Cardiovascular System: The Heart Vocabulary

Dual Circulatory Systems of the Heart

• The heart functions as a dual-pump system operating two distinct circulatory circuits simultaneously:
  • Pulmonary Circuit: Powered by the right side of the heart (the first pump). It receives oxygen-poor ($O_2$-poor), carbon dioxide-rich ($CO_2$-rich) blood returning from body tissues and pumps it into the lungs. Within the pulmonary capillaries, the blood discharges $CO_2$ and absorbs fresh $O_2$
  • Systemic Circuit: Powered by the left side of the heart (the second pump). It receives oxygen-rich ($O_2$-rich) blood returning from the lungs and pumps it into systemic arteries to supply all tissue beds throughout the body

Structural and Functional Properties of Cardiac Muscle

• Cardiomyocyte Populations: The heart muscle (myocardium) consists of two specialized populations of cells:

  • Contractile Fibers: Constitute approximately $99\%$ of all cardiac muscle cells. They perform the mechanical work of pumping blood
  • Autorhythmic Fibers: Constitute approximately $1\%$ of cardiac cells. They lack contractile elements and instead form the intrinsic conduction system responsible for generating and propagating electrical impulses

• Histological Similarities to Skeletal Muscle:

  • Contain organized actin and myosin myofilaments arranged in sarcomeres
  • Possess a resting membrane potential (RMP)
  • Are electrically excitable cells
  • Maintain a greater concentration of positive ions on the extracellular surface relative to the intracellular fluid at rest
  • Depolarize when positive ions enter the cell; if depolarization reaches threshold, an action potential is triggered
  • Contain a sarcoplasmic reticulum (SR) that stores internal calcium ions ($Ca^{2+}$), which can be released into the sarcoplasm to trigger cross-bridge cycling and mechanical contraction
  • Repolarize when positive ions efflux from the cell, with $\text{Na}^+/\text{K}^+$ ATPase pumps working to restore baseline concentration gradients

• Histological and Functional Differences from Skeletal Muscle:

  • Morphology: Cardiac muscle fibers are shorter, wider (fatter), branched, and contain only 1 (occasionally 2) centrally located nuclei, whereas skeletal muscle fibers are long, cylindrical, non-branched, and multinucleated
  • Intercalated Discs: Individual cardiomyocytes are structurally and functionally connected end-to-end by intercalated discs containing two key specialized structures:
    • Desmosomes: Structural anchors that prevent adjacent myocytes from pulling apart during vigorous mechanical contraction
    • Gap Junctions: Protein channels that electrically couple adjacent myocytes, allowing free passage of ions between cells for rapid impulse propagation
  • Functional Syncytium: Because gap junctions permit direct electrical communication throughout the tissue, all cardiomyocytes contract together as a single functional unit, or none do
  • Metabolic Profile: Cardiomyocytes possess an exceptionally high aerobic capacity due to an abundance of mitochondria. Mitochondria account for approximately $30\%$ of cardiac cell volume (compared to only $2\%$ in skeletal muscle cells), representing a 15-fold increase. ATP production relies almost exclusively on aerobic cellular respiration, making cardiac muscle absolute dependent on a continuous supply of oxygen
  • Electrophysiological Parameters: Contractile cardiac muscle fibers exhibit a steady baseline RMP averaging $-90\,\text{mV}$, specialized ion channel dynamics, and an extended action potential duration resulting in a prolonged, sustained mechanical contraction

