10.1 Cardiovascular & Respiratory Physiology

Heart Anatomy & Cardiac Conduction System

The mammalian cardiovascular system is a closed, dual-circuit muscular pump responsible for delivering oxygenated blood to systemic tissues and deoxygenated blood to the pulmonary gas-exchange apparatus. The heart consists of four chambers: two upper receiving atria and two lower muscular pumping ventricles.

Internal Heart Anatomy & Valve Dynamics

Unidirectional blood flow through the cardiac chambers is maintained by two pairs of fibrous valves that open and close passively in response to hydrostatic pressure gradients:

1. Atrioventricular (AV) Valves: Prevent backflow from ventricles into atria during ventricular contraction (systole).
   • Tricuspid Valve: Located between the right atrium and right ventricle; composed of three fibrous cusps.
   • Mitral (Bicuspid) Valve: Located between the left atrium and left ventricle; composed of two fibrous cusps.
2. Semilunar Valves: Prevent backflow from major arterial trunks into ventricles during ventricular relaxation (diastole).
   • Pulmonary Valve: Situated between the right ventricle and the pulmonary artery trunk.
   • Aortic Valve: Situated between the left ventricle and the ascending aorta.

Mnemonic - LAB RAT:

• Left Atrium = Bicuspid (Mitral) valve
• Right Atrium = Tricuspid valve

                                  [Superior / Inferior Vena Cava]
                                                 |
                                                 v
                                         [Right Atrium]
                                                 |
                                        (Tricuspid Valve)
                                                 |
                                                 v
                                         [Right Ventricle]
                                                 |
                                         (Pulmonary Valve)
                                                 |
                                                 v
                                         [Pulmonary Artery]
                                                 |
                                           (Lungs / Gas Exchange)
                                                 |
                                                 v
                                         [Pulmonary Veins]
                                                 |
                                                 v
                                          [Left Atrium]
                                                 |
                                        (Bicuspid/Mitral Valve)
                                                 |
                                                 v
                                          [Left Ventricle]
                                                 |
                                          (Aortic Valve)
                                                 |
                                                 v
                                          [Ascending Aorta]
                                                 |
                                      [Systemic Circulation]

Cardiac Electrical Conduction Pathway

Cardiac myocytes possess intrinsic autorhythmic properties. Depolarization originates in specialized pacemaker tissue and propagates rapidly through a dedicated electrical conduction network:

1. Sinoatrial (SA) Node: Located in the superior wall of the right atrium. Serves as the primary pacemaker of the heart, generating spontaneous action potentials at an intrinsic rate of $60\text{--}100\text{ beats/min}$ via hyperpolarization-activated cyclic nucleotide-gated (HCN) "funny" current ($I_f$) channels.
2. Internodal Pathways: Depolarization waves spread rapidly across atrial myocardium, contracting both atria simultaneously.
3. Atrioventricular (AV) Node: Located in the lower interatrial septum. The AV node introduces a critical 0.1-second (100 ms) conduction delay. This physiological delay permits complete atrial contraction and ventricular filling (atrial kick) prior to ventricular excitation.
4. Bundle of His (Atrioventricular Bundle): Transmits electrical impulses from the AV node through the fibrous insulating skeleton of the heart into the interventricular septum.
5. Right and Left Bundle Branches: Descend along the interventricular septum toward the cardiac apex.
6. Purkinje Fibers: Large-diameter specialized conductive fibers that rapidly distribute action potentials from the apex upward through the ventricular myocardium, ensuring synchronized bottom-up ventricular ejection.

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Cardiac Cycle & Hemodynamics

Phases of the Cardiac Cycle

The cardiac cycle alternates between two primary mechanical phases:

• Systole: Isovolumetric ventricular contraction followed by ventricular ejection. Intraventricular pressure surges, snapping the AV valves shut (producing the $S_1$ "lub" heart sound) and forcing open the semilunar valves to eject blood into the aorta and pulmonary artery.
• Diastole: Isovolumetric ventricular relaxation followed by passive and active ventricular filling. As ventricles relax, intraventricular pressure drops below arterial pressure, causing semilunar valves to snap shut (producing the $S_2$ "dub" heart sound) and AV valves to open.

Cardiac Output Calculation

Cardiac Output (CO) represents the volume of blood pumped by a single ventricle per unit time (typically expressed in liters per minute):

$$\text{CO} = \text{HR} \times \text{SV}$$

Where:

• $\text{HR}$ is Heart Rate (beats per minute, $\text{bpm}$).
• $\text{SV}$ is Stroke Volume (volume of blood ejected per beat, $\text{mL/beat}$), defined as End-Diastolic Volume minus End-Systolic Volume ($\text{SV} = \text{EDV} - \text{ESV}$).

