VF BSCI #2

What is the difference in energy generation of cells that have or do not have mitochondria and good oxygenation? List the mitochondrial energy-generating pathways.

Pyruvate can be:
1. Oxidatively decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex (PDH) in the mitochondria under aerobic conditions.
2. Reduced to lactate in the cytosol under anaerobic conditions.
3. Carboxylated to oxaloacetate in the mitochondria under aerobic conditions.
4. Transaminated to alanine in the cytosol. This can be under either aerobic or anaerobic conditions, depending on the needs of the cell.

The Krebs cycle is located in the mitochondrial matrix (mitosol).

Its catabolic function is to take acetyl-CoA that is produced by the PDH complex, certain amino acids, or fatty acid beta-oxidation, and produce reduced cofactors (3 NADH and 1 FADH2) and a molecule of GTP per acetyl-CoA molecule.

NADH and FADH2 enter the terminal oxidation system to produce ATP.

The anabolic function of the Krebs cycle is to supply starting material for different biosynthetic processes, including gluconeogenesis, amino acid synthesis, etc. The cycle is regulated by feedback inhibition by its products NADH and succinyl-CoA, as well as by ATP.

The chemiosmotic–coupling mechanism involves the generation of a proton gradient and reversal of an ATP-dependent proton pump.

An electrochemical gradient of protons is established across the inner mitochondrial membrane during electron transport by pumping protons from the mitosol to the inter-membrane space. Once a gradient is established, the dissipation of the gradient is coupled to synthesis of ATP by the mitochondrial F1F0 ATPase.

While the energy carried by NADH is sufficient for the production of 3 ATPs, FADH2 energy is only enough to produce 2 ATPs in the terminal oxidation system.

Cardiac muscle cells utilize fuel molecules in aerobic energy generation pathways. Although cardiomyocytes can utilize glucose, fatty acids, and amino acids for energy generation, they prefer fatty acids, since much more energy can be generated from 1 molecule of fatty acid than from 1 molecule of glucose or amino acid.

They also can use stored energy in the form of glycogen (glucose, which is utilized in glycolysis) and creatine phosphate for quick energy (ATP) release.

Angina pectoris is chest pain from reversible myocardial ischemia, usually due to coronary artery narrowing. Ischemia forces cardiac tissue into anaerobic metabolism, producing lactate and H⁺, which activate nociceptors and cause pain.

Symptoms include substernal pressure radiating to the arms, jaw, or neck, typically triggered by exertion and relieved by rest. If ischemia persists, it can lead to myocardial infarction, where cell death occurs due to complete vessel blockage, often from a blood clot, causing more severe and prolonged pain.

Plasma lipoproteins, made in the liver and intestine, transport lipids in the blood. LDL, VLDL remnants, and chylomicron remnants are rich in cholesterol and increase atherosclerosis risk. In contrast, HDL removes cholesterol from arteries and is protective. Thus, LDL is "bad" cholesterol, and HDL is "good" cholesterol. Atherosclerosis involves cholesterol buildup in arterial walls, macrophage infiltration, smooth muscle proliferation, and fibrosis.

Atherosclerosis begins with LDL (especially oxidized LDL) entering the arterial wall via endothelial receptors. Monocytes migrate into the intima, become macrophages, and ingest oxidized LDL, forming foam cells. Foam cell death and lipid accumulation trigger inflammation, smooth muscle proliferation (via PDGF), and fibrosis. This forms plaques that narrow arteries, reducing blood flow (ischemia). Plaque rupture can cause clot formation, leading to myocardial infarction.

There are certain forms of proteins (e.g., cardiac troponin I, cTnI) that are found in specific cell types, like cardiac muscle cells, but not other cells. Under normal conditions, these cardiac muscle-specific proteins may be present in the blood at low levels (i.e., within the normal reference range) due to normal cell turnover. When a myocardial infarction occurs, cardiac muscle cells may experience extended lack of oxygen, die, break open, and spill their intracellular contents into the blood. This is why elevated plasma cardiac troponin I (cTnI) can serve as a diagnostic marker of myocardial infarction. It is also a highly-sensitive marker of myocardial infarction.

1. Widely available and inexpensive 2. Sensitive = test’s ability to designate an individual with disease as positive 3. Specific = test’s ability to designate an individual without disease as negative 4. High Positive Predictive Values (PPV) = those among who tested positive do have the condition of interest 5. Precise = <10% difference between two repeated/parallel measures (reproducibility of the test) 6. Quantitative 7. Can be used to clearly distinguish between normal and pathological levels of markers.

Serum/plasma cardiac troponin I (cTnI) levels as detected by the high-sensitivity assay (hs-cTnI) are elevated above normal values at < 1 - 3 hours after the MI, peak at between 12 - 24 hours, and stay elevated for varies - 14 days. cTnI is the newest FDA-approved biomarker used in high-sensitivity assays to detect cardiac cell death. Serum/plasma cardiac troponin I (cTnI) levels as detected by the conventional assay are elevated above normal values at 4 hours after the MI, peak at about 24 hours and stay elevated for 7 - 10 days. Serum/plasma CK-MB levels are elevated above normal values at 6 - 12 hours after the MI, peak around 16 - 24 hours and go back to normal in 48 hours. Both the conventional cTnI assay and the CK-MB measurement have widely been replaced by the superior hs-cTnI measurement, but the conventional cTnI assay and the CK-MB assay are still covered in your First Aid book (i.e., the Step 1 exam).

