Myosin IX is a group of single-headed motor proteins. It was first shown to be minus-end directed, [ 51 ]  but a later study showed that it is plus-end directed. [ 52 ]  The movement mechanism for this myosin is poorly understood.


Myosin X is an unconventional myosin motor, which is functional as a  dimer . The dimerization of myosin X is thought to be antiparallel. [ 53 ]  This behavior has not been observed in other myosins. In mammalian cells, the motor is found to localize to  filopodia . Myosin X walks towards the barbed ends of filaments.  Some research suggests it preferentially walks on bundles of actin, rather than single filaments. [ 54 ]  It is the first myosin motor found to exhibit this behavior.


Myosin XI directs the movement of organelles such as  plastids  and  mitochondria  in plant cells. [ 55 ]  It is responsible for the light-directed movement of  chloroplasts  according to light intensity and the formation of  stromules  interconnecting different plastids. Myosin XI also plays a key role in polar root tip growth and is necessary for proper  root hair  elongation. [ 56 ]  A specific Myosin XI found in  Nicotiana tabacum  was discovered to be the fastest known processive  molecular motor , moving at 7μm/s in 35 nm steps along the  actin  filament. [ 57 ]


This myosin group has been found in the  Apicomplexa  phylum. [ 58 ]  The myosins localize to plasma membranes of the intracellular  parasites  and may then be involved in the cell invasion process. [ 59 ]


This myosin is also found in the ciliated protozoan  Tetrahymena thermophila .  Known functions include: transporting phagosomes to the nucleus and perturbing the developmentally regulated elimination of the  macronucleus  during conjugation.


Myosin XV is necessary for the development of the actin core structure of the non-motile  stereocilia  located in the inner ear. It is thought to be functional as a monomer.


MYO18A A gene on chromosome 17q11.2 that encodes actin-based motor molecules with ATPase activity, which may be involved in maintaining stromal cell scaffolding required for maintaining intercellular contact.


Unconventional myosin XIX (Myo19) is a mitochondrial associated myosin motor. [ 60 ]


Note that not all of these genes are active.


Myosin light chains are distinct and have their own properties.  They are not considered "myosins" but are components of the macromolecular complexes that make up the functional myosin enzymes.


Paramyosin is a large, 93-115kDa  muscle   protein  that has been described in a number of diverse  invertebrate  phyla. [ 61 ]  Invertebrate thick filaments are thought to be composed of an inner paramyosin core surrounded by myosin.  The myosin interacts with  actin , resulting in fibre contraction. [ 62 ]  Paramyosin is found in many different invertebrate species, for example,  Brachiopoda ,  Sipunculidea ,  Nematoda ,  Annelida ,  Mollusca ,  Arachnida , and  Insecta . [ 61 ]   Paramyosin is responsible for the "catch" mechanism that enables sustained contraction of muscles with very little energy expenditure, such that a  clam  can remain closed for extended periods.


Paramyosins can be found in seafood. A recent computational study showed that following human intestinal digestion, paramyosins of  common octopus ,  Humboldt squid , Japanese abalone, Japanese scallop,  Mediterranean mussel ,  Pacific oyster ,  sea cucumber , and  Whiteleg shrimp  could release short  peptides  that inhibit the enzymatic activities of  angiotensin converting enzyme  and  dipeptidyl peptidase . [ 63 ]


A  neuromuscular junction  (or  myoneural junction ) is a  chemical synapse  between a  motor neuron  and a  muscle fiber . [ 1 ]


It allows the motor neuron to transmit a signal to the muscle fiber, causing  muscle contraction . [ 2 ]


Muscles require innervation to function—and even just to maintain  muscle tone , avoiding  atrophy . In the  neuromuscular system , nerves from the  central nervous system  and the  peripheral nervous system  are linked and work together with muscles. [ 3 ]  Synaptic transmission at the neuromuscular junction begins when an  action potential  reaches the presynaptic terminal of a  motor neuron , which activates  voltage-gated calcium channels  to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins ( synaptotagmins ) on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent  neurotransmitter  release from the motor neuron into the  synaptic cleft . In  vertebrates , motor neurons release  acetylcholine  (ACh), a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to  nicotinic acetylcholine receptors  (nAChRs) on the cell membrane of the muscle fiber, also known as the  sarcolemma . nAChRs are  ionotropic  receptors, meaning they serve as  ligand -gated  ion channels . The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that eventually results in muscle contraction.