Electrophysiology and Contraction Mechanism of Contractile Cardiomyocytes

• The action potential of contractile cardiomyocytes is characterized by three distinct sequential phases:
  • Phase 1: Rapid Depolarization:
    • Initiated by an influx of sodium ions ($\text{Na}^+$) through fast voltage-gated $\text{Na}^+$ channels
    • Opening of these channels initiates a positive feedback loop: initial depolarization rapidly opens additional voltage-gated $\text{Na}^+$ channels, steeply reversing the membrane potential from $-90\,\text{mV}$ to approximately $+20\,\text{mV}$ to $+30\,\text{mV}$
    • Phase ends when fast $\text{Na}^+$ channels rapidly undergo voltage-dependent inactivation
  • Phase 2: Plateau Phase:
    • Depolarization opens slow voltage-gated calcium channels (L-type $Ca^{2+}$ channels) located in the sarcolemma and T-tubules, allowing extracellular $Ca^{2+}$ to trickle slowly into the sarcoplasm
    • Simultaneously, most voltage-gated potassium ($\text{K}^+$) channels remain closed, limiting $\text{K}^+$ efflux
    • The balance between slow $Ca^{2+}$ influx and minimal $\text{K}^+$ efflux holds the membrane potential in a prolonged depolarized plateau state, significantly lengthening both the action potential duration and mechanical contraction
  • Phase 3: Repolarization:
    • Slow $Ca^{2+}$ channels gradually close and undergo inactivation
    • Voltage-gated $\text{K}^+$ channels fully open, permitting a rapid outward flux of $\text{K}^+$ ($\text{K}^+$ efflux)
    • Outward movement of positive charge restores the membrane potential to its resting voltage of $-90\,\text{mV}$

• Excitation-Contraction Coupling:

  • As the action potential travels down the T-tubules, the initial extracellular $Ca^{2+}$ entering through slow sarcolemmal $Ca^{2+}$ channels acts as a trigger signal
  • This entry of extracellular $Ca^{2+}$ binds to and opens calcium-sensitive ryanodine receptor channels on the sarcoplasmic reticulum (SR), inducing a massive flooding of stored $Ca^{2+}$ from the SR interior into the sarcoplasm (a mechanism known as $Ca^{2+}$-induced $Ca^{2+}$ release)
  • Flooding of the intracellular space with $Ca^{2+}$ allows binding to troponin, initiating actin-myosin cross-bridge cycling and muscle contraction
  • Influence on Contractility: The amount of extracellular $Ca^{2+}$ entering the cell directly determines the amount of $Ca^{2+}$ released from the SR; higher intracellular $Ca^{2+}$ levels directly enhance myocardial contractility (contractile force)

• Absolute Refractory Period:

  • The absolute refractory period in contractile cardiac fibers is unusually long, lasting approximately $200\,\text{ms}$ to $250\,\text{ms}$ (nearly as long as the entire mechanical contraction itself)
  • This prolonged refractory state prevents tetanic contractions, ensuring the heart alternates between distinct contraction (pumping) and relaxation (filling) phases

Autorhythmic Fibers and the Intrinsic Conduction System

• Automaticity (Autorhythmicity):

  • Specialized non-contractile autorhythmic cardiac cells possess automaticity, meaning they spontaneously generate periodic action potentials without requiring external nervous system stimulation
  • Autorhythmic cells set the intrinsic heart rate and propagate electrical impulses sequentially through the entire myocardium

• Pacemaker Potentials (Unstable Resting Potentials):

  • Autorhythmic cells lack a constant resting membrane potential. Instead, they exhibit continuously unstable resting potentials termed pacemaker potentials
  • At the end of repolarization, the membrane potential reaches its most negative peak at $-60\,\text{mV}$
  • Depolarization Mechanism: Membrane permeability to $\text{K}^+$ progressively decreases (preventing $\text{K}^+$ exit), while $\text{Na}^+$ and $Ca^{2+}$ continuously leak inward through slow channels. This continuous inward flux of positive ions causes a gradual, linear depolarization toward threshold
  • Threshold and Action Potential Generation: Threshold is reached at $-40\,\text{mV}$. At threshold, voltage-gated fast $Ca^{2+}$ channels open, triggering a rapid influx of $Ca^{2+}$ that generates the rising phase of the action potential
  • Repolarization: Fast $Ca^{2+}$ channels close, and voltage-gated $\text{K}^+$ channels open, causing an outward flux of $\text{K}^+$ that repolarizes the membrane back to $-60\,\text{mV}$, whereupon the cycle immediately repeats

