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					The Heart                                                                                 Ahmed Rabiey



                                       The Heart

        Heart is one of the most, if the most, important organ of the body. It allows the blood to
circulate through the whole body, ensuring a proper nutrition and withdrawal of waste from the
different organs of our body.

        The most relevant thing about the heart that we usually don’t know is its ability to generate
its own rhythmicity, without any neuronal control. Indeed, neuronal control only regulates it! Two
types of tissues are to be distinguished in the heart: the nodal tissues (Sinoatrial and Atrioventricular
node, also called pacemaker cells) and the non-nodal tissue (what left: AV/His Bundle, Bundle
Branches, Purkinje Fibers).

        To fully understand and pass everything about the heart, you need to know:

                                 - What is the Slow Action Potential?
                                 - What is the Fast Action Potential?
                           - What are the mechanical events of the heart?
                               - Law of Laplace, how is it is implicated?
                              - How autonomic innervations regulates?
    -   ECG: How is it working, what can be the change in case of disease? (I, however, won’t explain
                                                  this part)
                             - Disease, malfunction related to the heart.

I. Electrophysiology of Heart

    1) Global View
        So the main characteristic of the heart is its ability to contract even without neural input.
        This is done thanks to some tissues present in the heart, which generate spontaneous
        depolarization. These are the Sinoatrial Node (SA node), the Atrioventricular Node (AV node)
        and in a lesser extent the AV bundle, Branches bundle and Purkinje Fibers. All of them have
        different firing rate, from highest to lowest: SA node > AV Node > Non nodal tissues

        Thus In vivo, the most important tissues concerning electrophysiology are the SA and AV
        node; it will be those, together with neural control that will give us a Heart beat of
        approximately 60-70 beat/sec. If SA node is malfunctioning, AV node firing rate will
        determine the Heart Beat (which will be equal to 45-50 min-1) and if AV node is
        malfunctioning, fibers will determine the Heart Beat (which will be equal to 25-40 min-1)

        Nodal tissues (SA and AV node) will generate Slow Action potential while Non nodal tissues
        (AV bundle, bundle branches, Purkinje Fibers) will generate fast action potential.




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The Heart                                                                                Ahmed Rabiey


       2) Slow Action Potential
          a) Typical shape and explanation


  0




                                                                                                  3


 mV




                                                                            2

                                            Slow Diastolic
                                            Depolarization
 -65

                                      1

                                                                                         Ik
                                                                       ICaT     ICaL
                                              If




  1
         Beginning of the funny current (If); the hyperpolarization triggers the opening of the
Nonspecific cation channels that will start to slowly depolarizes the membrane: this is the slow
diastolic depolarization.



  2
         T-Type Calcium channels (ICaT) in a first time, and then L-Type (ICaL) will open and provoke
a True Action Potential. The action potential is due to an inward flow of Calcium.



  3
         Repolarization, then hyperpolarization, will occur via the late potassium channels (IK) that
will trigger finally another funny current. Potassium channels close as the membrane potential
decrease.




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The Heart                                                                               Ahmed Rabiey


       b) Difference between SA and AV node

            (1) Longer diastolic depolarization: The SA node will spread its AP toward the atria and
                finally reach the AV node (located in the interatrial wall). The AV node can generate
                its own AP, but their diastolic depolarization is slower than the SA action potential:
                Before the true AP of AV node is done, AP of SA node will arrive and trigger a true
                AP. SA rhythm will therefore determine the AV rhythm.

               In absence of SA node, AV applies its rhythmicity to the heart, which will beat at
               45/55 min-1.




                  SA Node




                                                                       With SA node            Without SA node




                    AV Node




                       : Hypothetic True AP. Would happen without the SA node.




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The Heart                                                                                  Ahmed Rabiey


            (2) Smaller amplitude, and longer true AP: This will imply important things :
                               1) it delays the ventricular contraction, very important to ensure
                                   proper ventricular filling (we need time to transfer blood from
                                   atrium to ventricle)
                               2) It limits the firing rate (see graph).