Neuromuscular junction diseases  can be of  genetic  and  autoimmune  origin.  Genetic disorders, such as  Congenital myasthenic syndrome , can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as  myasthenia gravis , occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma.


At the  neuromuscular junction , presynaptic motor axons terminate  30 nanometers from the cell membrane  or  sarcolemma  of a muscle fiber.  The sarcolemma at the junction has  invaginations  called postjunctional folds, which increase its surface area  facing the synaptic cleft. [ 4 ]   These postjunctional folds form the motor endplate, which is studded with  nicotinic acetylcholine receptors  (nAChRs) at a density of 10,000 receptors/μm 2 . [ 5 ]   The presynaptic axons terminate in bulges called terminal boutons (or presynaptic terminals) that project toward the postjunctional folds of the sarcolemma. In the frog each motor nerve terminal contains about 300,000  vesicles , with an average  diameter of 0.05 micrometers.  The vesicles contain acetylcholine.  Some of these vesicles  are gathered  into groups of fifty, positioned at active zones close to the nerve membrane.  Active zones are about 1 micrometer apart.
The 30 nanometer cleft between nerve ending and endplate contains a meshwork of  acetylcholinesterase  (AChE) at a density of 2,600 enzyme molecules/μm 2 , held in place by the structural proteins  dystrophin  and  rapsyn .  Also present is the  receptor tyrosine kinase  protein  MuSK , a signaling protein involved in the development of the neuromuscular junction, which is also held in place by rapsyn. [ 4 ]


About once every second in a resting junction randomly one of the synaptic vesicles fuses with the presynaptic neuron's  cell membrane  in a process mediated by  SNARE  proteins. Fusion results in the emptying of the vesicle's contents of 7000–10,000 acetylcholine molecules  into the  synaptic cleft , a process known as  exocytosis . [ 6 ]  Consequently, exocytosis releases  acetylcholine in packets that are called quanta. The acetylcholine quantum diffuses through the acetylcholinesterase meshwork, where the high local transmitter concentration occupies all of the binding sites on the enzyme in its path.  The acetylcholine that reaches the endplate activates ~2,000 acetylcholine receptors, opening their ion channels which permits sodium ions to move into the endplate producing a depolarization of ~0.5 mV known as a miniature endplate potential (MEPP). By the time the acetylcholine is released from the receptors the acetylcholinesterase has destroyed its bound ACh, which takes about ~0.16 ms,  and hence is available to destroy the  ACh released from the receptors. [ citation needed ]


When the motor nerve is stimulated there is a delay of only 0.5 to 0.8 msec between the arrival of the nerve impulse in the motor nerve terminals and the first response of the endplate  [ 7 ]   The arrival of the motor nerve  action potential  at the presynaptic neuron terminal opens  voltage-dependent calcium channels , and Ca 2+   ions  flow from the extracellular fluid into the presynaptic neuron's  cytosol . This influx of Ca 2+  causes several hundred  neurotransmitter -containing  vesicles  to fuse with the presynaptic neuron's cell membrane through  SNARE  proteins to release their acetylcholine quanta by exocytosis. The endplate depolarization by the released acetylcholine is called an endplate potential (EPP). The EPP is accomplished when ACh binds the nicotinic acetylcholine receptors (nAChR) at the motor end plate, and causes an influx of sodium ions. This influx of sodium ions generates the EPP (depolarization), and triggers an action potential that travels along the sarcolemma and into the muscle fiber via the  T-tubules  (transverse tubules) by means of voltage-gated sodium channels. [ 8 ]  The conduction of action potentials along the T-tubules stimulates the opening of voltage-gated Ca 2+  channels which are mechanically coupled to Ca 2+  release channels in the sarcoplasmic reticulum. [ 9 ]  The Ca 2+  then diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction. The endplate potential is thus responsible for setting up an action potential in the muscle fiber which triggers muscle contraction.  The transmission from nerve to muscle is so rapid because each quantum of acetylcholine reaches the endplate in millimolar concentrations, high enough to combine with a receptor with a low affinity, which then swiftly releases the bound transmitter. [ citation needed ]