Blood clots related to a myocardial infarction can be dissolved by the enzyme plasmin. Plasmin circulates in blood in an inactive form, plasminogen. Plasmin is activated by tissue plasminogen activator (t-PA).

Cross-striations visible in light micrographs are evidence of organization of contractile proteins in sarcomeres. Thin (actin) and thick (myosin) filaments are organized in a regular arrangement allowing the overlapping filaments to slide over one another shortening the fiber with an efficient and coordinated force.

Cardiac muscle fibers are joined together end to end by intercalated discs which contain the following types of junctions:
1. fascia adherens
2. macula adherens (desmosomes)
3. gap junctions.

The intercalated disk has a step-like configuration with different junctions occupying vertical and horizontal domains. Fascia adherens are analogous to zonula adherens in function (cell-cell adhesion) and are mediated by the same molecules (cadherins), however they are sheet-like rather than circumferential. The many gap junctions present in cardiac muscle tissue are responsible for the electrical coupling between adjacent cardiomyocytes so the heart muscle contracts as a unit.

Myofiber Shape Cardiac Muscle: Cylindrical, Branched;
Smooth Muscle: Fusiform (tapered ends).

Nucleus Cardiac Muscle: Single (sometimes 2), Central; Smooth Muscle: Single, Central.

Sarcomeres/Striations Cardiac Muscle: Yes; Smooth Muscle: No.

Myofilaments (Actin-Myosin) Cardiac Muscle: Yes; Smooth Muscle: Yes.

Dense Bodies Cardiac Muscle: No; Smooth Muscle: Yes.

T-Tubules Cardiac Muscle: Yes; Smooth Muscle: No.

Caveolae Cardiac Muscle: No; Smooth Muscle: Yes.

Junctions Cardiac Muscle: Intercalated Discs (3 types: FA, MA, Gap jxns); Smooth Muscle: Gap jxns.

C. Endothelial injury and dysfunction

B. It acts as a chemotactic factor for monocytes

A. Collagen and smooth muscle cells

C. Thrombosis overlying a ruptured plaque

A. Platelet-derived growth factor (PDGF)

C. Left anterior descending artery

C. 12-24 hours

C. 1-3 days

C. 5-7 days

E. More than 2 weeks post-MI

C. 12-24 hours

C. Acute fibrinous pericarditis

B. Right coronary artery

E. 1-3 months

B. Papillary muscle rupture

A. Left ventricular free wall rupture

B. Acute pericarditis

B. Dressler syndrome

The non-modifiable risk factors are his age. The Family history is not significant. It would be significant if his father had Coronary artery disease prior to age 55. The modifiable risk factors he has that we know from the case are that he has Diabetes, Hypertension and that he is Obese. Smoking is no longer a risk factor for him as he quit 20 years ago.

A. ST segment depression on Electrocardiogram

Troponin

Cell 2 has the smaller slope. Therefore cell 2 needs less charge, and therefore less current, to increase the membrane potential to a given voltage. Cell 2 is therefore easier to depolarize.

C. Mg2+ The resting membrane potential will be closest to the equilibrium potential for the ion with the highest permeability. Physiologically this is usually K+ because the cell has many open K+ channels at rest. However, in theory it can be any ion.

EK = 61 mV/1 log(6/140) EK = -83 mV

a. decreased Na+ channel availability

a. Na+ channel activation gate: Closed, Na+ channel inactivation gate: Open, K+ channel activation gate: Closed

d. decreased Na+ channel opening

Voltage-gated K+ channels have only a single activation gate. They open upon membrane depolarization but do so more slowly than voltage-gated Na+ channels. They also close gradually upon membrane repolarization. These channels do not require an inactivation gate because the efflux of K+ ions itself repolarizes the membrane, which then causes the activation gate to close.

e. Action potentials have a constant, characteristic threshold potential within each tissue

a. Phase 0 of the AV nodal action potential is carried by Ca2+ current, not Na+ current

c. Purkinje cells have a higher cell diameter than ventricular cells

b. The cardiac cell at rest has a high permeability to K+

The L-type Ca2+ channel and the Na+-Ca2+ exchanger (3 Na+ in for 1 Ca2+ out) both tend to depolarize the membrane. This opposes the delayed rectifier channels (mostly IKr and IKs in the ventricle) and makes the voltage “hang up”. The result is a plateau phase where the opposing currents “cancel out” and the voltage decreases only very slowly.

d. Increased “funny” current, If

A mutation in the cardiac chloride channels (CLCN1 gene) leading to decreased chloride ion conductance would most prominently cause a prolonged QT interval on the electrocardiogram (EKG)

a. Less inactivation of INa

a. Higher (less negative)

**Metabolism** is the **sum of chemical reactions** in a cell, tissue, or body, built by purposeful enzyme pathways.

Its purpose is to **generate energy from fuel molecules to feed all cells** and synthesizereak down biomolecules.

**Energy Generation** can occur in two main ways.

**Anaerobic conditions**: **Without oxygen and mitochondria**.

The only energy-generating pathway is **glycolysis**, which utilizes glucose to produce a **small amount of energy (2 ATP)** and **lactic acid**.

Cells lacking mitochondria or oxygen can only rely on glycolysis.

Examples include **mature erythrocytes, white skeletal muscle cells, retina and sclera cells, and chondrocytes**.

**Aerobic conditions**: Requires the **presence of mitochondria and oxygen**.

This process produces **much more energy** and involves the **Pyruvate Dehydrogenase (PDH) complex, the Krebs cycle (TCA), and terminal oxidation**.