      SA Node




        AV Node




                           : We clearly see the difference between the 2 AP. AV action
                           potential is longer, permitting the delay of ventricular
                           contraction
                           : Hypothetic increase of firing rate, limited by the Absolute
                           refractory period and relative refractory period of AV node.

            ARP            : Absolute Refractory Period

            ARP            : Relative Refractory Period




                                                           ARP        RRP
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The Heart                                                                                  Ahmed Rabiey


   3) Fast Action potential
       a) Typical shape and explanation

             There is a resting membrane potential, opposite
             to the slow action potential.
             Its value is – 90 mV.


                    0                         2                     3




                mV


                                 1
                                                                                                        4
                                                            ARP                          RRP




                -90



                1       : First, the action potential arriving to the cell will open the (1) fast voltage
                        gated sodium channels; causing a fast depolarization. Calcium channels also
                        open but do not play a major role in this fast depolarization.

                2       : Just after this upstroke, we observe a slow repolarization due to the
                        opening of (2) early potassium channels. Moreover, chloride channels also
                        open and contribute to repolarization.

                3       : This is the plateau phase. VERY IMPORTANT! It corresponds to an
                        equilibrate outflow and inflow of calcium and potassium, therefore leaving a
                        stable membrane potential. (3) Calcium inflow is mainly due to L-Type.




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The Heart                                                                                Ahmed Rabiey


                  4       : Here, two more potassium channels open to repolarize the cell:

                                                 (4) The late potassium channels
                                                 (5) Inward rectifier current channel


       b) Significance of refractory period

       It can be interesting to notice that the “refractory state” of the heart coincide with the
       plateau phase: why and what is this state?

       After activation of Sodium (Na+) Channels, those will go to their “inactivated” mode
       (remember cell bio), forbidding any new AP = this is the absolute refractory period.

       During the repolarization, generation of AP is possible but not easy = this is the relative
       refractory period.

       Important consequences:

               1) No tetany! Single cardiac contraction never fuse (the contraction can’t be
                  maintained). Increase of firing rate won’t “hold” the contraction, because of the
                  refractory period.
               2) If there is a premature beat/contraction, we will see a “Compensatory Pause”




       c) Characteristics of the non-nodal fibers: AV bundle (or his bundle), bundle
          branches, Purkinje fibers.

                         Spontaneous Action Potential

                          Under physiological condition, those fibers don’t generate action potential.
                          However, they can and they do it in complete conduction block.
                          In this case, they will set the Heart beat at 25-40 min-1.

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The Heart                                                                                 Ahmed Rabiey



                        Spread of excitation

                         ... is allowed thanks to those 3 fibers
                         … is very fast (0,08 sec to go to ventricular myocytes, this is a usual written
                         question)
                         Pathway is: AV bundle/bundle of HIS  Bundle branches  Purkinje fibers
                          Ventricular Myocytes.




                                                                                                  AV bundle, or
                                                  AV                                              bundle of HIS
                              SA




                                                                                                           Bundle
                                                                                                           Branches




                                                                                                           Purkinje
                                                                                                           Fibers


II. Neuronal Regulation
    We just saw that the heart can beat by his own. But in vitro condition, the heart should beat at
100 min-1; however in vivo, we observe a beat frequency of 65-70 min-1… How come?

This is due to the parasympathetic and sympathetic regulations of the heart.

To speak about those innervations and consequences, we need to define 4 terms:

                    1.   Inotropic Effect : acting on contractile force
                    2.   Chronotropic Effect : acting on Heart Beat
                    3.   Dromotropic Effect : acting on conduction velocity
                    4.   Bathmotropic Effect : acting on excitability

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The Heart                                                                                Ahmed Rabiey


   This effect can be positive, it will then increase the corresponding characteristic, or negative,
where it will decrease the corresponding characteristic. E.g.: Positive Inotropic effect = Increased
contractile force.

