Cardiac muscle

# Overview
- Cardiac muscle is a type of involuntary striated muscle found in the walls of the myocardium.
- Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle.
- Coordinated contractions of cardiac muscle cells during systole propel blood out of the atria and ventricles to the blood vessels of the systemic and pulmonary circulatory systems.
- The inherent contractile activity of the heart is extensively regulated by the autonomic nervous system.

# Metabolism
- Cardiac muscle is adapted to be highly resistant to fatigue:
It has a large number of mitochondria enabling continuous aerobic respiration.
The heart is so tuned to aerobic metabolism that it is unable to pump sufficiently in ischaemic conditions. At basal metabolic rates, about 1% of energy is derived from anaerobic metabolism. This can increase to 10% under moderately hypoxic conditions, but under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contractions. 
It has numerous myoglobins (oxygen storing pigment).
It has good blood supply throught the coronary arteries, which provides metabolic substrate and oxygen.
- It has a large number of mitochondria enabling continuous aerobic respiration.
The heart is so tuned to aerobic metabolism that it is unable to pump sufficiently in ischaemic conditions. At basal metabolic rates, about 1% of energy is derived from anaerobic metabolism. This can increase to 10% under moderately hypoxic conditions, but under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contractions. 
- The heart is so tuned to aerobic metabolism that it is unable to pump sufficiently in ischaemic conditions. At basal metabolic rates, about 1% of energy is derived from anaerobic metabolism. This can increase to 10% under moderately hypoxic conditions, but under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contractions. 
- It has numerous myoglobins (oxygen storing pigment).
- It has good blood supply throught the coronary arteries, which provides metabolic substrate and oxygen.
- The sources of energy under basal aerobic conditions:
60% of energy comes from fat (free fatty acids and triacylglycerides)
35% of energy comes from carbohydrates
5% of energy comes from amino acids and ketone bodies
- 60% of energy comes from fat (free fatty acids and triacylglycerides)
- 35% of energy comes from carbohydrates
- 5% of energy comes from amino acids and ketone bodies
- However, these proportions vary widely according to nutritional state. For example, in starvation, lactate can be recycled by the heart. There is a cost to lactate recycling, since one NAD+ is reduced to get pyruvate from lacate, but the pyruvate can then be burnt aerobically in the TCA cycle, liberating much more energy.
- In diabetes, more fat and less carbohydrate is used, due to the reduced induction of GLUT4 glucose transporters to the cell surfaces. However, contraction itself plays a part in bringing GLUT4 transporters to the surface.

# Contraction of the Cardiac Muscle

## Characteristics of the Contraction of the Cardiac Muscle

### Self Excitability:
- Unlike skeletal muscle, which contracts in response to nerve stimulation, and like single unit smooth muscle, cardiac muscle is myogenic, meaning that it is self-excitable stimulating contraction without a requisite electrical impulse coming from the central nervous system.

### Synchrony:
- A single cardiac muscle cell, if left without input, will contract rhythmically at a steady rate; if two cardiac muscle cells are in contact, whichever one contracts first will stimulate the other to contract, and so on.
- This transmission of impulses makes cardiac muscle tissue similar to nerve tissue, although cardiac muscle cells are notably connected to each other by intercalated discs.
Intercalated discs support synchronized contraction of cardiac tissue.
Intercalated discs conduct electrochemical potentials directly between the cytoplasms of adjacent cells via gap junctions.
In contrast to the chemical synapses used by neurons, electrical synapses, in the case of cardiac muscle, are created by ions flowing from cell to cell, known as an action potential.
- Intercalated discs support synchronized contraction of cardiac tissue.
- Intercalated discs conduct electrochemical potentials directly between the cytoplasms of adjacent cells via gap junctions.
- In contrast to the chemical synapses used by neurons, electrical synapses, in the case of cardiac muscle, are created by ions flowing from cell to cell, known as an action potential.
- If synchronization of cardiac muscle contraction is disrupted for some reason (for example, in a heart attack), uncoordinated contraction known as fibrillation can result.

### Regulation:
- Specialized pacemaker cells in the sinoatrial node normally determine the overall rate of contractions, with an average resting pulse of 72 beats per minute.
- The central nervous system does not directly create the impulses to contract the heart, but only sends signals to speed up or slow down the heart rate through the autonomic nervous system using two opposing kinds of modulation:
- 1- Sympathetic nervous system (fight or flight response)
- 2- Parasympathetic nervous system (rest and repose)
- Since cardiac muscle is myogenic, the pacemaker serves only to modulate and coordinate contractions. The cardiac muscle cells would still fire in the absence of a functioning SA node pacemaker, albeit in a chaotic and ineffective manner. This condition is known as fibrillation. Note that the heart can still beat properly even if its connections to the central nervous system are completely severed.