Example Calculation: A resting individual with a heart rate of $70\text{ bpm}$ and a stroke volume of $70\text{ mL/beat}$ yields:

$$\text{CO} = 70\text{ beats/min} \times 0.070\text{ L/beat} = 4.9\text{ L/min}$$

Hemodynamics & Poiseuille's Law

Blood flow through the vascular tree is governed by pressure differentials and vascular resistance. Mean Arterial Pressure (MAP) is defined as:

$$\text{MAP} = \text{CO} \times \text{TPR}$$

Where $\text{TPR}$ is Total Peripheral Resistance. Clinically, MAP can also be approximated from Systolic Pressure (SP) and Diastolic Pressure (DP):

$$\text{MAP} \approx \text{DP} + \frac{1}{3}(\text{SP} - \text{DP})$$

Vascular resistance ($R$) to laminar fluid flow through a cylindrical vessel is described quantitatively by Poiseuille's Law:

$$R = \frac{8 \eta L}{\pi r^4}$$

Where:

• $\eta$ is dynamic blood viscosity.
• $L$ is vessel length.
• $r$ is internal vessel radius.

AAMC MCAT Trap: Notice that vascular resistance is inversely proportional to the fourth power of vessel radius ($r^4$). Halving the radius of a blood vessel ($r \rightarrow \frac{1}{2}r$) increases vascular resistance by a factor of $2^4 = 16$-fold! Small arterioles, which possess thick vascular smooth muscle layers, undergo controlled vasoconstriction and vasodilation to act as the primary regulatory resistance vessels in the human body.

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Respiratory System & Gas Exchange Infrastructure

The respiratory system facilitates cellular respiration by supplying $\text{O}_2$ and clearing metabolic $\text{CO}_2$. Air travels along the anatomical path: Nasal Cavity $\rightarrow$ Pharynx $\rightarrow$ Larynx $\rightarrow$ Trachea $\rightarrow$ Mainstem Bronchi $\rightarrow$ Bronchioles $\rightarrow$ Alveolar Ducts $\rightarrow$ Alveoli.

Alveolar Architecture & Pulmonary Surfactant

Gas exchange occurs across approximately 300 million micro-spherical alveoli, providing a massive mucosal surface area ($\,\sim 100\text{ m}^2$) bounded by a thin alveolar-capillary membrane ($< 0.5\ \mu\text{m}$ thick).

1. Type I Pneumocytes: Extremely thin squamous epithelial cells comprising $\sim 95\%$ of alveolar surface area; optimized for rapid gas diffusion.
2. Type II Pneumocytes: Cuboidal cells that synthesize and secrete Pulmonary Surfactant.

Pulmonary Surfactant is an amphipathic lipoprotein complex composed primarily of dipalmitoylphosphatidylcholine (DPPC). Surfactant reduces surface tension at the alveolar air-water interface. According to Laplace's Law for a spherical bubble:

$$P = \frac{2T}{r}$$

Where $P$ is collapse pressure, $T$ is surface tension, and $r$ is alveolar radius. Without surfactant, smaller alveoli (smaller $r$) would experience higher collapse pressures than larger alveoli, causing air to empty from smaller into larger alveoli and leading to widespread alveolar collapse (atelectasis). By concentrating DPPC molecules more densely in smaller alveoli, surfactant lowers surface tension $T$ proportionally with radius $r$, stabilizing alveoli of varying sizes and increasing pulmonary compliance.

Fick's Law of Diffusion

The rate of gas diffusion across the respiratory membrane ($V_{\text{gas}}$) is modeled by Fick's Law:

$$V_{\text{gas}} = \frac{A \cdot D \cdot (P_1 - P_2)}{T}$$

Where $A$ is surface area, $D$ is the gas diffusion constant (proportional to solubility divided by $\sqrt{\text{MW}}$), $(P_1 - P_2)$ is the partial pressure gradient across the membrane, and $T$ is membrane thickness.

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Oxygen-Hemoglobin Dissociation & Affinity Shifts

Oxygen is carried in blood primarily bound to Hemoglobin (HbA) inside red blood cells (RBCs), with $< 2\%$ dissolved directly in plasma. Hemoglobin is a heterotetramer (comprising $2\alpha$ and $2\beta$ subunits), each containing an iron-bound ($\text{Fe}^{2+}$) heme prosthetic group capable of reversibly binding one molecule of $\text{O}_2$.

   Oxygen Saturation (% SO2)
   100 |                     ,---' Left Shift (Increased Affinity: High pH, Low Temp, Low 2,3-BPG, HbF)
    80 |                 _--'
    60 |               _-'   <--- Normal Baseline (P50 = 26.6 mmHg)
    40 |            _-'
    20 |         _-'         `--- Right Shift (Decreased Affinity: Low pH, High Temp, High 2,3-BPG, High PCO2)
     0 +--------+---------+---------+---------+
       0       20        40        60        80   PO2 (mmHg)

Sigmoidal Curve & Cooperative Binding

Hemoglobin exhibits cooperative binding kinetics, generating a characteristic sigmoidal (S-shaped) oxygen dissociation curve:

• T-State (Tense): Deoxygenated conformation with low $\text{O}_2$ affinity.
• R-State (Relaxed): Oxygenated conformation with high $\text{O}_2$ affinity.

