Cardiac Muscle and Pathophysiology Notes

Regulation of Vascular Tone

  • Vasodilators: Reduce pressure by relaxing vascular smooth muscle, dilating resistance vessels and increasing capacitance.

Nitric Oxide

  • Acts in smooth muscles.
  • Activates guanylyl cyclase.
  • Guanylyl cyclase converts GTP to cyclic guanosine monophosphate (cGMP).
  • cGMP causes relaxation in blood vessels.

Control of Smooth Muscle and Calcium

  1. Sarcoplasmic Reticulum (SR):

    • Stores calcium ions within the cell.
    • Calcium ion release is highly regulated.

  2. Trigger Calcium (Extracellular):

    • Enters the cell via L-type calcium channels.
    • Binds to Ryanodine receptors on the SR.

  3. Trigger Calcium-Ryanodine Receptor Complex:

    • Releases calcium from the SR into the cytoplasm.

  4. Calcium in the Cytoplasm:

    • Forms a complex with calmodulin (CM).

  5. Calcium-Calmodulin Complex:

    • Activates myosin light chain kinase (MLCK).

  6. Myosin Light Chain Kinase (MLCK):

    • Phosphorylates myosin light chain.
    • Phosphorylation leads to muscle contraction.

Hyperpolarization vs. Depolarization

  • Endothelium-Derived Hyperpolarizing Factor:

    • Binds to receptors.
    • Causes opening of potassium channels and closing of calcium channels.

Review of Renin-Angiotensin-Aldosterone System (RAAS)

Cardiac Electrophysiology

  • Cardiac Action Potential
  • Non-Pacemaker Cells
  • Pacemaker Cells
  • Electrocardiogram (ECG)
  • Conduction Velocity
  • Excitability
  • Autonomic Effects on Heart Rate and Conduction Velocity

Non-Pacemaker Cells

  • Do not initiate action potentials.
  • Includes atria, ventricles, and Purkinje system.
  • Electrophysiology is divided into 4 phases.
Phase 4: Flat Line

  • Represents the resting membrane potential (cell at rest).

  • Overall charge is negative.

  • Fewer cations inside the cell compared to outside.

  • Reason for Negative Charge:

    • Potassium equilibrium potential.
    • Potassium ions move outward (PISO).
    • Movement along the concentration gradient.
    • Resting membrane potential is approximately −90-90 millivolts.
Phase 0: Straight Vertical Line
  • Cell becomes electropositive (fast depolarization).
  • More sodium channels open.
  • Increased sodium inside the cell (cation influx) increases the electrical charge.
  • Cell undergoes stimulation (upstroke in action potential).
Phase 1: Peak Going Down (Half)
  • Brief initial repolarization.
  • Repolarization: returning to resting membrane potential.
  • Sodium channels close.
  • Potassium channels open, making the cell less positive.
Phase 2: Gentle Slope
  • Plateau phase.
  • Balanced movement of calcium and potassium ions.
  • Potassium exits the cell, making it less positive.
  • Calcium enters the cell, making it more positive.
  • Net charge is balanced (approximately 0).
Phase 3: Steep Slope Downwards
  • Repolarization of cardiac cells.
  • Calcium channels close.
  • Potassium channels remain open.

Pacemaker Cells

  • SA node dominates.

  • Can initiate heartbeat without any stimulus.

  • Unique Characteristics:

    • No Phase 2: No balanced movement of calcium and potassium.
    • No Phase 1: No brief repolarization.
    • Phase 4: Depolarization; not a flat line, but with a slope.
    • Unstable resting membrane potential.
    • Automaticity: spontaneous depolarization.
Pacemaker Cell Phases
  • Phase 0: Characterized by calcium ion conductance.
  • Phase 3: Repolarization going to hyperpolarization.

Electrocardiogram (ECG)

  • Records cardiac beat (heartbeat).
P Wave
  • Atrial depolarization (atria contract).
PR Interval
  • Period between the beginning of P wave and the beginning of Q wave.
  • Represents AV nodal conduction velocity.
  • Time consumed for action potential transfer from SA node to AV node.
  • Also known as dromotropy.
    • Short PR interval: fast transmission of AP, fast heartbeat (+dromotropy: Sympathetic ANS effects).
    • Long PR interval: slow transmission of AP, slow heartbeat (-dromotropy: Parasympathetic ANS effects).
PR Segment
  • Flat line between the end of P wave and the start of QRS complex.
  • Reflects the time delay between atrial and ventricular activation.
  • Isoelectric (simultaneous calcium and potassium conductance).
  • Represents atrial relaxation to pass blood into ventricles.
QRS Complex
  • From the beginning of Q wave until the beginning of S wave.
  • Represents ventricular depolarization (contraction of ventricles).
ST Segment
  • From the end of S wave until the beginning of T wave.
  • Flat line (isoelectric).
  • Period when ventricles are still somehow depolarized.
  • Connected to Phase 2 of cardiac action potential (balance movement of ions).
T Wave
  • Ventricular repolarization (relaxation of ventricles).
QT Interval
  • Total period of depolarization and repolarization of the ventricles.