Acetylcholine  is a  neurotransmitter  synthesized from dietary  choline  and  acetyl-CoA  (ACoA), and is involved in the stimulation of  muscle tissue  in  vertebrates  as well as in some  invertebrate  animals. In vertebrates, the acetylcholine receptor subtype that is found at the neuromuscular junction of  skeletal muscles  is the  nicotinic acetylcholine receptor  (nAChR), which is a  ligand-gated ion channel .  Each subunit of this receptor has a characteristic "cys-loop", which is composed of a  cysteine  residue followed by 13  amino acid  residues and another cysteine residue. The two cysteine residues form a  disulfide linkage  which results in the "cys-loop" receptor that is capable of binding acetylcholine and other ligands.  These cys-loop receptors are found only in  eukaryotes , but  prokaryotes  possess ACh receptors with similar properties. [ 5 ]   Not all species use a  cholinergic  neuromuscular junction; e.g.  crayfish  and fruit flies have a  glutamatergic  neuromuscular junction. [ 4 ]


AChRs at the skeletal neuromuscular junction form heteropentamers composed of two α, one β, one ɛ, and one δ subunits. [ 10 ]   When a single ACh ligand binds to one of the α subunits of the ACh receptor it induces a  conformational change  at the interface with the second AChR α subunit.  This conformational change results in the increased  affinity  of the second α subunit for a second ACh ligand.  AChRs, therefore, exhibit a sigmoidal dissociation curve due to this  cooperative binding . [ 5 ]   The presence of the inactive, intermediate receptor structure with a single-bound ligand keeps ACh in the  synapse  that might otherwise be lost by  cholinesterase  hydrolysis or diffusion.  The persistence of these ACh ligands in the synapse can cause a prolonged post-synaptic response. [ 11 ]


The development of the neuromuscular junction requires signaling from both the motor neuron's terminal and the muscle cell's central region. During development, muscle cells produce acetylcholine receptors (AChRs) and express them in the central regions in a process called prepatterning.  Agrin , a heparin  proteoglycan , and MuSK kinase are thought to help stabilize the accumulation of AChR in the central regions of the myocyte. MuSK is a receptor  tyrosine kinase —meaning that it induces cellular signaling by binding  phosphate  molecules to self regions like  tyrosines , and to other targets in the  cytoplasm . [ 12 ]  Upon activation by its ligand agrin, MuSK signals via two proteins called " Dok-7 " and " rapsyn ", to induce "clustering" of acetylcholine receptors. [ 13 ]  ACh release by developing motor neurons produces postsynaptic potentials in the muscle cell that positively reinforces the localization and stabilization of the developing neuromuscular junction. [ 14 ]


These findings were demonstrated in part by mouse " knockout " studies.  In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in  Dok-7  did not form either acetylcholine receptor clusters or neuromuscular synapses. [ 15 ]


The development of neuromuscular junctions is mostly studied in model organisms, such as rodents. In addition, in 2015 an all-human neuromuscular junction has been created in vitro using human  embryonic stem cells  and somatic muscle stem cells. [ 16 ]   In this model presynaptic  motor neurons  are activated by  optogenetics  and in response synaptically connected muscle fibers twitch upon light stimulation.