Cells with both mitochondria and sufficient oxygen can utilize **glucose, fatty acids, and ketone bodies** (during extended fasting/starvation) for energy.

The major energy-generating reactions in mitochondria are the **Pyruvate Dehydrogenase (PDH) complex, fatty acid beta-oxidation, the Krebs cycle (TCA), and terminal oxidation (electron transport chain and oxidative phosphorylation)**.

These processes are **localized in the mitochondria**.

The **outer mitochondrial membrane (OMM)** is simple and permeable to most biomolecules.

The **inner mitochondrial membrane (IMM)** is complex, semi-permeable, heavily folded into cristae, and contains most of the electron transport and oxidative phosphorylation enzymes, dehydrogenases, and transport systems.

Transport across the IMM is regulated by **transporters** (e.g., for ATP/ADP, Pi, TCA intermediates) and **substrate shuttles** (for reduced coenzymes like NADH from the cytosol).

**Location**: **Mitochondrial matrix (mitosol)**.

**Function**: Catalyzes a **multiple-step, irreversible reaction** that converts **pyruvate into acetyl-CoA, carbon dioxide (CO2), and NADH**.

Acetyl-CoA then enters the Krebs cycle, and NADH enters terminal oxidation for ATP generation.

**Coenzymes**: Requires **vitamins B1 (thiamine pyrophosphate), B2 (FAD), B3 (NAD+), B5 (CoA), and lipoic acid**.

**Eat your water-soluble vitamins daily** for proper PDH function.

**Regulation**: It is a **heavily regulated system**.

**Feedback inhibition** by its products: **acetyl-CoA and NADH**.

**Phosphorylation/Dephosphorylation**: The active form is dephosphorylated, while the inactive form is phosphorylated. A protein kinase, stimulated by ATP, acetyl-CoA, and NADH, inactivates PDH by phosphorylation, while pyruvate inhibits this kinase.

**PDH Deficiency**: A **mitochondrial disorder** inherited in an **X-linked dominant manner**, it is the **most common cause of congenital lactic acidosis**.

Due to the deficiency, pyruvate cannot be converted to acetyl-CoA; instead, it forms **lactate via lactate dehydrogenase**, leading to **chronic lactic acidosis**.

Affected children often show **elevated serum levels of lactate, pyruvate, and alanine**, and frequently exhibit **severe neurological defects, often resulting in death**.

**Location**: **Mitochondrial matrix (mitosol)**.

**Sources of Acetyl-CoA**: Produced by the PDH complex (from pyruvate), fatty acid beta-oxidation, and certain amino acids.

**Catabolic Function**: The cycle performs the **complete oxidation of acetyl-CoA to CO2**, generating **1 GTP molecule** and **reduced cofactors (3 NADH and 1 FADH2)** per acetyl-CoA molecule.

NADH and FADH2 are then channeled to terminal oxidation for ATP production.

**Anabolic Function**: Krebs cycle intermediates serve as **precursors for various biosynthetic processes**, including gluconeogenesis, amino acid synthesis, fatty acid synthesis, and steroid synthesis.

**Anaplerotic (Filling) Reactions**: These reactions replenish TCA intermediates that are removed for biosynthetic purposes.

The most important step is the **pyruvate carboxylase (PC) reaction, which converts pyruvate into oxaloacetate**.

**Energetics**: One acetyl-CoA molecule entering the Krebs cycle yields a total of **12 ATPs** (11 from reduced cofactors in terminal oxidation and 1 from GTP via substrate-level phosphorylation).

**Regulation**: Regulated by the supply of acetyl-CoA, PDH regulation, the availability of NAD+, FAD, GDP, and Pi, and the coupling to terminal oxidation (availability of ADP+Pi and oxygen). Feedback inhibition by products like NADH, succinyl-CoA, and ATP also plays a role.

Key regulatory enzymes include citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase.

**Genetic Abnormalities**: Genetic abnormalities of TCA enzymes are very rare and often incompatible with life due to the pathway's critical role.

**Definition**: It is the **last step in extracting energy from fuel molecules**.

It consists of two parts: **Electron Transport (Part 1)** where electron carriers stepwise transfer electrons and protons from **reduced coenzymes (NADH and FADH2) to molecular oxygen (O2)**, which is the final electron acceptor; and **Oxidative Phosphorylation (Part 2)** where this reducing power is then converted into **ATP energy**.

**Location**: **Mitochondrial inner membrane**.

**Sources of NADH and FADH2**: These reduced coenzymes come from the PDH complex, the TCA cycle, fatty acid beta-oxidation (all in the mitosol), and cytosolic processes (like glycolysis) via mitochondrial shuttles.

**Electron Transport Chain Components**: Comprises **4 large multi-subunit enzyme complexes (Complex I-IV), coenzyme Q, and cytochrome C**.

Remember to **eat your vitamins (NAD+, FAD, FMN) and minerals (iron and copper)** for proper ETC function.

**Electron Flow**: NADH enters at Complex I; FADH2 enters at coenzyme Q; electrons are transferred sequentially through Complexes, CoQ, and Cytochrome c, finally to Complex IV, which transfers electrons to **molecular oxygen (O2)**, producing water.

**Proton Gradient**: As electrons are transferred, **protons are ejected from the mitochondrial matrix into the intermembrane space at Complexes I, III, and IV**. This creates an **electrochemical gradient (proton gradient)** across the inner mitochondrial membrane.