Conduction Velocity

  • Reflects the time required for excitation to spread throughout cardiac tissue.
  • Depends on the size of the inward current during the upstroke of the action potential.
  • The larger the inward current, the higher the conduction velocity.
  • Fastest in the Purkinje system.
  • Slowest in the AV node.
Implications
  • Fast conduction velocity in AV node: premature contraction; not enough blood filled in the atria which leads to low cardiac output.
  • Slow conduction velocity in Purkinje system: delayed ventricular contraction; not enough blood to deliver in the systemic circulation.

Excitability

  • Ability of cardiac cells to initiate action potentials in response to inward, depolarizing current.
  • Reflects the recovery of channels that carry the inward currents for the upstroke of the action potential.
  • Changes over the course of the action potential.
  • Changes are described by refractory periods.

Autonomic Effects

  • Chronotropy (Heart Rate):

    • Related to the firing of SA node.
    • Phase 4 of SA node (depolarization).
      • Parasympathetic Effect: Slow phase 4 depolarization.
      • Sympathetic Effect: Increases the rate of depolarization.

Control of Normal Cardiac Contractility

  • Autorhythmicity: Pacemaker cells of the SA node spontaneously depolarize.
  • Excitation-Contraction Coupling (EC Coupling): Links action potential to myofibril contraction.
  • Cardiac Muscle Myofibrils: Comprise myofilaments that overlap to form sarcomeres.

Myofibril and Myofilaments

  1. A Band (Dark Band): Overlap of thin and thick filaments.
  2. I Band (Light Band): No overlap between thin and thick filaments.
  3. Sarcomere: From Z disk to Z disk; functional unit of the myofibrils.
  4. Thick Filament - Myosin (Protein): During contraction, myosin head binds with actin to form cross-bridges.
  5. Thin Filament - Actin: Comprises multiple polypeptide subunits called globular actin.
  • Troponin binds ICFCa2+ICF Ca^{2+}.
  • Tropomyosin moves, exposing myosin-binding sites.
  • Myosin binds actin, cross-bridge cycling contracts myofibrils.
  • Excitation – contraction coupling; calcium-induced calcium release.

Cardiac Muscle Cells

  • Action potential and L-type calcium channel.
  • Calcium influx and calcium spark.
  • Creation of signal and binding with troponin.
  • Relaxation.
  • Calcium is pumped back in SR and exchange via NCX.

Ejection Fraction

  • Refers to the amount of blood being pumped out of the left ventricle each time it contracts.
  • The left ventricle is the hearts main pumping chamber.

Heart Failure

  • Occurs when the cardiac output is inadequate to provide oxygen needed by the body
  • The heart may not provide tissues with adequate blood for metabolic needs, and cardiac-related elevation of pulmonary or systemic venous pressures may result in organ congestion.
  • Can result from abnormalities of systolic or diastolic function or, commonly, both.

Types of Heart Failure

  • Low-output failure: decreased pumping efficiency

    • Factors: Myocardial ischemia, Myocardial infarction, Cardiomyopathy

  • High-output failure: cardiac output is normal or elevated

    • Caused by: Hyperthyroidism (hypermetabolism), Anemia (reduced oxygen-carrying capacity)

  • Left Heart Failure: Responsible for pumping oxygenated blood from the lungs out to the peripheral tissues of the body.

    • Common Causes: Myocardial infarction, Chronic hypertension, Cardiomyopathy

  • Right Heart Failure

Compensatory Mechanisms

  • Baroreceptor
  • RAAS
  • Combined

Types of Heart Failure

  • Left-sided heart failure, Right-sided heart failure, Biventricular heart failure
Left-Sided Heart Failure

  • The left ventricle of the heart no longer pumps enough blood around the body, results in the build-up of blood in the pulmonary veins.