José del Castillo and  Bernard Katz  used ionophoresis to determine the location and density of  nicotinic acetylcholine receptors  (nAChRs) at the neuromuscular junction.  With this technique, a microelectrode was placed inside the motor endplate of the muscle fiber, and a micropipette filled with acetylcholine (ACh) was placed directly in front of the endplate in the synaptic cleft.  A positive voltage was applied to the tip of the micropipette, which caused a burst of positively charged ACh molecules to be released from the pipette. These ligands flowed into the space representing the synaptic cleft and bound to AChRs.  The intracellular microelectrode monitored the  amplitude  of the  depolarization  of the motor endplate in response to ACh binding to nicotinic (ionotropic) receptors.  Katz and del Castillo showed that the amplitude of the depolarization ( excitatory postsynaptic potential ) depended on the proximity of the micropipette releasing the ACh ions to the endplate.  The farther the micropipette was from the motor endplate, the smaller the depolarization was in the muscle fiber.  This allowed the researchers to determine that the nicotinic receptors were localized to the motor endplate in high density. [ 4 ] [ 5 ]


Toxins are also used to determine the location of acetylcholine receptors at the neuromuscular junction.  α-Bungarotoxin  is a toxin found in the snake species  Bungarus multicinctus  that acts as an ACh antagonist and binds to AChRs irreversibly.  By coupling assayable enzymes such as  horseradish peroxidase  (HRP) or fluorescent proteins such as  green fluorescent protein  (GFP) to the α-bungarotoxin, AChRs can be visualized and quantified. [ 4 ]


Nerve gases bind to and phosphorylate AChE, effectively deactivating them. The accumulation of ACh within the synaptic cleft causes muscle cells to be perpetually contracted, leading to severe complications such as paralysis and death within minutes of exposure.


Botulinum toxin  (also known as botulinum  neurotoxin , and commercially sold under the trade name Botox) inhibits the release of acetylcholine at the neuromuscular junction by interfering with SNARE proteins. [ 4 ]  This toxin crosses into the nerve terminal through the process of  endocytosis  and subsequently cleaves SNARE proteins, preventing the ACh vesicles from fusing with the intracellular membrane. This induces a transient  flaccid paralysis  and chemical denervation localized to the striated muscle that it has affected. The inhibition of ACh release does not set in until approximately two weeks after the injection is made. Three months after the inhibition occurs, neuronal activity begins to regain partial function, and six months after, complete neuronal function is regained. [ 17 ]


Tetanus toxin, also known as  tetanospasmin  is a potent neurotoxin produced by  Clostridium tetani  and causes the disease state, tetanus. The LD 50  of this toxin has been measured to be approximately 1 ng/kg, making it second only to botulinum toxin D as the deadliest toxin in the world. It functions very similarly to botulinum neurotoxin by attaching and endocytosing into the presynaptic nerve terminal and interfering with SNARE proteins. It differs from botulinum neurotoxin in a few ways, most apparently in its end state, wherein tetanospasmin causes  spastic paralysis  as opposed to the flaccid paralysis demonstrated with botulinum neurotoxin.


Latrotoxin  (α-Latrotoxin) found in venom of widow spiders also affects the neuromuscular junction by causing the release of acetylcholine from the presynaptic cell. Mechanisms of action include binding to receptors on the presynaptic cell activating the  IP3/DAG pathway  and release of calcium from intracellular stores and pore formation resulting in influx of calcium ions directly. Either mechanism causes increased calcium in presynaptic cell, which then leads to release of synaptic vesicles of acetylcholine. Latrotoxin causes pain, muscle contraction and if untreated potentially paralysis and death.


Snake venoms act as toxins at the neuromuscular junction and can induce weakness and  paralysis . Venoms can act as both presynaptic and postsynaptic neurotoxins. [ 18 ]


Presynaptic neurotoxins, commonly known as β-neurotoxins, affect the presynaptic regions of the neuromuscular junction. The majority of these neurotoxins act by inhibiting the release of neurotransmitters, such as acetylcholine, into the synapse between neurons. However, some of these toxins have also been known to enhance neurotransmitter release. Those that inhibit neurotransmitter release create a  neuromuscular blockade  that prevents signaling molecules from reaching their postsynaptic target receptors. In doing so, the victim of these snake bite suffer from profound weakness. Such neurotoxins do not respond well to anti-venoms. After one hour of inoculation of these toxins, including  notexin  and  taipoxin , many of the affected nerve terminals show signs of irreversible physical damage, leaving them devoid of any  synaptic vesicles . [ 18 ]