**ATP Synthesis**: Protons flow back into the matrix through the **F0F1-ATPase (Complex V)**, located in the inner membrane. The energy from this proton gradient is used to synthesize **ATP from ADP and Pi**.

This process is known as **chemiosmotic coupling**.

**Energetics**: Oxidation of **NADH yields approximately 3 ATPs**, while **FADH2 yields approximately 2 ATPs**.

**Coupling**: ATP production is **tightly coupled to electron transport**; inhibition of one process stops the other.

**Uncoupling**: Electron flow and ATP synthesis can be **uncoupled** (e.g., in brown adipose tissue by uncoupling protein 1, UCP-1) to generate **heat** instead of ATP.

**Cardiac muscle cells require a continuous supply of ATP** and **continuous oxygen supply** to function.

They are **highly aerobic**, with mitochondria making up about half of their volume.

**Energy Reserves**: Include **glycogen** (stored glucose for glycolysis) and **phosphocreatine** (a high-energy chemical bond that rapidly hydrolyzes to yield ATP).

**Normal Energy Sources**: Under normal conditions, cardiac muscle cells favor **fatty acids** due to their high energy yield, but also use glucose.

**Energy Sources During Starvation**: **fatty acids and ketone bodies** become the major energy sources for cardiac muscle.

**Myocardial Ischemia**: Occurs when the **oxygen supply to cardiac muscle is lower than normal**.

Glycolysis increases, producing **lactic acid**.

Lactic acid lowers pH, leading to **lactic acidosis**.

Excess protons (H+) stimulate **pain nerve cells (nociceptors)**, which generates pain (e.g., angina pectoris).

**Angina Pectoris**: Defined as **chest pain associated with reversible myocardial ischemia**.

It results from an **imbalance between the demand for and supply of blood flow/oxygen to cardiac muscle cells**, most commonly caused by **narrowing of the coronary arteries due to atherosclerosis** or temporary spasms.

The pain is described as substernal heaviness, often radiating to the left shoulder, arm, jaw, or neck. Attacks typically occur with exertion, last 1 to 15 minutes, and are relieved by resting.

**Myocardial Infarction (MI)**: Occurs when **ischemia persists long enough to cause severe damage (necrosis, or cell death) to the heart muscle**.

A **blood clot (thrombus) forms at the site of artery narrowing and completely obstructs the vessel**, leading to tissue death and more severe, longer-lasting pain.

**Coronary Heart Disease (CHD) Risk Factors**: Major risk factors include **diabetes, smoking, hypertension, a family history of premature CHD, high serum triglyceride levels, and elevated serum cholesterol levels (particularly LDL)**.

Plasma Lipoproteins: These are **delivery vehicles for lipids** (triglycerides, cholesterol, etc.).

**Structure**: Lipoproteins have a hydrophilic outer layer (apoprotein, phospholipids, cholesterol) and a hydrophobic inner nucleus (triglycerides, cholesterol ester).

**LDL (Low-Density Lipoprotein)**: Primarily **delivers cholesterol to peripheral tissues**.

It poses a **direct risk for atherogenesis** and is often called "bad cholesterol," especially if it circulates in the blood for prolonged periods.

**HDL (High-Density Lipoprotein)**: Synthesized by the liver and intestine.

Plays an **essential role in "picking up" cholesterol from the periphery and delivering it to the liver (reverse cholesterol transport)**.

HDL is known as "good cholesterol" for its role in fighting atherogenesis.

Lipoproteins rich in cholesterol (LDL, VLDL remnants, chylomicron remnants) are associated with an **increased risk of CHD**.

HDL, conversely, is associated with a **decreased risk**.

**Total cholesterol (TC)**: Normal values are 120 - 200 mg/dL.

Primarily reflects LDL levels.

**HDL cholesterol (HDLC)**: Normal values are > 40 mg/dL.

**Triglycerides (TG)**: Normal values are 70 - 150 mg/dL.

**LDL cholesterol (LDLC)**: Calculated, normal values are < 100 mg/dL.

**Atherosclerosis**: It is a **disorder of the arterial wall**.

**Characterized by**: 1. **Accumulation of cholesteryl esters in cells derived from the monocyte-macrophage lineage**; 2. **Smooth muscle cell proliferation**; 3. **Fibrosis**.

These processes result in **narrowed blood vessels**.

High circulating lipids initiate a cascade of events.

**Injured endothelial cells** trigger monocyte migration and macrophage formation.

**Oxidized LDL** more easily enters the intima and is engulfed by macrophages via **scavenger receptors**.

Macrophages transform into **foam cells**, which become trapped in the intima.

**Platelet-derived growth factor (PDGF)** and other growth factors stimulate **smooth muscle cell migration from the media to the intima and proliferation**.

Smooth muscle cells deposit **collagen** and other extracellular matrix proteins, leading to **arterial wall thickening and hardening**.

The resultant plaque narrows the blood vessel, decreasing blood flow and causing ischemia.

**Plaque rupture can initiate blood clotting**, which may lead to complete arterial blockage and a myocardial infarction.

**General Characteristics of Good Biomarkers**: Tissue-specific, time of appearance, time of disappearance, and availability of reliable assays.

**General Characteristics of Good Biomarker Assays**: Widely available and inexpensive, sensitive, specific, high positive predictive value (PPV), quantitative, precise (reproducible), and clearly distinguish between normal and pathologic levels.