    1) Sympathetic effects
        Easy to remember: ALL BECOME POSITIVE. When we apply a sympathetic innervation
    there is a positive inotropic, chronotropic, dromotropic, bathmotropic effect.

        a) In the SA node :

            Adrenaline and noradrenalin, which are the main neurotransmitter of sympathetic
        innervations, act on Beta1 receptor, increasing the cAMP level, via Gs (to understand
        everything here, please refer the “endocrinology chapter”, section VII.Catecholamines; you
        can also take a look at the “receptors chapter”, section II.7-TM receptors).

            cAMP level is critical for opening and closure of cationic channels responsible of the
        funny current.

        There are 3 related cAMP effects, and thus 3 sympathetic consequences:

                                     1. The diastolic depolarization becomes steeper, so the true
                                        AP is generated earlier  Positive Chronotropic effect.




                                     2. The funny current start earlier (the maximum repolarization
                                        limits is pushed towards more positive value)
                                     3. The threshold of the true AP is pushed toward more negative
                                        value.  Positive Bathmotropic Effects




                                                             3.


                                            2.



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The Heart                                                                                 Ahmed Rabiey


                     Those are the most important effects you need to know for the SCT and/or
                     Oral. I added others because I read it somewhere, but I never saw any question
                     on those last.

       b) In the AV node

              Phosphorylation of Calcium (Ca2+) channels occurs, causing a Dromotropic effect.

       c) In fast conducting fibers (our 3 famous fibers)

          It will open de chloride (Cl-) channels of early repolarization; early repolarization will be
       more efficient  Positive chronotropic effect.

   2) Parasympathetic effects
       Two things important to remember: ALL BECOME NEGATIVE and it ONLY ACT ON
   PACEMAKER CELLS.

       a) In the SA node

               It acts through mAch muscarinic receptors coupled to Gi. What does it mean? Again,
       I would advise you to read the endocrinology and receptor chapter to understand
       everything. But basically, when a receptor is coupled to Gi is means that it will decrease the
       cAMP level.
       We will therefore have opposite effects compared to those seen before (1. 2., 3.)!

               Moreover, there is another pathway to apply its negative effect: indeed, in SA node
       we find some Potassium (K+) channels gates Ach sensitive. Those will hyperpolarize the
       membrane: the diastolic depolarization will start later and reach the threshold slower:




       b) In the AV node

              We also find there some Potassium (K+) channels gates Ach sensitive

III. The cardiac cycle
            See the cardiac cycle.docx.

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The Heart                                                                                Ahmed Rabiey


IV. Contractility of the Heart

   1) Global view of contraction in myocardium
       a) Calcium inward and calcium release (Initiation of contraction)

              Very simple, the action potential will arrive to the cell, opening the ryanodine
       receptors of the sarcoplasmic reticulum thanks to the depolarization. This will release the
       Calcium (Ca2+) stored in the SR. 90% of the calcium needed for initiation of contraction
       comes from here.

       b) Proper contraction

              It will occur as usual. Calcium (Ca2+) will bind to troponin C, troponin C will change his
       conformation, moving the tropomyosin, letting a free binding site on action for myosin.

       c) Calcium evacuation

              Two transporters are important here for evacuation of calcium after contraction: the
       SERCA pump and the 3Na+/Ca2+ exchanger.

              The SERCA pump is embedded in the sarcoplasmic reticulum and ATP driven. It’s a
       primary active transport that takes the Calcium from the cytoplasm to the SR.

       The 3Na+/Ca2+ exchanger is embedded in the plasma membrane. It takes 3 Na+ to eject 1
       Ca2+. It is thus a secondary coupled active transport.
       This transporter is quite important for the future because it’s one of the main targets to treat
       heart failure. Here is how we think: by increasing the Na+ intracellular concentration, the
       gradient which was allowing this transporter to work properly will be cancelled (Na+
       gradient). Ca2+ will thus stay longer in the cell and allow a proper contraction. We can use
       drugs such as cardiac glycosides (ouabain, etc.) that will block the Na+/K+ pump. This will
       increase the Na+ concentration.

