Cardiac Output: Inotropic and Chronotropic Factors

Cardiac Output Equation Components

• The primary equation for cardiac output is defined as the product of heart rate and stroke volume: $CO = HR \times SV$
• Heart Rate ($HR$): The number of times the heart beats per minute.
• Stroke Volume ($SV$): The volume of blood ejected by the ventricle in a single contraction.
• Stroke Volume is calculated by subtracting the blood remaining in the ventricle after contraction from the blood volume before contraction: $SV = EDV - ESV$
• End Diastolic Volume ($EDV$): The volume of blood in the ventricle at the end of the filling phase (diastole).
• End Systolic Volume ($ESV$): The volume of blood remaining in the ventricle after it has finished contracting (systole).

Defining Inotropic and Chronotropic Factors

• Inotropic Factors:
  • "Ino" refers to muscle; "tropic" refers to change.
  • These factors change the contractility of the cardiac muscle.
  • They primarily affect stroke volume ($SV$) by decreasing the $ESV$. By subtracting a smaller $ESV$ from the $EDV$, a larger stroke volume is produced.
• Chronotropic Factors:
  • "Chrono" refers to time (e.g., chronometer, chronological, Kronos).
  • These factors change the timing or rate of the heart (the heart rate).

Nature of Inotropic Factors and Contractility

• Inotropic factors are distinct from preload (the Frank-Starling Law).
• Preload is dependent on muscle length (the degree of stretch in the sarcomere).
• Inotropic factors are independent of length. They affect the ability of the muscle to contract regardless of whether the sarcomere is compressed or stretched.
  • In a compressed sarcomere where Z-discs, actin, and myosin (thick filaments) are already close together, inotropic factors enhance the contraction further.
  • In a stretched sarcomere, these factors still improve contractility effectively.

Positive Inotropic Factors

Positive inotropic factors enhance contractility and stroke volume, largely by increasing intracellular calcium release.

• Extracellular and Intracellular Calcium:
  • Striated muscle contraction depends on intracellular calcium.
  • In cardiac muscle, $20\%$ of intracellular calcium comes from the extracellular fluid during contraction.
  • Therefore, an increase in extracellular calcium (hypercalcemia) acts as a positive inotropic factor by facilitating harder ventricular contractions and ejecting more blood, leading to a lower $ESV$.
• Epinephrine and Norepinephrine:
  • These are released by the sympathetic nervous system (norepinephrine) or the endocrine system (epinephrine).
  • They utilize a second messenger system known as the adenylate cyclase system.
  • This system increases levels of Cyclic Adenosine Monophosphate ($CAMP$).
  • $CAMP$ activates kinases, which phosphorylate calcium channels in the cardiac muscle cell membrane.
  • This phosphorylation increases the influx of extracellular calcium, allowing for more calcium to bind to troponin and creating more crossbridge formations for harder contractions, regardless of initial muscle length.
• Thyroxine ($T_3$ and $T_4$):
  • Increases overall body metabolism, heat production, and energy stores.
  • Increases intracellular calcium and the binding of calcium to Troponin C, thereby increasing the power stroke in cardiac muscle cells.
• Glucagon:
  • Increases available energy and $ATP$.
  • $ATP$ is required to release the myosin head from the actin filament after a power stroke. Glucagon ensures $ATP$ availability so the heart can "let go" of a contraction and reset for a "bigger bite" (moving Z-discs toward the M-line) in the next contraction.
• Digitalis (Digoxin):
  • Derived from the Foxglove plant.
  • Increases contractility regardless of starting length.
  • Safety Caveat: Foxglove is poisonous because digitalis can improve contractility so drastically that it induces cardiac arrest. The heart may enter a state of tetanic contraction, where it stays locked in a contracted state and ceases to function as a pump.
• Hypokalemia:
  • Low blood potassium levels act as a positive inotropic factor.

Negative Inotropic Factors

These factors decrease contractility, increase $ESV$, and consequently decrease $SV$ and $CO$.

• Low Calcium: Decreased intracellular or extracellular calcium levels.
• Low Hormonal Levels: Reduced epinephrine, thyroxine, or glucagon.
• Parasympathetic Activation:
  • While the parasympathetic system directly affects the SA node, it also utilizes reverberating circuits to inhibit sympathetic nervous system activation in the ventricles.
  • An increase in parasympathetic drive acts as a negative inotropic factor by decreasing contractility.
• Hyperkalemia (High Blood Potassium):
  • Increased blood potassium ($K^+$) hyperpolarizes cells, making it harder to reach the threshold and open calcium channels.
• Calcium Channel Blockers:
  • These drugs block the entry of calcium into the cardiac muscle cell.
  • They decrease the $20\%$ calcium influx required for a strong contraction, thereby inhibiting contractility.

Chronotropic Factors (Heart Rate Regulation)

To increase cardiac output, the body typically increases both stroke volume and heart rate simultaneously to achieve a synergistic effect. Consequently, the lists for positive and negative chronotropic factors are largely identical to the inotropic lists.

• Positive Chronotropic Factors:
  • Hypercalcemia: Brings pacemaker cells closer to the threshold.
  • Epinephrine/Sympathetic Nervous System: Directly speeds up the SA node by increasing extracellular calcium influx, bringing pacemaker cells closer to threshold.
  • Thyroxine: Elevated levels (hyperthyroidism) can cause a racing heart rate.
  • Glucagon: Increases the heart rate through energy availability.
  • Digitalis: Indirectly increases heart rate through the Bainbridge reflex (vein bridge reflex). Increased contractility increases stroke volume and venous return, which increases preload and excites nerves to increase the heart rate.
  • Hypokalemia: Low blood potassium increases the rate.
• Negative Chronotropic Factors:
  • Calcium Channel Blockers: Slow down the rate of electrical firing.
  • Hypocalcemia: Low blood calcium.
  • Parasympathetic Drive:
  • Involves Acetylcholine ($ACh$) binding to receptors (notably identified as nicotinic receptors in the context of the SA node in this discussion).
  • Hyperpolarizes pacemaker cells so they take longer to reach the threshold.
  • This slows the SA node's intrinsic rate from approximately $100\,\text{beats per minute}$ to the typical resting rate of $70$ or $75\,\text{beats per minute}$.
  • Hyperkalemia: High blood potassium inhibits the rate.

Clinical Correlations Summary

• Hypercalcemia: High blood calcium (Positive factor).
• Hypocalcemia: Low blood calcium (Negative factor).
• Hypokalemia: Low blood potassium (Positive factor).
• Hyperkalemia: High blood potassium (Negative factor).
• These electrolyte imbalances are critical clinical concerns for cardiovascular health as they directly influence the efficiency of the heart as a pump.