**Sensitive**: The test's ability to designate individuals with the disease as positive.

**Specific**: The test's ability to designate individuals without the disease as negative.

**High Positive Predictive Value (PPV)**: The probability that a positive test result correctly identifies an individual who actually has the condition of interest.

**Precise (reproducible)**: Results show less than 10% difference between repeated or parallel measures.

Normal is considered the 99th percentile or upper reference limit.

**Protein Isoforms**: Proteins (or enzymes) that fulfill the same function but differ slightly in amino acid composition due to arising from different genetic loci.

**Key Biomarkers for MI**: High-sensitivity cardiac troponin I (hs-cTnI), conventional cardiac troponin I (cTnI), and Creatine kinase (CK)-MB.

**High-sensitivity cardiac troponin I (hs-cTnI)**: **Elevated <1 to 3 hours after MI**, **peaks 12 to 24 hours**, and **returns to normal in a variable period up to 14 days**.

It is the newest FDA-approved biomarker assay (2017) and is used at Rush.

**Conventional cardiac troponin I (cTnI)**: **Elevated at 4 hours after MI**, **peaks around 24 hours**, and **returns to normal in 7 to 10 days**.

Though replaced by high-sensitivity assays in clinical labs, it remains relevant for Step 1 exams.

**Creatine kinase (CK)-MB**: **Elevated 6 to 12 hours after MI**, **peaks 16 to 24 hours**, and **returns to normal in 48 hours**.

**Plasmin**: A natural enzyme in the blood that **dissolves clots**.

It circulates in an inactive form called **plasminogen**.

**Tissue Plasminogen Activator (t-PA)**: A therapeutically administered enzyme that **converts inactive plasminogen into active plasmin**.

**Morphology**: Fibers typically have **one, sometimes two, centrally located nuclei**. The cells **branch** (note the forks in cells). **Cross-striations are present**.

The sarcoplasm is rich in **many elongated mitochondria**, which constitute approximately **40% of the cardiac muscle cell volume** (compared to ~2% in skeletal muscle).

This high mitochondrial content is essential to **power the constant contraction of the heart** with continuous ATP supply.

**Intercalated Disks**: These are **specialized junctions that connect adjacent cardiac muscle cells end-to-end**.

They contain: **Fascia adherens (FA)** and **desmosomes (D)** which anchor the cytoskeletons, and **Gap junctions (GJ)** which allow **ions to pass directly between adjacent fibers, transmitting electrical impulses** for coordinated contraction.

**Capacity for Repair**: Cardiac muscle tissue generally **does not regenerate**. Damaged tissue from an infarction is typically replaced with a **fibrous scar**.

**Location**: Found in the **walls of visceral organs and blood vessels**.

**Morphology**: Cells are **fusiform (spindle-shaped)** with a **single, centrally located nucleus**. They **lack striations (smooth)** because their contractile proteins are not arranged in sarcomeres.

**Control**: Smooth muscle contraction is modulated by autonomic innervation, hormones, or local signals (e.g., stretch). Smooth muscle cells primarily rely on **influx of external Ca2+** for contraction.

**Growth and Regeneration**: Smooth muscle cells **maintain the potential to divide mitotically** for growth and repair. They **readily regenerate** to repair damaged tissue. Smooth muscle tissue mass can also increase through both **hyperplasia and hypertrophy**.

**Transmembrane Potential (Vm)**: The difference in electrical potential across the cell membrane, calculated as **Vm = Vi - Ve** (intracellular potential minus extracellular potential).

**Resting Potentials**: **Cardiac and skeletal muscle cells typically have resting potentials around -90 mV**, while nerve cells are usually around -70 mV.

**Electroneutrality**: The principle that the number of positive and negative charges is equal in the bulk intracellular and extracellular solutions.

**Nernst Equation**: This equation describes the **equilibrium potential (Ex)** for a single permeable ion, which is the electrical potential required to balance the concentration gradient for that ion across the membrane.

The equation is **Ex = (61mV / z) log ([X]e / [X]i)**, where 'z' is the ion's valence, '[X]e' is the external concentration, and '[X]i' is the internal concentration.

**Typical Equilibrium Potentials**: **Na+ ~ +60 mV, K+ ~ -95 mV, Cl- ~ -50 to -85mV, Ca2+ ~ +130 mV**.

**Membrane Capacitance (Cm)**: A measure of **how much charge is needed to create a given membrane potential**.

**Capacitance increases linearly with membrane area**; larger cells have higher capacitance.

**Capacitance decreases with effective membrane thickness**; thicker membranes have lower capacitance. Myelin, for example, effectively increases membrane thickness, reducing capacitance.

The **most permeable ions (those with the highest conductance)** have the **greatest effect on the transmembrane potential**.

In many cells, chloride is **passively distributed** across the membrane (meaning it is not actively transported).

In such cases, the **chloride equilibrium potential (ECl) is equal to the membrane potential (Vm)** at rest.

This pump is **electrogenic**, meaning it moves **3 Na+ ions out of the cell and 2 K+ ions into the cell** for every molecule of ATP hydrolyzed.

**Characteristics**: APs are **all-or-none**, **non-decremental**, **unidirectional**, and characterized by **refractory periods**.

APs are initiated when the membrane is depolarized to its **threshold potential**.

**Rising Phase (Phase 0 / Upstroke)**: Caused by the **rapid opening (activation) of voltage-gated Na+ channels**. This process involves **positive feedback**.

**Falling Phase (Downstroke / Repolarization)**: Caused by the **inactivation of voltage-gated Na+ channels** and the **opening (activation) of voltage-gated K+ channels**.

