant in blood for a sufficient lenght of time to allow a high rate diagnosis, Measurement of the marker should be easy, inexpensive, and rapid.  Definition of Myocardial Infarction (MI) MI is a damaging process, in which ischemic injury is irreversible, leading to cell death and necrosis. Diagnosis of AMI relies upon the clinical history of patient, interpretation of the ECG and measurement of serum levels of cardiac- specific biomarkers, According to recent concensus, cTnT and cTnI now represent the cornerstone for detection of MI.  Cardiac Biomarkers in MI Typically, CK-MB or troponin levels in the blood become elevated 4 to 6 hours after the onset of chest pain. These biomarkers have high diagnostic value within 8 to 12 hours after presentation, This time course represents the classic temporal pattern of CK-MB changes and is often helpful in distinguishing uncomplicated MI from extension or reinfarction. Creatine Kinase (CK) & Creatine Kinase MB (CK-MB) The first cardiac biomarker to fit many of criteria is CK-MB. CK-MB is one of three isoenzymes arising from total creatine kinase (CK). Total CK is a dimeric enzyme composed of two subunits, termed “M” to denote muscle origin or “B” to designate brain origin. There are three major CK isoenzymes; the two homodimers CK-MM and CK-BB and the heterodimer CK-MB. Myocardium is the only tissue that has a high proportion and concentration of CK-MB. Cardiac Biomarkers in MI The diagnosis of MI requires analysis of blood samples taken at appropriate intervals, Guidelines have recommanded a sampling sequence including sample collecting time at 2 to 4 hours, 6 to 8 hours and 12 hours after a MI is suspected. This time can be extended if the earlier samples were negative and clinical index of suspicion was high. Cardiac Biomarkers in MI During the initial course of an MI, an elevated CK-MB and normal total CK can be detected. A distinct rise and fall of the CK values can occur, in some cases these rise do not exceed the upper limit.  Cardiac Biomarkers in Coronary Disease Troponin (T&I) elevation are substantially more sensitive and specific for cardiac injury than CK-MB. Thus, the troponins have been generally accepted the preferred biomarker of cardaic disease.  Diagnostic Use of Cardiac Troponins Troponin plays a vital role in the diagnosis and risk assessment in ACS. Several general inference can be made regarding to troponins; – The release kinetics of cTnI and cTnT are similar to those of CK-MB after MI, – Troponin remains elevated in blood for 4 to 10 days after MI. Diagnostic Use of Cardiac Troponins – Very low troponin values in patient without cardiac disease permit the use of lower discriminatory values for determination of MI. – Troponin’s cardiac specificity helps eliminate to diagnostic uncertinity caused by increased CK-MB following skeletal muscle injury.  Cardiac Troponin I (cTnI) Although cTnI has a lower molecular weight (27 kDa) than cTnT (37 kDa) and CK-MB (85 kDa), its release kinetics and use as an early indicator of MI is similar to those of cTnT and CK-MB. cTnI is similar to cTnT in most clinical applications, and its measurement offers the same advantage over CK-MB. Cardiac Troponin I (cTnI) cTnI remains elevated 3 to 7 days after acute MI, Thus, cTnI and CK-MB have comparable diagnostic sensitivity for initial 48 to 72 hours, But, cTnI has an improved sensitivities from 72 to 96 hours after MI. Cardiac Troponin I (cTnI) In contrast to CK-MB and total CK, cTnI is not elevated in patients extreme skeletal muscle injury including; – Acute skeletal muscle injury following marathon racing, – Chronic myopathy of Duchenee’s muscular distrophy, – Chronic renal failure requiring dialysis.  Cardiac Troponin T (cTnT) Once an MI has occured, cTnT increases in serum after 4 hours, It has a peak value or plateau at 1 to 6 days, a second peak may be observed due to the presence of a second pool of ‘bound fraction’, According to WHO definition, the clinical sensitivity of cTnT is similar to that of CK-MB during the first 48 hours after onset of chest pain. Cardiac Troponin T (cTnT) Because of the extended life time in the serum, cTnT may offer substantially information about the recent history of myocardial dysfunctions. Sensitivity & Specifity of CMs  Myoglobin Myoglobin is present in both cardiac and skeletal muscle, limiting its diagnostic specificity. Myoglobin is the most effective early marker for MI. A rises is detectable in blood as early as 1 to 2 hours after symptome onset. Myoglobin Myoglobin is not cardiac specific and patient with; – Renal failure – Injury, trauma – Disease involving skeletal muscle can have abnormal concentrations in the absence of MI. The presence of myoglobinuria can be used to confirm massive muscle cell damage (trauma and drug induced). https://www.biomerieux-diagnostics.com/vidasr-acute-coronary-syndrome-acs-panel  CK & CK Isoenzymes in Non-MI Conditions In condition other than MI, the isoenzyme pattern does not follow a rise and fall pattern, but instead is chronically elevated. Duchenne’s muscular distrophy, polymyositis, rhambdomyositis frequently show increased levels of CK-MB in serum. CK & CK Isoenzymes in Non-MI Conditions Because the absolute CK amount in skeletal muscle is about 5 to 10 fold of cardiac muscle, the total CK levels observed in skeletal muscle abnormalities dramatically higher than those of observed in MI.