Postsynaptic neurotoxins, otherwise known as α-neurotoxins, act oppositely to the presynaptic neurotoxins by binding to the postsynaptic acetylcholine receptors. This prevents interaction between the acetylcholine released by the presynaptic terminal and the receptors on the postsynaptic cell. In effect, the opening of sodium channels associated with these acetylcholine receptors is prohibited, resulting in a neuromuscular blockade, similar to the effects seen due to presynaptic neurotoxins. This causes paralysis in the muscles involved in the affected junctions. Unlike presynaptic neurotoxins, postsynaptic toxins are more easily affected by anti-venoms, which accelerate the dissociation of the toxin from the receptors, ultimately causing a reversal of paralysis. These neurotoxins experimentally and qualitatively aid in the study of acetylcholine receptor  density  and  turnover , as well as in studies observing the direction of  antibodies  toward the affected acetylcholine receptors in patients diagnosed with  myasthenia gravis . [ 18 ]


Any  disorder  that compromises the synaptic transmission between a motor neuron and a muscle cell is categorized under the umbrella term of  neuromuscular diseases . These disorders can be  inherited  or acquired and can vary in their severity and mortality. In general, most of these disorders tend to be caused by mutations or autoimmune disorders. Autoimmune disorders, in the case of neuromuscular diseases, tend to be  humoral  mediated,  B cell  mediated, and result in an  antibody  improperly created against a motor neuron or muscle fiber protein that interferes with synaptic transmission or signaling.


Myasthenia gravis  is an autoimmune disorder where the body makes antibodies against either the acetylcholine receptor (AchR) (in 80% of cases), or against postsynaptic muscle-specific kinase (MuSK) (0–10% of cases). In seronegative myasthenia gravis  low density lipoprotein  receptor-related protein 4 is targeted by  IgG1 , which acts as a competitive inhibitor of its ligand, preventing the ligand from binding its receptor. It is not known if seronegative myasthenia gravis will respond to standard therapies. [ 19 ]


Neonatal MG is an autoimmune disorder that affects 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis (MG). MG can be transferred from the mother to the fetus by the movement of AChR antibodies through the  placenta . Signs of this disease at birth include weakness, which responds to anticholinesterase medications, as well as fetal akinesia, or the lack of fetal movement. This form of the disease is transient, lasting for about three months. However, in some cases, neonatal MG can lead to other health effects, such as arthrogryposis and even fetal death. These conditions are thought to be initiated when maternal AChR antibodies are directed to the  fetal  AChR and can last until the 33rd week of  gestation , when the γ subunit of AChR is replaced by the ε subunit. [ 20 ]   [ 21 ]


Lambert–Eaton myasthenic syndrome  (LEMS) is an autoimmune disorder that affects the presynaptic portion of the neuromuscular junction. This rare disease can be marked by a unique triad of symptoms: proximal muscle weakness,  autonomic dysfunction , and areflexia. [ 22 ]  Proximal muscle weakness is a product of  pathogenic  autoantibodies directed against P/Q-type voltage-gated calcium channels, which in turn leads to a reduction of acetylcholine release from motor nerve terminals on the presynaptic cell. Examples of autonomic dysfunction caused by LEMS include  erectile dysfunction  in men,  constipation , and, most commonly,  dry mouth . Less common dysfunctions include  dry eyes  and altered  perspiration .  Areflexia  is a condition in which tendon reflexes are reduced and it may subside temporarily after a period of exercise. [ 23 ]


50–60% of the patients that are diagnosed with LEMS also have present an associated  tumor , which is typically  small-cell lung carcinoma  (SCLC). This type of tumor also expresses  voltage-gated calcium channels . [ 23 ]  Oftentimes, LEMS also occurs alongside myasthenia gravis. [ 22 ]


Treatment for LEMS consists of using 3,4-diaminopyridine as a first measure, which serves to increase the compound muscle action potential as well as muscle strength by lengthening the time that voltage-gated calcium channels remain open after blocking voltage-gated potassium channels. In the US, treatment with 3,4-diaminopyridine for eligible LEMS patients is available at no cost under an expanded access program. [ 24 ] [ 25 ]  Further treatment includes the use of  prednisone  and  azathioprine  in the event that 3,4-diaminopyridine does not aid in treatment. [ 23 ]