**Voltage-Gated Na+ Channels**: Possess **two gates**: an **activation gate** and an **inactivation gate**. **Both gates must be open** for Na+ ions to cross the membrane. At the **resting potential (~-90 mV)**, the **activation gate is closed and the inactivation gate is open**.

**Voltage-Gated K+ Channels**: Have **only a single activation gate**. They open upon membrane depolarization but do so **more slowly** than voltage-gated Na+ channels. They **do not require an inactivation gate** because K+ efflux itself repolarizes the membrane.

**Refractory Periods**: These periods ensure **unidirectional propagation** of action potentials by preventing immediate re-excitation.

**Absolute refractory period**: During this time, it is **absolutely impossible to produce another action potential** because essentially all voltage-gated Na+ channels are inactivated until the membrane potential largely returns to its resting level.

**Relative refractory period**: During this time, it is **relatively more difficult (but not impossible)** to produce another action potential because K+ permeability remains elevated.

**Threshold Potential**: The membrane potential (always depolarized relative to rest) that is **just sufficient to produce an action potential**.

**Threshold is not a fixed value**; it is influenced by the **resting membrane permeability to K+ and/or Cl-**, the **number of voltage-gated Na+ channels available to open**, and the **rate at which the membrane depolarizes**.

**Basic Mechanism**: A region of the membrane undergoing an action potential acts as a stimulus, depolarizing neighboring regions and causing them to initiate their own action potentials.

**Factors Influencing Propagation Speed**: **Cell/fiber diameter** (larger leads to faster), **resting membrane resistance (Rm)** (higher leads to faster), **intracellular longitudinal resistance (Ri)** (lower leads to faster), **number of voltage-gated Na+ channels** (higher density leads to faster), and **membrane capacitance (Cm)** (lower leads to faster).

**Myelination (in Nerve Axons)**: Myelin is formed by **oligodendrocytes (in the CNS) or Schwann cells (in the PNS)**, which repeatedly wrap around nerve cell axons.

**Nodes of Ranvier**: Small, exposed regions (a few µm) along the axon that contain **high densities of voltage-gated Na+ and K+ channels**.

Myelin **increases the axonal membrane resistance and decreases its effective capacitance** in the internodal regions.

**Saltatory Conduction**: Action potential conduction in myelinated nerves is **discontinuous**, essentially **"jumping" from node to node**.

Cardiac APs are **much longer in duration** than those in nerve and skeletal muscle. They are described in **phases 0-4**.

**Phase 0 (Rapid Upstroke)**: Primarily due to the **rapid activation of voltage-gated Na+ channels**.

**Phase 1 (Early Partial Repolarization)**: Caused by the **inactivation of voltage-gated Na+ channels** and the **activation of transient outward K+ channels (Ito1)**.

**Phase 2 (Prolonged Plateau)**: The membrane potential remains relatively stable (near 0 to +10 mV) for 100-300 milliseconds.

**Key Inward Current**: Maintained primarily by the **opening of L-type Ca2+ channels (ICa,L)**, which activate slowly and inactivate very slowly, triggering contraction and maintaining depolarization. The **Na+/Ca2+ exchanger** also contributes a depolarizing inward current.

**Phase 3 ("Rapid" Repolarization)**: A relatively rapid return to the resting membrane potential.

**Causes**: **Gradual inactivation and deactivation of L-type Ca2+ channels** and a **gradual increase in voltage-gated K+ currents** (especially IKs). The IK1 current also increases as the membrane repolarizes, aiding in repolarization.

**Phase 4 (Resting Potential)**: In ventricular and atrial myocytes, this is the period when the membrane is at its **resting potential, typically around -90 mV**. At this phase, **K+ permeability is highest**, primarily due to IK1 channels.

These cells exhibit **no true resting potential**; instead, they show **continuous phase 4 depolarization**.

**Phase 4 (Spontaneous Depolarization / Pacemaker Activity)**: This slow depolarization leads to the initiation of the next action potential. It involves the **opening of pacemaker channels (If)** and the **characteristics of IK1** and **T-type Ca2+ channels (ICa,T)**.

**Opening of pacemaker channels (If)**: These "funny" channels activate when the membrane **hyperpolarizes** (becomes more negative than -35 mV), causing a depolarizing inward current.

The upstroke in SA and AV nodal cells is **much more gradual** than in ventricular/atrial myocytes. It is primarily supported by **T-type and (more importantly) L-type Ca2+ channels**.

Conduction through the SA node and especially the AV node is **quite slow**, resulting in the **AV nodal delay**. Reasons include absence of Na+ channels, low density of Ca2+ channels, and fewer gap junctions.

The SA node typically generates APs at a faster rate (~70/min) than the AV node (~50/min), making the **SA node the normal pacemaker for the entire heart**.

**Regulatory (Modulatory) Channels in the Heart**: ACh-activated K+ channel (IK,ACh), ATP-dependent K+ channel (IK,ATP), and cAMP-dependent Chloride channel (ICl,cAMP).

**ACh-activated K+ channel (IK,ACh)**: Activated by acetylcholine released from **parasympathetic (vagal) nerves**. This causes **hyperpolarization** of atrial and nodal tissues, which **slows the rate of spontaneous phase 4 depolarization and thus decreases heart rate**.

**ATP-dependent K+ channel (IK,ATP)**: These channels are normally closed but **open in response to low intracellular ATP levels**, which typically occurs during **ischemia**.

