Muscle Diseases & Biomarkers Overview

Cardiac & Skeletal Muscle Disease, and Muscle Biomarkers

• The presentation covers cardiac and skeletal muscle diseases, and muscle biomarkers.
• The presentation date is 17-18/12/2024.
• The presenter is Dr. Halil Resmi.

Muscle Anatomy and Function

• There are three types of muscle: skeletal, cardiac, and smooth.
• Skeletal muscle consists of unbranched, cylindrical muscle cells arranged in parallel bundles.
• Skeletal muscle fibers are neurogenic, meaning their contraction is initiated by nerve impulses.
• Skeletal muscles can be further categorized into fast-twitch and slow-twitch types, differing in their biochemical properties.
• Cardiac muscle is found exclusively in the heart.
• Like skeletal muscle, cardiac muscle contains actin and myosin filaments.
• Cardiac muscle contractions are involuntary, termed myogenic.
• Smooth muscle is composed of elongated, non-striated cells with a single, centrally located nucleus.
• Smooth muscle is involuntary.
• Smooth muscle is found in the walls of tubes and sacs like blood vessels, the uterus, bladder, and intestines.

Pathological Conditions

• Cardiac Disorders:

  • Ischemia: Inadequate blood supply to an organ.
  • Atherosclerosis: The most common cause of ischemia, involving cholesterol buildup in the arteries. This can lead to occlusion (blockage) of the artery.
  • Ischemic heart disease ranges from unstable angina (reversible myocardial injury) to frank myocardial infarction (large areas of necrosis).
  • Acute coronary syndrome (ACS) is a group of conditions that block or severely reduce blood flow to the heart muscle. This can damage the heart muscle, with heart attack and unstable angina being examples.
  • Congestive heart failure (CHF): A disease related to decreased pumping capability. It represents a spectrum of diseases from left ventricular dysfunction (LVD) to overt CHF. Angiotensin-converting enzyme (ACE) inhibitors are an important therapy for CHF.

• Cardiomyopathy: Characterized by inadequate muscle contraction from direct damage to myocardium cells, leading to heart failure. Typically results in enlargement throughout the four chambers of the heart.

• Skeletal Muscle Disorders:

  • Diseases of skeletal muscles manifest as motor function issues, most commonly as muscular weakness. This can be categorized into neurogenic muscular atrophies, muscle fiber disorders (myopathies), and disturbances of neuromuscular junctions.

• Muscular Dystrophies: A group of genetic chronic diseases affecting muscle. These conditions show progressive weakness and degeneration of skeletal muscles, often without neural degeneration. The age of onset, course, and fiber type effects vary among the diseases. Pseudohypertrophic muscular dystrophy (Duchenne's muscular dystrophy) is the most common type, often involving a deletion in the dystrophin gene.. Serum creatine kinase (CK) levels are often elevated even before symptoms arise.

  • No effective treatment currently exists for most of the muscular dystrophies. Gene therapy is a possible approach.

Changes of Analytes in Disease

• Myocardiocyte Biomarkers: When cardiac myocytes die (become necrotic), they lose their membrane integrity and intracellular components enter the bloodstream. These circulating molecules are called cardiac biomarkers.

• Ideal Cardiac Marker Criteria:

  • Abundant within myocytes, low within the bloodstream.
  • Released early after injury.
  • Absent in non-myocardial tissues.
  • A direct relationship between the plasma level of the cardiac marker and the severity of myocardial injury.
  • Persistent in the blood for an extended period to allow for timely diagnosis.
  • Affordable and rapid to measure.

• Myocardial Infarction (MI) Definition: A damaging process where ischemic injury is irreversible and causes cell death (necrosis). MI diagnosis involves clinical history of the patient, electrocardiogram (ECG) interpretation, and measurement of specific cardiac biomarkers. cTnT and cTnI have become the cornerstone for detecting MI through increased serum levels.

Cardiac Biomarkers in MI and Coronary Disease

• Biomarkers such as CK-MB and various Troponin levels rise in the bloodstream following an MI, often 4-6 hours after chest pain onset. These biomarkers, notably Troponin, have greater sensitivity and specificity for detecting cardiac injury compared to CK-MB.

• CK-MB: The first cardiac marker discovered, although other biomarkers including Troponin rise and remain in the bloodstream for a longer period

  • This molecule, a component of creatine kinase (CK), rises 2-3 hours after MI symptoms and peaks within 1-2 days.

• Troponins (cTnT & cTnI): More sensitive and specific markers for cardiac injury than CK-MB. They demonstrate high diagnostic value 8-12 hours after MI presentation. cTnI remains elevated for 3-7 days post-MI.

  • Troponin assays show a more extended time in blood flow, making them valuable in detecting myocardial dysfunction history.

• Guidelines for MI Diagnosis: Analysis of blood samples is required over a sequential period following suspicion of an MI, guidelines recommend sample collection times at 2-4 hours, 6-8 hours, and also 12 hours post-suspicion. These times may extend based on the results of earlier samples and clinical suspicion.

• CK and CK Isoenzymes in Non-MI Conditions: In non-MI conditions, the isoenzyme pattern differs from the rise and fall pattern seen in MI, instead often remaining chronically elevated. Conditions such as Duchenne's muscular dystrophy or polymyositis frequently exhibit elevated CK-MB levels in the serum as a result of skeletal muscle abnormalities

• Myoglobin: Myoglobin, present in both cardiac and skeletal muscles, is not cardiac-specific and can be elevated in various skeletal muscle conditions, such as renal failure, injury or diseases impacting skeletal muscle. However, it is one of the earliest indicators for MI. Rises are detectable as early as 1 to 2 hours after symptom onset. Myoglobinuria is a clinical finding suggesting massive muscle cell damage (trauma or drug-induced).

Diagnostic Use of Cardiac Troponins

• Troponin plays a significant role in both diagnosing and assessing risk in cases of acute coronary syndrome (ACS).
• Very low troponin values in patients without cardiac disease allow for the use of lower discriminatory values for MI diagnosis.
• Troponin's specificity aids in reducing diagnostic uncertainty from increased CK-MB levels following skeletal muscle injury.