Neuromyotonia  (NMT), otherwise known as Isaac's syndrome, is unlike many other diseases present at the neuromuscular junction. Rather than causing muscle weakness, NMT leads to the hyperexcitation of motor nerves. NMT causes this hyperexcitation by producing longer depolarizations by down-regulating  voltage-gated potassium channels , which causes greater neurotransmitter release and repetitive firing. This increase in rate of firing leads to more active transmission and as a result, greater muscular activity in the affected individual. NMT is also believed to be of  autoimmune  origin due to its associations with autoimmune symptoms in the individual affected. [ 20 ]


Congenital myasthenic syndromes  (CMS) are very similar to both MG and LEMS in their functions, but the primary difference between CMS and those diseases is that CMS is of genetic origins. Specifically, these syndromes are diseases incurred due to mutations, typically  recessive , in 1 of at least 10 genes that affect presynaptic, synaptic, and postsynaptic proteins in the neuromuscular junction. Such mutations usually arise in the ε-subunit of AChR, [ 20 ]  thereby affecting the kinetics and expression of the receptor itself.  Single nucleotide substitutions or deletions may cause loss of function in the subunit. Other  mutations , such as those affecting  acetylcholinesterase  and  acetyltransferase , can also cause the expression of CMS, with the latter being associated specifically with episodic  apnea . [ 26 ]  These syndromes can present themselves at different times within the life of an individual. They may arise during the fetal phase, causing fetal  akinesia , or the perinatal period, during which certain conditions, such as  arthrogryposis ,  ptosis ,  hypotonia ,  ophthalmoplegia , and feeding or breathing difficulties, may be observed. They could also activate during adolescence or adult years, causing the individual to develop slow-channel syndrome. [ 20 ]


Treatment for particular subtypes of CMS (postsynaptic fast-channel CMS) [ 27 ] [ 28 ]  is similar to treatment for other neuromuscular disorders.  3,4-Diaminopyridine , the first-line treatment for LEMS, is under development as an orphan drug for CMS [ 29 ]  in the US, and available to eligible patients under an expanded access program at no cost. [ 24 ] [ 25 ]


The  thoracic diaphragm , or simply the  diaphragm  ( / ˈ d aɪ ə f r æ m / ; [ 1 ]   Ancient Greek :  διάφραγμα ,  romanized :  diáphragma ,  lit.   'partition'), is a sheet of internal  skeletal muscle [ 2 ]  in  humans  and other  mammals  that extends across the bottom of the  thoracic cavity . The diaphragm is the most important  muscle of respiration , [ 3 ]  and separates the  thoracic cavity , containing the  heart  and  lungs , from the  abdominal cavity : as the diaphragm contracts, the volume of the thoracic cavity increases, creating a negative pressure there, which draws air into the lungs. [ 4 ]  Its high oxygen consumption is noted by the many  mitochondria  and  capillaries  present; more than in any other skeletal muscle. [ 3 ]


The term  diaphragm  in anatomy, created by  Gerard of Cremona , [ 5 ]  can refer to other flat structures such as the  urogenital diaphragm  or  pelvic diaphragm , but "the diaphragm" generally refers to the thoracic diaphragm. In humans, the diaphragm is slightly asymmetric—its right half is higher up (superior) to the left half, since the large liver rests beneath the right half of the diaphragm. There is also speculation that the diaphragm is lower on the other side due to heart's presence.


Other  mammals  have diaphragms, and other  vertebrates  such as  amphibians  and  reptiles  have diaphragm-like structures, but important details of the anatomy may vary, such as the position of the lungs in the thoracic cavity.