   2) Other processes implicated in Heart contraction
       a) General rules to understand.

            Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)

            SV = End Diastolic Volume (EDV) – End Systolic Volume (ESV)

               Now, what all that means? Cardiac output is the amount of blood ejected from your
            heart in a minute. Heart rate is… well you know that. Stroke volume is the amount of
            blood ejected from your heart at each beat.

               EDV is the amount of blood left in your heart at the end of the diastole, and ESV is
            the amount of blood left in your heart at the end of the systole. We can consider the
            atrium or the ventricle for those last 2, but we usually consider the ventricle.


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The Heart                                                                                     Ahmed Rabiey


             The stroke volume HAS TO BE EQUAL to the amount of blood received:


                                                       2.
                                        1.   Vena    Heart       Aorta      1.




                                                       2.

                                    1.       Vena     Heart      Aorta 1. 1.




                                                        2.

                                                      Heart        Aorta         1.
                                   1.        Vena



                Please notice the arrows: 1. as the inward volume (called Venous Return) increases,
                the outward volume (stroke volume) increases also. Venous return = Stroke volume.

                2. As the venous return increases, there is more blood to eject. Therefore, the heart
                contraction has to increase to follow the rule VR = SV

       b) Frank starling Mechanism or Heteromeric Regulation

            When the VR increases, due to the compliance of the heart, the wall will stretch.

            In order to understand everything we have to know that at rest, in each myocyte, only
            25% of the total cross-bridges between myosin and actin can be made.

                                   Myosin                                                             Myosin

                    Myosin                                                            Myosin




                  : Cross-Bridge                                                      Actin



            The power of contraction is directly proportional to the number of cross-bridge.

            Two things will happen when the wall stretches…




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The Heart                                                                              Ahmed Rabiey


                           1. Number of cross bridge will increase, allowing a stronger contraction.
                              (expressed by the                  )
                           2. Troponin C will be more sensitive to calcium, therefore more binding
                              sites will be freed from tropomyosin, and a stronger contraction will
                              occur.



                      This can be expressed by the length diagram tension (final topic!)


                            1.

                      2.


                 3.

            4.

      5.




                                             Total
                                             Tension
  Tension
                                 3.



                                                                       Passive
                                                                       Tension
            2.                           Active        4.                                  Maximum overlap
                                         Tension                                           of filament =
                                                                                           maximum number
                                                                                           of cross bride =
                                                                                           maximum strength
                                                                                           of contraction
      1.                                                       5.


                                                                    Sarcomere Length




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The Heart                                                                                 Ahmed Rabiey


       Finally, we have to talk about the law of Laplace to see how pressure and wall tension are
       related:




       Where:

                                    o    Tw : tension of wall
                                    o    P : Pressure in cavity
                                    o    R : radius of cavity
                                    o    d : thickness of wall

       c) The sympathetic intervention or Homeotropic Regulation

           So we just see that by heterotropic regulation, increase of Venous Return will result in an
       increase of Wall Stretch = increase contraction = increase of stroke volume.

       But this is not the only regulation: Sympathetic has also a positive inotropic effect (increase
       contraction). This will increase the stroke volume.

       BUT! Here the EDV is kept constant, opposite to the heterotropic regulation! We don’t
       need an increase of blood return to increase contraction!

       This is actually the main effect during physical activity. Indeed, the heterotropic effect is very
       effective but it needs some time: we have to wait the heart is fulfilled, the wall stretched, to
       have an increase of contraction.

       In physical activity, there isn’t enough time for this, the EDV is even decreasing (your heart is
       beating faster; the diastole is shorter so there is less time to transfer blood from atrium to
       ventricle)! Therefore heterotropic regulation doesn’t occur or at a less extent.




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