• Components and Sequence of the Intrinsic Conduction System:
  1. Sinoatrial (SA) Node: Located in the right atrial wall. It depolarizes faster than any other autorhythmic region because its membranes are most permeable to leaking $\text{Na}^+$ and $Ca^{2+}$ and least permeable to exiting $\text{K}^+$. Reaching threshold fastest, it acts as the primary pacemaker of the heart, setting the default sinus rhythm
  2. Internodal Pathway: Conducts the depolarizing impulse across the atrial walls from the SA node to the AV node
  3. Atrioventricular (AV) Node: Located in the inferior interatrial septum. It delays impulse transmission by approximately $0.1\,\text{s}$ ($100\,\text{ms}$) due to smaller fiber diameters and fewer gap junctions. This delay permits complete atrial contraction and ventricular filling prior to ventricular excitation
  4. Atrioventricular (AV) Bundle (Bundle of His): Located in the superior interatrial and interventricular septum. It serves as the sole electrical connection between the atria and ventricles
  5. Right and Left Bundle Branches: Formed by division of the AV bundle, these branches course down the interventricular septum toward the cardiac apex
  6. Subendocardial Conducting Network (Purkinje Fibers): Large-diameter fibers that extend through the apex and sweep upward throughout the outer ventricular walls, rapidly depolarizing contractile myocytes of both ventricles simultaneously

Clinical Pharmacology and Cardiovascular Therapeutics

• Calcium Channel Blockers:

  • Examples: Verapamil, Procardia (Nifedipine)
  • Effect on Heart Rate (HR): Decreases HR by slowing the rate of SA node depolarization toward threshold
  • Effect on Contractility: Decreases contractility by reducing extracellular $Ca^{2+}$ influx during the plateau phase of contractile cells, which reduces subsequent $Ca^{2+}$ release from the sarcoplasmic reticulum
  • Verapamil Specificity: Depresses automaticity in atrial tissues; indicated for treating supraventricular tachycardia (SVT)
  • Procardia Specificity: Primarily targets vascular smooth muscle in systemic and coronary blood vessels. Induces vascular smooth muscle relaxation and arterial dilation:
    • Dilated coronary arteries increase blood flow to the oxygen-demanding myocardium
    • Dilated systemic arteries decrease peripheral vascular resistance, thereby reducing cardiac afterload and overall workload on the heart

• Catecholamines (Epinephrine and Norepinephrine):

  • Function as calcium channel "enhancers"
  • Increase both the rate and total amount of extracellular $Ca^{2+}$ entering cardiac cells
  • Clinical Outcome: Significantly increases both HR and myocardial contractility

• Sodium Channel Blockers:

  • Example: Lidocaine
  • Mechanism: Blocks fast voltage-gated $\text{Na}^+$ channels, depressing automaticity in conducting pathways within the ventricles
  • Clinical Use: "Silences" or depresses ectopic pacemakers (ectopic foci) in the ventricles. Preferred agent for treating life-threatening ventricular arrhythmias, including Ventricular Tachycardia (VT), Ventricular Fibrillation (V-Fib), and Premature Ventricular Contractions (PVCs)

• Digitalis Glycosides:

  • Example: Digoxin (derived from the foxglove plant, Digitalis purpurea)
  • Mechanism and Indications: Widely prescribed for Atrial Fibrillation (A-Fib), Atrial Flutter (A-Flutter), and Congestive Heart Failure (CHF)
  • Clinical Effects: Decreases heart rate while simultaneously increasing myocardial contractility. By slowing HR and enhancing pumping efficiency via increased intracellular $Ca^{2+}$ availability, it conserves cardiac energy expenditure

Dynamics of the Cardiac Cycle

• Definition: The cardiac cycle encompasses all blood flow events occurring through the heart during one complete heartbeat. It consists of atrial systole and diastole followed by ventricular systole and diastole

• Functional Parameters of Cycle Phases:

  • Systole: Period of myocardial contraction. Pressure within the affected chamber increases significantly, forcing blood to be ejected out of the chamber
    • End Systolic Volume (ESV): The volume of blood remaining inside a ventricle at the conclusion of its contraction phase (normally approximately $50\,\text{mL}$ at rest)
  • Diastole: Period of myocardial relaxation. Pressure within the affected chamber drops dramatically, allowing blood to flow into the chamber for filling
    • End Diastolic Volume (EDV): The total volume of blood that collects within a ventricle during diastole, just prior to contraction (normally approximately $120\,\text{mL}$ at rest)

• Phases of the Cardiac Cycle & ECG Correlations:

  1. Atrial Systole: Triggered by atrial depolarization (P-Wave on ECG). Atria contract, raising intra-atrial pressure and forcing the final volume of blood into the ventricles
  2. Ventricular Systole (First Phase - Isovolumetric Contraction): Ventricular depolarization occurs (QRS Complex on ECG). Ventricles begin contracting, causing intraventricular pressure to rise rapidly and snap the AV valves closed. Closure of the AV valves produces the first heart sound ($S_1$, or "lub"). Ventricular volume remains constant as all four valves are temporarily closed
  3. Ventricular Systole (Second Phase - Ventricular Ejection): Intraventricular pressure exceeds pressure in the major outflow arteries (aorta and pulmonary trunk), forcing the semilunar valves open. Blood is forcefully ejected from the ventricles into the aorta and pulmonary artery
  4. Ventricular Diastole (Early Phase - Isovolumetric Relaxation): Ventricles repolarize (T-Wave on ECG) and begin relaxing. Intraventricular pressure drops below arterial pressure, causing blood to flow backward toward the heart and snap the semilunar valves shut. Closure of the semilunar valves produces the second heart sound ($S_2$, or "dub")
  5. Ventricular Diastole (Late Phase - Passive Filling): As ventricular pressure drops below atrial pressure, the AV valves fall open. Blood that has collected in the atria flows passively into the relaxing ventricles, accounting for roughly $80\%$ of total ventricular filling before the next atrial systole begins

Regulation of Cardiac Output and Stroke Volume

• Cardiac Output ($CO$): The volume of blood pumped by each individual ventricle per minute

  • Formula: $CO = \text{Heart Rate (HR)} \times \text{Stroke Volume (SV)}$
  • Resting Baseline Calculation:$CO = 75\,\text{beats/min} \times 70\,\text{mL/beat} = 5250\,\text{mL/min} = 5.25\,\text{L/min}$

• Stroke Volume ($SV$): The volume of blood ejected by a single ventricle with each beat

  • Formula: $SV = EDV - ESV$
  • Standard Values at Rest: $120\,\text{mL} \text{ (EDV)} - 50\,\text{mL} \text{ (ESV)} = 70\,\text{mL/beat} \text{ (SV)}$
  • Determinants of EDV: Affected by the duration of ventricular diastole (filling time) and venous pressure
  • Determinants of ESV: Affected by arterial blood pressure (afterload) and the force of ventricular contraction (contractility)

• Primary Regulation Factors of Stroke Volume:

  1. Preload (Degree of Stretch):
     • Definition: The extent of stretch experienced by cardiac muscle tissue prior to contraction
     • Frank-Starling Law of the Heart: The critical factor controlling preload is venous return (the volume of blood returning to the heart). Increased venous return increases EDV, which distends and stretches ventricular muscle cells
     • Under resting conditions, cardiac muscle fibers are held at lengths shorter than their optimal length. Stretching cardiac fibers brings their actin and myosin filaments into an optimal alignment for cross-bridge formation, dramatically increasing contractile force, raising stroke volume, and elevating cardiac output:         $\uparrow \text{Venous Return} \rightarrow \uparrow EDV \rightarrow \uparrow SV \rightarrow \uparrow CO$
     • Slow heart rate (allowing more filling time) and physical exercise (via muscular pump action) significantly increase venous return
  2. Contractility:
     • Definition: The extrinsic contractile strength achieved at a given muscle length, independent of muscle stretch or EDV
     • Positive Inotropic Stimuli: Sympathetic nervous stimulation (releasing norepinephrine) and circulating hormones (epinephrine, thyroxine, and glucagon) increase intracellular $Ca^{2+}$ influx
     • Greater $Ca^{2+}$ availability leads to more extensive sarcoplasmic reticulum $Ca^{2+}$ release, enhancing cross-bridge cycling force, lowering ESV, and increasing total stroke volume
  3. Afterload:
     • Definition: The arterial blood pressure that the ventricles must overcome to push open the semilunar valves and eject blood
     • Baseline Pressures: Aortic pressure averages $\sim 80\,\text{mmHg}$; pulmonary arterial pressure averages $\sim 8\,\text{mmHg}$
     • In healthy individuals, afterload remains constant and does not significantly alter SV
     • Pathological Effects of Hypertension: Elevated arterial blood pressure increases afterload. High resistance hinders valve opening, resulting in an increased ESV and a reduced SV. To compensate and maintain overall $CO$, the heart must increase its rate ($HR$
     • Hypertensive Crisis: In severe clinical crises where aortic diastolic pressure exceeds $170\,\text{mmHg}$, afterload becomes so extreme that stroke volume can approach zero