The diaphragm is an upward curved, c-shaped structure of  muscle  and  fibrous tissue  that separates the  thoracic cavity  from the abdomen. [ 6 ]  The superior surface of the dome forms the floor of the thoracic cavity, and the inferior surface the roof of the abdominal cavity. [ 7 ]


As a dome, the diaphragm has peripheral attachments to structures that make up the abdominal and chest walls. The muscle fibres from these attachments converge in a  central tendon , which forms the crest of the dome. [ 7 ]  Its peripheral part consists of muscular fibers that take origin from the circumference of the  inferior thoracic aperture  and converge to be inserted into a central tendon.


The muscle fibres of the diaphragm radiate outward from the central tendon. While the diaphragm is one muscle, it is composed of two distinct muscle regions: the costal, which serves as the driver in the work of breathing, and crural diaphragm, which serves as an "anchor;" attaching the muscle to the lower ribs and lumbar vertebrae. The costal diaphragm is further divided into ventral, medial, and dorsal costal portions.  [ 8 ] [ 9 ]


The vertebral part of the diaphragm arises from the crura and arcuate ligaments. Right crus arises from L1-L3 vertebral bodies and their intervertebral discs. Smaller left crus arises from L1, L2 vertebral bodies and their intervertebral discs. [ 8 ] [ 7 ] [ 10 ]  Medial arcuate ligament arises from the fascia thickening from body of L2 vertebrae to transverse process of L1 vertebrae, crossing over the body of the  psoas major  muscle. The  lateral arcuate ligament  arises from the transverse process of L1 vertebrae and is attached laterally to the 12th rib. The lateral arcuate ligament also arises from fascia thickening that covers the  quadratus lumborum  muscle. The  median arcuate ligament  arises from the fibrous parts of right and left crura where descending  thoracic aorta  passes behind it. No diaphragmatic muscle arises from the median arcuate ligament. [ 8 ]  Both adrenal glands lie near the diaphragmatic crus and arcuate ligament. [ 11 ]


The costal part of diaphragm arises from the lower four ribs (7 to 10) costal cartilages. [ 8 ]


The  central tendon  of the diaphragm is a thin but strong  aponeurosis  near the center of the vault formed by the muscle, closer to the front than to the back of the  thorax . The central part of the tendon is attached above to  pericardium . The both sides of the posterior fibres are attached to paracolic gutters (the curving of ribs before attaching to both sides of the vertebral bodies). [ 8 ]


There are a number of openings in the diaphragm through which structures pass between the thorax and abdomen. There are three large openings — one for the  aorta  ( aortic hiatus ), [ 2 ]  one for the  esophagus  ( esophageal hiatus ), and one for the  inferior vena cava  (the  caval opening ), [ 8 ]  as well as a series of smaller openings. [ 12 ] [ 13 ]


The inferior vena cava passes through the caval opening, a quadrilateral opening at the junction of the right and middle leaflets of the  central tendon , so that its margins are tendinous. Surrounded by tendons, the opening is stretched open every time inspiration occurs. However, there has been argument that the caval opening actually constricts during inspiration. Since thoracic pressure decreases upon inspiration and draws the caval blood upwards toward the right atrium, increasing the size of the opening allows more blood to return to the heart, maximizing the efficacy of lowered thoracic pressure returning blood to the heart. The  aorta  does not pierce the diaphragm but rather passes behind it in between the left and right crus. [ citation needed ]


There are several structures that pierce through the diaphragm, including:  left phrenic nerve  pierces through the central tendon, greater, lesser, and least  thoracic splanchnic nerves  pierces through bilateral crura, and lymphatic vessels that pierce throughout the diaphragm, especially behind the diaphragm. [ 8 ]


The diaphragm is primarily innervated by the  phrenic nerve  which is formed from the  cervical nerves  C3, C4 and C5. [ 7 ]   While the central portion of the diaphragm sends sensory afferents via the phrenic nerve, the peripheral portions of the diaphragm send sensory afferents via the  intercostal  (T5–T11) [ 8 ]  and  subcostal nerves  (T12). [ citation needed ]


Arteries and veins above and below the diaphragm supply and drain blood.