## Excitation Contraction Coupling
- In contrast to skeletal muscle, cardiac muscle cannot contract in the absence of extracellular calcium ions as well as extracellular potassium ions.
- In this sense, it is intermediate between smooth muscle, which has a poorly developed sarcoplasmic reticulum and derives its calcium across the sarcolemma; and skeletal muscle which is activated by calcium stored in the sarcoplasmic reticulum (SR).
- Change in the voltage of the sarcolemma causes the dihydropyridine receptors to open and allows an initial calcium flow to the sarcoplasm.
- The small concentration of calcium that entered binds to ryanodine receptors on the sarcoplasmic reticulum and causes the release of larger stores of calcium from the sarcoplasmic reticulum. This is referred to as calcium-induced calcium release.
Ryanodine receptors are blocked by plant alkaloid ryanodine.
Ryanodine receptors are activated by methyl xanthine caffeine.
- Ryanodine receptors are blocked by plant alkaloid ryanodine.
- Ryanodine receptors are activated by methyl xanthine caffeine.
- The high concentration of calcium promotes actin-myosin bridging and subsequent cardiac muscle contraction.
- At the end of cardiac contraction, the concentration of calcium inside of the sarcoplasm declines:
80% of calcium is reabsorbed into the sarcoplasmic reticulum via an ATP dependent pump:
The ATP dependent pump is regulated by phospholamban.
Phosphorylated phospholamban is the active form. For example, norepinephrine causes the phosphoryllation of phospholamban and thus promotes calcium re-uptake and cardiac muscle relaxation.
20% of calcium is taken out of the cell by one of two mechanisms:
1- Calcium ATPase pump
2- Na+/Ca++ exchanger
- 80% of calcium is reabsorbed into the sarcoplasmic reticulum via an ATP dependent pump:
The ATP dependent pump is regulated by phospholamban.
Phosphorylated phospholamban is the active form. For example, norepinephrine causes the phosphoryllation of phospholamban and thus promotes calcium re-uptake and cardiac muscle relaxation.
- The ATP dependent pump is regulated by phospholamban.
- Phosphorylated phospholamban is the active form. For example, norepinephrine causes the phosphoryllation of phospholamban and thus promotes calcium re-uptake and cardiac muscle relaxation.
- 20% of calcium is taken out of the cell by one of two mechanisms:
1- Calcium ATPase pump
2- Na+/Ca++ exchanger
- 1- Calcium ATPase pump
- 2- Na+/Ca++ exchanger
- Na+/Ca++ exchanger allows the entry of 3 molecules of sodium in exchange with one molecule of calcium.
Digitalis blocks Na+/K+ ATPase which is usually present on the sarcolemma and leads to the following sequence of events:
The intracellular sodium concentration increases.
The gradient of sodium concentration across the sarcolemma decreases.
This decrease in sodium gradient will decrease the activity of the Na+/Ca++ exchanger.
The intracellular concentration of calcium increases.
Cardiac muscle contractility increases.
- Digitalis blocks Na+/K+ ATPase which is usually present on the sarcolemma and leads to the following sequence of events:
The intracellular sodium concentration increases.
The gradient of sodium concentration across the sarcolemma decreases.
This decrease in sodium gradient will decrease the activity of the Na+/Ca++ exchanger.
The intracellular concentration of calcium increases.
Cardiac muscle contractility increases.
- The intracellular sodium concentration increases.
- The gradient of sodium concentration across the sarcolemma decreases.
- This decrease in sodium gradient will decrease the activity of the Na+/Ca++ exchanger.
- The intracellular concentration of calcium increases.
- Cardiac muscle contractility increases.
- The excitation contraction coupling in the cardiac muscle, unlike that in the skeletal muscle, is modulated in such a way that different calcium levels can cause different degree of contractility.
- Shown below is a scheme summarizing the different steps in the excitation-contraction coupling in the cardiac muscle cell:

# Histological Appearance

## Multinucleated Cardiac Muscle Cells
- The cells that comprise cardiac muscle, called cardiomyocytes or myocardiocyteal muscle cells,can contain one, two, or very rarely three or four cell nuclei.

## Striation
- Cardiac muscle exhibits cross striations formed by alternation segments of thick and thin protein filaments which are anchored by segments called Z-lines.
- The primary structural proteins of cardiac muscle are actin and myosin.
The actin filaments are thin causing the lighter appearance of the I bands in muscle
The myosin is thicker and darker lending a darker appearance to the alternating A bands in cardiac muscle as observed by a light enhanced microscope.
- The actin filaments are thin causing the lighter appearance of the I bands in muscle
- The myosin is thicker and darker lending a darker appearance to the alternating A bands in cardiac muscle as observed by a light enhanced microscope.

## T-Tubules
- Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in cardiac muscle are shorter, broader and run along the Z-Discs.
- There are fewer T-tubules in comparison with Skeletal muscle.

## Intercalated Discs
- An intercalated disc is an undulating double membrane separating adjacent cells in cardiac muscle fibers.
- Intercalated discs support synchronized contraction of cardiac tissue.
- Three types of membrane junctions exist within an intercalated disc:
1- Fascia adherens are anchoring sites for actin, and connects to the closest sarcomere.
2- Macula adherens stop separation during contraction by binding intermediate filaments joining the cells together, also called a desmosome.
3- Gap junctions allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle.
- 1- Fascia adherens are anchoring sites for actin, and connects to the closest sarcomere.
- 2- Macula adherens stop separation during contraction by binding intermediate filaments joining the cells together, also called a desmosome.
- 3- Gap junctions allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle.
- Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells.
- The intercalated discs run perpendicular to the direction of muscle fibers.
- Under electron microscopy, an intercalated disc's path appears more complex.
At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line.
At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section. Gap junctions (or nexus junctions) fascia adherens (resembling the zonula adherens), and desmosomes are visible.
In transverse section, the intercalated disk's appearance is labyrinthine and may include isolated interdigitations.
- At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line.
- At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section. Gap junctions (or nexus junctions) fascia adherens (resembling the zonula adherens), and desmosomes are visible.
- In transverse section, the intercalated disk's appearance is labyrinthine and may include isolated interdigitations.