**cAMP-dependent Chloride channel (ICl,cAMP)**: Activated by the **sympathetic nervous system**, this channel contributes to the **shortening of the cardiac action potential**.

Unlike skeletal muscle, cardiac muscle and many types of smooth muscle **do not require nervous system input to generate action potentials**; instead, they exhibit spontaneous rhythmic activity.

**Key EKG findings**: **Peaked T waves and a widened QRS complex**.

These changes are primarily due to **decreased availability of voltage-gated Na+ channels (resting inactivation)**, which results from the progressive depolarization of the resting membrane potential caused by **elevated extracellular potassium concentration ([K+]e)**.

**Arteriosclerosis**: A **generic term indicating arterial wall thickening and loss of elasticity**.

**Atheroma (Atherosclerotic Plaque)**: These are **patchy intimal thickenings with lipid accumulation** in the arterial wall. They appear as raised white-to-yellow lesions composed of cells, extracellular matrix, and both intracellular and extracellular lipid.

**Contraction Band Necrosis**: This is a **type of necrosis unique to cardiac myocytes**. It is a **characteristic histologic finding of a very recent myocardial infarction**.

**Reperfusion Injury**: This phenomenon describes the **late restoration of blood flow into ischemic tissues** that paradoxically incites **even more extensive local myocardial damage**.

**Coronary Artery Disease (CAD)**: **narrowing of the coronary arteries** primarily caused by atherosclerotic obstruction of epicardial vessels, and rarely by spasms.

Occurs when narrowing **exceeds 65-70%**, potentially leading to **myocardial ischemia**.

**Ischemia**: Develops when the **demand for oxygen by the myocardium exceeds the supply**.

**Stable Angina**: Characterized by **fixed narrowing of the arteries**, causing symptoms when oxygen demand outweighs supply. Symptoms are **relieved by rest**.

**Unstable Angina**: Involves the **disruption of an atherosclerotic plaque with transient thrombotic occlusion**. It presents as **new-onset, crescendo (increasing severity), or rest angina lasting >20 minutes**, or previous angina that is increasing in intensity, duration, and frequency. **Serum troponin is negative**.

**Non-modifiable**: **Age, male gender, and a family history of premature CAD** (before age 55 in men and before age 65 in women).

**Modifiable**: **Hyperlipidemia (particularly low-density lipoprotein, LDL), hypertension, diabetes mellitus, smoking (quitting can reduce risk), obesity, and physical inactivity**.

**Classic Presentation**: **Chest pain described as squeezing, heaviness, or tightness**, which is retrosternal and may **radiate to the back, jaw, or left shoulder**. It can be associated with left arm numbness, **nausea**, diaphoresis, or shortness of breath.

**Atypical Presentations (especially in females)**: May include discomfort in the neck, jaw, shoulder, or upper abdomen, along with shortness of breath, pain in one or both arms, nausea or vomiting, sweating, fatigue, and heartburn.

**Diagnosis of ACS**: Involves **clinical presentation**, **EKG findings**, and **cardiac biomarkers**.

**Ischemia** may show **ST segment depression**.

**Infarction (STEMI)** is characterized by **ST elevation, T wave peaking, and the formation of Q waves**.

**Gold Standard**: **Coronary angiogram ("cardiac cath")** to assess coronary artery patency.

**Electrical Complications**: Include **arrhythmias** (e.g., bradyarrhythmias, atrial and ventricular tachyarrhythmias) and **conduction abnormalities** (e.g., first, second, and third-degree heart block).

**Mechanical Complications**: Involve right and left **ventricular failure**.

**Structural Complications**: Infarction of myocardial regions can result in **free wall rupture, ventricular septal defect, or acute mitral regurgitation** (due to papillary muscle rupture).

**P wave**: Represents **atrial depolarization**.

**PQ interval (PR interval)**: Represents **AV nodal delay**.

**QRS wave**: Represents **ventricular depolarization**.

**T wave**: Represents **ventricular repolarization**.

**ST segment elevation**: Highly suggestive of an **acute myocardial infarction**.

**ST-segment elevations in leads II, III, and aVF**: Indicative of an **inferior wall myocardial infarction**, most likely due to **occlusion of the right coronary artery**.

**Metabolism** is the **sum of the chemical reactions that occur in a cell, a tissue or in the body.**

The purpose of the intermediary metabolism is to generate **energy from fuel molecules to feed all cells of the body.**

**Energy (ATP) can be generated and utilized in two ways**: anaerobic (in the absence of oxygen and/or mitochondria) and aerobic (in the presence of oxygen and mitochondria).

The major energy-generating reactions in mitochondria: **Pyruvate dehydrogenase complex (PDH), Fatty acid beta-oxidation, Krebs cycle (TCA), Terminal oxidation (Electron transport and Oxidative phosphorylation)**.

Mitochondria have two membranes, a simple outer and a complex inner one. The **outer mitochondrial membrane (OMM)** is a simple membrane with a few enzymatic or transport functions and it is permeable to most biomolecules. The **inner mitochondrial membrane (IMM)** is heavily folded to supply a large surface area for the biochemical processes, is more complex with 80% protein content. It is semi-permeable and contains most of the electron transport and oxidative phosphorylation enzymes, various dehydrogenases and several transport systems.

Coenzymes: (vitamins from food sources) **thiamine pyrophosphate (TPP, vitamin B1), lipoic acid (a vitamin), coenzyme A (vitamin B5), FAD (vitamin B2), NAD+ (vitamin B3)**.