Pathophysiology of Congestive Heart Failure

• Pathology: Congestive Heart Failure (CHF) is a progressive condition where the myocardium weakens over time until cardiac output becomes insufficient to satisfy systemic tissue metabolic demands
• Etiologies: High blood pressure (hypertension), myocardial infarction (MI), coronary artery disease (CAD), and chronic valvular incompetence
• Hemodynamic Alterations: Decreased contractile force produces a decline in stroke volume ($\downarrow SV$) and a rise in residual blood remaining after contraction ($\uparrow ESV$). Compensatory tachycardia (elevated HR) routinely develops as the body attempts to compensate for diminished stroke volume to preserve total cardiac output
• Structural Manifestations:
  • Systolic Heart Failure: Characterized by stretched, thin-walled ventricular chambers that fail to contract forcefully (heart cannot pump)
  • Diastolic Heart Failure: Characterized by stiff, abnormally thickened ventricular walls that resist passive stretching (heart cannot fill)
• Patterns of Tissue Edema (Fluid Retention):
  • Right-Sided Heart Failure: Failure of the right ventricular pump causes blood to back up into the systemic venous circulation, producing severe systemic peripheral edema (fluid accumulation in the lower extremities, feet, ankles, and abdominal cavity)
  • Left-Sided Heart Failure: Failure of the left ventricular pump causes blood to back up into pulmonary blood vessels, increasing pulmonary capillary hydrostatic pressure and producing pulmonary edema (fluid accumulation within the lungs and alveoli, leading to severe dyspnea)

Neural, Chemical, and Physical Regulation of Heart Rate

• Autonomic Nervous System (ANS) Regulation:

  • Regulated by cardioregulatory centers located within the medulla oblongata
  • Cardioinhibitory Center (Parasympathetic): Transmits inhibitory signals via the vagus nerves (CN X), releasing acetylcholine (ACh) onto SA and AV nodes to slow down heart rate
    • Vagal Tone: Intrinsic SA node automaticity without external influence would generate a heart rate of approximately $100\,\text{beats/min}$. At rest, dominant parasympathetic vagal inhibition maintains a normal baseline resting heart rate of $\sim 75\,\text{beats/min}$
    • Increasing Heart Rate up to $100\,\text{beats/min}$: Accomplished simply by withdrawing resting parasympathetic vagal tone
    • Increasing Heart Rate above $100\,\text{beats/min}$: Requires active stimulation of the sympathetic nervous system
  • Cardioacceleratory Center (Sympathetic): Transmits excitatory signals via sympathetic cardiac nerves, releasing norepinephrine (NE). Targets the SA node, AV node, myocardium, and coronary arteries to increase both heart rate and contractile force

• Chemical Regulation of Heart Rate:

  • Hormonal Control:
    • Epinephrine: Secreted by the adrenal medulla during stress/exercise; increases HR and contractility
    • Glucagon: Released during fight-or-flight states; increases both HR and contractility
    • Thyroxine: Secreted in excess during hyperthyroidism; directly enhances myocardial responsiveness to epinephrine and norepinephrine, leading to sustained increases in HR and contractility
  • Ionic Balance: Cardiac rhythmicity and electrical conductivity are highly sensitive to abnormal extracellular concentrations of potassium ($\text{K}^+$) and calcium ($Ca^{2+}$)

• Miscellaneous Regulatory Factors:

  • Physical Exercise: Regular physical training increases stroke volume and myocardial pumping efficiency, resulting in a lower resting HR and reduced baseline blood pressure; also triggers systemic endorphin release
  • Body Temperature (Heat vs. Cold):
    • Heat: For every $1^\circ\text{C}$ / $1^\circ\text{F}$ increase in core internal body temperature, heart rate increases by approximately $10\,\text{beats/min}$
    • Cold: Exposure to cold temperatures induces peripheral vasoconstriction, forcing the heart to exert greater force to pump blood through narrowed peripheral vessels