Cardiovascular-Cardiac Muscle

Cardiovascular-Cardiac Muscle

1. Structure of Cardiac Muscle

   • Cardiac muscle is similar to skeletal muscle in that it is striated and that the sarcomere is the contractile unit, with contraction being achieved by the relationship between calcium, troponins and the myofilaments.
   • However, cardiac muscle has a number of notable histological differences including
     • Branching fibres
     • Centrally located nucleus (occasionally two nuclei per cell)
     • T tubules lie in register with the Z band and not the AI junction (as in skeletal muscle).
   • Arguably the most important feature of cardiac muscle is its intercalated discs and gap junctions. The disks act as the Z band would in skeletal muscle, demarcating where a cardiac muscle cell meets the next. The transverse portions form adherens-type junctions (attachments) and desmosomes, holding the muscle cells together, while the lateral portions form gap junctions that allow for quick conduction of action potentials. This is crucial to allow the heart to contract in a coordinated manner and pump the blood.
   • Cardiac muscle is myogenic (creates its own action potentials) but is regulated by the pacemaker cells – the sino-atrial node and atrioventricular node. These cells spontaneously depolarise to trigger a cardiac action potential. However the cells of the bundle of His and the Purkinje cells are also capable of spontaneous depolarisation. However it should be noted that purkinje fibres are NOT cardiac muscle cells- they are larger cells with far fewer myofilaments and extensive gap junctions, as well as lots of glycogen. They conduct action potentials much faster allowing for synchronous contraction of the ventricles.
   • Clinical Relevance – Cardiac Hypertrophy: Hypertrophy refers to the thickening of muscle, in this case cardiac muscle, through an increase in muscle cell size. This occurs in response to pressure overload. Familial cardiomyopathic hypertrophy can cause sudden death in adults who are observed to be perfectly healthy. This is due to genetic defects in some of the proteins found in the sarcomere of cardiac muscle such as myosin and troponin. The condition is autosomal dominant so affected individuals will always have one affected parent. When the circuit of depolarisation is interrupted, for example following a myocardial infarction when there has been damage to the muscle (this can be due to a number of other causes also including hypertension and hypertrophy) the desynchronised contraction can result in abnormal heart rhythms, an arrhythmia.

2. Contraction of Cardiac Muscle

   • As in skeletal muscle, cardiac myocytes contract according to the sliding filament theory of muscle contraction.
   • Calcium-Induced Calcium Release
     • Calcium can be released from the sarcoplasmic reticulum by 2 ways
       • Via IP3
         • Gq-protein coupling facilitates the release of Ca2+ from the sarcoplasmic reticulum. This is particularly important in muscle types that require calcium induced calcium release (e.g. in cardiac muscle).
         • Gq activates the effector: Phospholipase C. Phospholipase breaks PIP2 into IP3 + DAG. IP3 binds IP3R of the SR. DAG acts on various proteins (e.g PKC). Action terminated by IP3 phosphatase (IP3 cleaved to IP2). Ca2+ channels on the SR opens and Ca2+ is released.
         • PIP2 (phosphatidylinositol 4,5-biphosphate) derived from cell membranes
       • Via Ryanodine receptors (RyR)
         • Membrane depolarisation opens voltage-operated calcium channels (VOCCs) in a T-tubule system. This calcium binds to RyR and this changes the conformation of a Ca2+ channel that is closely associated with this RyR. Ca2+ stored in the SR is released. This is the ‘calcium spark’.
     • Released calcium leads to a calcium spike which facilitates the binding to troponin C and thus activating the cross bridge cycling mechanism for contraction. After the stimulus is removed, sarco(endo)plasmic reticulum calcium ATPase (SERCA) pumps Ca2+ is moved into the lumen at the expense of ATP. This allows relaxation.
   • Pathway of Contraction
     • Pacemaker cells in the SA and AV nodes initiate an action potential which is conducted around the heart via gap junctions. The action potential travels down the T-tubules between sarcomeres resulting in an influx of calcium ions into the sarcoplasm through VOCCs. When calcium enters the sarcoplasm (through VOCCs and ryanodine receptors) it binds to cardiac troponin-C which moves the tropomyosin away from the actin binding site thus exposing it and initiating contraction.
     • Sliding Filament Model of Contraction
       • Cardiac muscle contraction occurs via the sliding filament model of contraction, much like skeletal muscle. Once calcium is bound to troponin-C and the conformational change of tropomyosin has occured myosin heads can bind to actin. Following this ADP and inorganic phosphate are released from the myosin head so the power stroke can occur, in this the myosin pivots and bends, pulling on the actin and moving it, causing muscle contraction. After this occurs a new molecule of ATP binds to the myosin head, causing it to detach from the actin. Finally, the ATP is hydrolysed into ADP and inorganic phosphate, following this the cycle can begin again and further contraction can occur.
     • Removal of Calcium
       • After the stimulus is removed intracellular calcium is then reduced by two main methods
         • By entering the sarcoplasmic reticulum for storage via a SERCA (sarco(endo)plasmic reticulum calcium-ATPase) channel at the expense of an ATP molecule.
         • Through an NCX (sodium-calcuim exchange) channel which extrudes a calcium ion and admits a sodium ion when membrane repolarisation starts.
       • Calcium is no longer bound to troponin C and the actin binding site is covered up ending contraction and relaxing the muscle.
   • Clinical Relevance – Troponin Assays
     • Some subtypes of troponin can be used as very specific and sensitive markers of damage to the cardiac muscle, particularly troponin I and T. They are typically measured in the blood to differentiate between unstable angina and myocardial infarctions, as they may present with similar symptoms. A patient suffering from a myocardial infarction would typically show elevated cardiac troponins within the blood, which would not be the case for unstable angina. Depending on the troponin measured the levels would peak a few hours following the damage and they can remain high for up to two weeks after the event. However it is important to note that they are not specific to myocardial infarction and only indicate cardiac muscle damage, as such they may also be elevated in conditions such as heart failure, pericarditis and amyloidosis. In addition to this, non-cardiac diseases such as sepsis or renal failure can also elevate troponins.

3. The Action Potential in Ventricular Cells

   • Action potentials in ventricular myocytes trigger the Ca2+ entry that is necessary for their contraction. Their synchronicity, characteristic shape and length safeguards the heart against abnormal electrical activity. When these safeguards go wrong it can be potentially life threatening.

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