**Nutrition note - Eat your vitamins!**

Oxidatively decarboxylated to **acetyl-CoA under aerobic conditions (PDH)**. Carboxylated to **oxaloacetate for gluconeogenesis**.

Reduced to **lactate, the end product of glycolysis under anaerobic conditions.**

**Location: mitochondrial matrix (the mitosol)**.

Reaction: **irreversible** (large free energy change).

**PDH deficiency is the most common cause of congenital lactic acidosis.**

Children diagnosed with pyruvate dehydrogenase deficiency usually exhibit **elevated serum levels of lactate**, pyruvate, and alanine.

The catabolic function of the tricarboxylic acid cycle is to **produce energy**.

The anabolic function of the TCA cycle is to **supply starting material for different biosynthetic processes**, including gluconeogenesis, amino acid synthesis, fatty acid synthesis, etc.

**Anaplerotic reactions replenish intermediates of TCA**.

**Terminal oxidation (2 parts)**: 1. Electron carriers transfer electrons and protons from **reduced coenzymes NADH and FADH2** (also called reduced cofactors) to **oxygen**. This is called **electron transport**. 2. This reducing power is then converted into **ATP energy by oxidative phosphorylation**.

**In the mitochondrial inner membrane.**

**4 large multi-subunit enzyme complexes (Complex I - IV), Coenzyme Q, Cytochrome C**. The Complexes contain redox enzymes, coenzymes and metal ions – all participate in the redox reactions.

**Nutrition note: Eat your vitamins (NAD+, FAD, FMN) and minerals (iron and copper)!**

**Protons are ejected from the mitochondrial matrix** (also known as the mitosol) into the intramembrane space at three points: at Complexes I, III, and IV. This creates an **electrochemical gradient (proton gradient)** that provides energy for ATP synthesis.

**NADH ~ 3ATPs**, **FADH2 ~ 2 ATPs**.

**Myocardial infarction**: happens when the heart cannot get enough oxygen and nutrients through the blood flow, and this ischemia persists long enough to cause **severe damage (necrosis) to the heart muscle**.

**Tissue-specific**, **Time of appearance**, **Time of disappearance**, **Availability of reliable assays**.

**Widely available and inexpensive**, **Sensitive**, **Specific**, **High Positive Predictive Value (PPV)**, **Quantitative**, **Precise (reproducible)**, **Clearly distinguish between normal and pathologic levels of markers**.

Please remember the assay’s **sensitivity, specificity, and high positive predictive value (PPV)**.

**Isoforms of proteins**: proteins that fulfill the same function, but differ slightly in amino acid composition, since they arise from different genetic loci.

**Isoenzymes**: enzymes that catalyze the same reaction, but differ slightly in amino acid composition, since they arise from different genetic loci.

**High-sensitivity cardiac troponin I (hs-cTnI)**: elevated **< 1 - 3 h**, peaks **12 - 24 h**, and returns to normal **varies - up to 14 days**.

**High-sensitivity cardiac troponin I (hs-cTnI)** is the newest (2017) FDA-approved biomarker assay.

**Conventional (i.e., not “high-sensitivity”) cardiac troponin I (cTnI)**: elevated at **4 h**, peaks at **~24 h**, and returns to normal **7 - 10 days**.

**CK-MB**: elevated **6 - 12 h**, peaks **16 - 24 h**, returns to normal **48 h**.

**Plasmin** is an enzyme in the blood that naturally dissolves clots.

**Plasmin circulates in blood as its inactive form (plasminogen).**

**Plasmin is activated by tissue plasminogen activator (t-PA).**

**Cross-striations visible in light micrographs are evidence of organization of contractile proteins in sarcomeres.**

Cardiac muscle fibers are joined together end to end by **intercalated discs which contain the following types of junctions: fascia adherens, macula adherens (desmosomes), and gap junctions.**

The **many gap junctions present in cardiac muscle tissue are responsible for the electrical coupling between adjacent cardiomyocytes so the heart muscle contracts as a unit.**

The **resting potential will be closest to the equilibrium potential for the ion with the highest permeability.**

With **hyperkalemia (high plasma potassium) EK, and therefore the resting potential, are less negative than normal. This causes Na+ channel inactivation gates to close. This raises the threshold potential in excitable cells and slows action potential propagation.**

**Closed**.

**Open**.

**Closed**.

The idea of a local anesthetic is to raise the threshold potential. **Blockage of Na+ channels**, therefore, raises the threshold potential.

**Phase 0 of the AV nodal action potential is carried by Ca2+ current, not Na+ current.**

**Purkinje cells have a higher cell diameter than ventricular cells.**

**IK1, the inward rectifier K+ channel is able to conduct the most K+ at rest. This channel makes the membrane very permeant to K+ and, therefore, makes the resting potential close to EK (-95 mV).**

**The L-type Ca2+ channel and the Na+-Ca2+ exchanger (3 Na+ in for 1 Ca2+ out) both tend to depolarize the membrane. This opposes the delayed rectifier channels (mostly IKr and IKs in the ventricle) and makes the voltage “hang up”.**

**Increased “funny” current, If.**

**Less inactivation of INa.**

**Ex = (61mV / z) log ([X]e / [X]i)**.

**Electroneutrality must be maintained on both sides of the membrane.**

**Action potentials are all-or-none, non-decremental, unidirectional, and characterized by refractory periods.**

The **rapid opening (activation) of voltage-gated Na+ channels**.