Binding of the first $\text{O}_2$ molecule to a heme subunit induces a structural shift that transitions neighboring subunits into the high-affinity R-state, facilitating subsequent $\text{O}_2$ binding. The standard partial pressure of $\text{O}_2$ at which hemoglobin is $50\%$ saturated is $P_{50} = 26.6\text{ mmHg}$.

Physiological Curve Shifts

Affinity changes alter $P_{50}$ to adapt oxygen delivery to metabolic demands:

1. Right Shift (Decreased $\text{O}_2$ Affinity / Higher $P_{50}$): Facilitates $\text{O}_2$ unloading in metabolically active tissues. Caused by:

   • Increased Temperature
   • Increased 2,3-Bisphosphoglycerate ($2,3\text{-BPG}$)
   • Increased $[\text{H}^+]$ (decreased pH)
   • Increased $P_{\text{CO}_2}$
   • The Bohr Effect: Increased $P_{\text{CO}_2}$ and $\text{H}^+$ bind allosterically to hemoglobin, stabilizing the low-affinity T-state.

   Mnemonic: "CADET face Right" (CO2, Acid, 2,3-DPG, Exercise, Temperature).

2. Left Shift (Increased $\text{O}_2$ Affinity / Lower $P_{50}$): Causes hemoglobin to hold $\text{O}_2$ tightly. Caused by decreased Temp, decreased $2,3\text{-BPG}$, decreased $[\text{H}^+]$ (higher pH), decreased $P_{\text{CO}_2}$, and Carbon Monoxide (CO) poisoning (locks bound subunits in high-affinity R-state).

3. Fetal Hemoglobin ($\text{HbF}$): Composed of $\alpha_2\gamma_2$ subunits. $\text{HbF}$ lacks key histidine residues required to bind $2,3\text{-BPG}$, resulting in a left-shifted curve relative to adult $\text{HbA}$. Higher $\text{O}_2$ affinity allows $\text{HbF}$ to extract $\text{O}_2$ efficiently from maternal blood across the placenta.

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Carbon Dioxide Transport & Chloride Shift

Carbon dioxide produced by cellular respiration is transported in blood through three mechanisms:

1. Dissolved directly in plasma ($\,\sim 7\%$).
2. Bound to hemoglobin as carbaminohemoglobin ($\,\sim 23\%$).
3. Converted into soluble bicarbonate ions ($\text{HCO}_3^-$) in plasma ($\,\sim 70\%$).

The Carbonic Anhydrase Reaction & Chloride Shift

In systemic tissue capillaries, $\text{CO}_2$ diffuses down its partial pressure gradient into red blood cells, initiating the carbonic anhydrase pathway:

$$\text{CO}_2 + \text{H}_2\text{O} \xrightleftharpoons{\text{Carbonic Anhydrase}} \text{H}_2\text{CO}_3 \xrightleftharpoons{\quad} \text{H}^+ + \text{HCO}_3^-$$

                               SYSTEMIC TISSUE CAPILLARY
       [Tissue Cell]                                          [Plasma]
      CO2 produced  ======>  CO2 enters RBC
                                   |
                            + H2O (Carbonic Anhydrase)
                                   |
                                   v
                                H2CO3
                                   |
                              +----+----+
                              |         |
                              v         v
                             H+       HCO3-  =======>  HCO3- exits RBC into plasma
                             |                             |
                     (Binds Hb: Bohr)                  (AE1 Exchanger)
                                                           |
                                      Cl-  <=======  Cl- enters RBC (Chloride Shift)

1. Bicarbonate Generation: $\text{CO}_2$ hydrates to form carbonic acid ($\text{H}_2\text{CO}_3$), which spontaneously dissociates into $\text{H}^+$ and $\text{HCO}_3^-$.
2. The Chloride Shift (Hamburger Phenomenon): As $\text{HCO}_3^-$ accumulates inside the RBC, it is transported out of the cell into plasma down its concentration gradient via the Anion Exchanger 1 (AE1 / Band 3) membrane transport protein. To preserve electrical neutrality across the erythrocyte membrane, an intracellular shift of chloride ($\text{Cl}^-$) from plasma into the RBC occurs.
3. Pulmonary Reversal: In pulmonary capillaries, low alveolar $P_{\text{CO}_2}$ reverses these equilibria: $\text{Cl}^-$ exits the RBC, $\text{HCO}_3^-$ enters, carbonic anhydrase converts $\text{HCO}_3^-$ back into $\text{CO}_2$ and $\text{H}_2\text{O}$, and $\text{CO}_2$ diffuses into alveoli for exhalation.