    • A. Systolic Failure
      • Also known as heart failure with reduced ejection fraction (HFrEF)
      • The left ventricle loses its ability to contract normally
    • B. Diastolic Failure
      • Also known as heart failure with preserved ejection fraction (HFpEF)
      • The left ventricle loses its ability to relax normally
Right-Sided Heart Failure
  • The right ventricle of the heart is too weak to pump enough blood to the lungs, causing blood build-up in the veins.
Biventricular Heart Failure
  • Both sides of the heart are affected causing the same symptoms as both left and right-sided heart failure, such as shortness of breath and build-up of fluid.

Cardiac Remodeling

  • Changes in the shape of the heart from normal to spherical due to myocardial infarction (heart attack).
  • During cardiac remodeling, the connective tissue cells and the abnormal myocardial cells undergoes proliferation and dilation instead of stretching under the influence of angiotensin II.

Coronary Artery Disease – Angina Pectoris

Causes

  • Atherosclerosis
  • Thrombosis
  • Embolism
  • Vasospasm

May Result To

  • Partial damage (Ischemia)
    • Decreased oxygenation of the myocardium but myocardial cells are still viable
  • Complete damage (Infarction)
    • Absence of oxygenation leading to myocardial necrosis or cell death

Angina Pectoris

  • Characteristic chest pain, pressure, or discomfort due to myocardial ischemia or infarction.
  • Heart is not receiving enough oxygen due to narrowed coronary artery.
Types of Angina Pectoris

  • Chronic Stable Angina Pectoris

    • A.K.A effort angina, classic angina
    • Chest pain lasting for 2-5 minutes
    • Provoked by physical exertion, emotional stress, exposure to cold, or smoking
    • No increase in severity, duration, and frequency for the last 1-2 months

  • Prinzmetal Angina

    • Also called variant angina; vasospastic angina; angina inversa
    • Due to transient spasm of localized portions of the blood vessels, usually associated with underlying atheromas
    • Can cause significant myocardial ischemia and pain
    • Pain occurs principally at rest, usually unprovoked by physical exertion
Pathophysiology of Angina
  • In CSAP: Imbalance between oxygen requirement of the heart and the oxygen supplied to it via coronary vessels
    • Effort = increase in workload = increase in oxygen demand
    • Myocardial oxygen is not proportional to coronary blood flow
    • Ischemia usually leads to pain, but is sometimes not accompanied by pain (“silent” or “ambulatory” ischemia)
  • In Variant Angina: Decrease in oxygen supply
    • Oxygen delivery decreases as a result of reversible coronary vasospasm

Arrhythmia

  • A heart condition where there are disturbances or disorders in:

    • Pacemaker impulse formation (problem is in the SA node)
    • Contraction impulse conduction; or
    • Both

  • Result in the rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output

Causes

  • Cardiac ischemia (MI)
  • Atherosclerotic heart disease
  • Excessive discharge or sensitivity to autonomic transmitters
  • Exposure to toxic substances
  • Administration of general anesthetics
  • Unknown etiology

Pathophysiology of Cardiac Arrhythmia

  • May result from the disorder of impulse formation, conduction, or both
  • May result in heart rates that are either too slow (bradycardia) or too fast (tachycardia)
Disorders of Impulse Formation

  • No signal from the pacemaker (bradyarrhythmia)

  • Development of an ectopic pacemaker which may arise from emergence of latent pacemakers

  • Too slow firing at the SA node

  • Abnormal acceleration of the latent pacemaker

  • Automaticity: spontaneous depolarization (especially for non-pacemaker cells)

  • Occur during late phase 2 or phase 3

    • Can lead to several rapid action potentials or a prolonged series of action potentials

  • Occur in late phase 3 or phase 4

    • Can lead to a series of rapid depolarizations
Disorders of Impulse Formation

  • May result in:

    • AV block: Bradycardia (not involving reentry)
    • Tachycardia (if reentrant circuit occurs – aka circus movement)

Types of Cardiac Arrhythmia

  • Arising from the Sinus Node

    • Sinus tachycardia (100-150bpm)
    • Sinus bradycardia (<60bpm)

  • Atrial Arrhythmia

    • Atrial fibrillation (around 350bpm)
    • Atrial flutter (250-350bpm)

  • Nodal and Other Supraventricular Arrhythmias

    • Atrioventricular block (Prolongation of PR interval)

  • Supraventricular Tachycardia

    • Intranodal SVT (Re-entry ‘circus’ tachycardia)
    • Extranodal SVT
    • Wolff-Parkinson-White Syndrome
    • Lown-Ganong-Levine Syndrome

  • Ventricular Arrhythmias

    • Ventricular Ectopic Beats
      • Abnormal QRS Complex
    • Ventricular Tachycardia
      • Rapid, wide QRS complex
    • Ventricular Fibrillation
      • Chaotic; circulatory arrest occurs immediately