From above, the diaphragm receives blood from branches of the  internal thoracic arteries , namely the  pericardiacophrenic artery  and  musculophrenic artery ; from the  superior phrenic arteries , which arise directly from the  thoracic aorta ; and from the lower  internal intercostal arteries . From below, the  inferior phrenic arteries  supply the diaphragm. [ 7 ]


The diaphragm drains blood into the  brachiocephalic veins ,  azygos veins , and veins that drain into the  inferior vena cava  and  left suprarenal vein . [ 7 ]


The sternal portion of the muscle is sometimes wanting and more rarely defects occur in the lateral part of the  central tendon  or adjoining muscle fibers.


The thoracic diaphragm develops during  embryogenesis , beginning in the third week after fertilization with two processes known as transverse folding and longitudinal folding. The  septum transversum , the primitive central tendon of the diaphragm, originates at the rostral pole of the  embryo  and is relocated during longitudinal folding to the ventral thoracic region.  Transverse folding brings the body wall anteriorly to enclose the gut and body cavities.  The pleuroperitoneal membrane and body wall myoblasts, from somatic lateral plate  mesoderm , meet the septum transversum to close off the pericardio-peritoneal canals on either side of the presumptive esophagus, forming a barrier that separates the peritoneal and pleuropericardial cavities.  Furthermore, dorsal  mesenchyme  surrounding the presumptive esophagus form the muscular crura of the diaphragm.


Because the earliest element of the embryological diaphragm, the septum transversum, forms in the cervical region, the  phrenic nerve  that innervates the diaphragm originates from the cervical spinal cord (C3,4, and 5).  As the septum transversum descends inferiorly, the phrenic nerve follows, accounting for its circuitous route from the upper cervical vertebrae, around the  pericardium , finally to innervate the diaphragm.


The diaphragm is the main  muscle of respiration  and functions in  breathing . During inhalation, the diaphragm contracts and moves in the inferior direction, enlarging the volume of the thoracic cavity and reducing intra-thoracic pressure (the  external intercostal muscles  also participate in this enlargement), forcing the lungs to expand. In other words, the diaphragm's movement downwards creates a partial  vacuum  in the thoracic cavity, which forces the lungs to expand to fill the void, drawing air in the process.


Cavity expansion happens in two extremes, along with intermediary forms. When the lower ribs are stabilized and the central tendon of the diaphragm is mobile, a contraction brings the insertion (central tendon) towards the origins and pushes the lower cavity towards the pelvis, allowing the thoracic cavity to expand downward. This is often called  belly breathing . When the central tendon is stabilized and the lower ribs are mobile, a contraction lifts the origins (ribs) up towards the insertion (central tendon) which works in conjunction with other muscles to allow the ribs to slide and the thoracic cavity to expand laterally and upwards.


When the diaphragm relaxes (moves in the superior direction), air is exhaled by elastic recoil process  of the lung and the tissues lining the thoracic cavity. Assisting this function with muscular effort (called forced  exhalation ) involves the  internal intercostal muscles  used in conjunction with the  abdominal muscles , which act as an  antagonist  paired with the diaphragm's contraction. Diaphragm dysfunction is a well-known factor associated with various complications in patients, such as prolonged respiratory failure, difficulties in weaning from mechanical ventilation, extended hospitalization, increased morbidity, and mortality. [ 15 ]  Studies have reported that a thin diaphragm leads to greater lung compliance, which can contribute to respiratory failure. Furthermore, reduction in diaphragm thickness during the early stages of disease can serve as a prognostic marker in sepsis patients, and COVID-19 patients. [ 16 ] [ 17 ]


The diaphragm is also involved in non-respiratory functions. It helps to expel  vomit ,  feces , and  urine  from the body by increasing intra-abdominal pressure, aids in childbirth, [ 18 ]  and prevents  acid reflux  by exerting pressure on the  esophagus  as it passes through the  esophageal hiatus .


In some non-human animals, the diaphragm is not crucial for breathing; a cow, for instance, can survive fairly asymptomatically with diaphragmatic paralysis as long as no massive aerobic metabolic demands are made of it.  [ citation needed ]


If either the  phrenic nerve ,  cervical spine  or  brainstem  is damaged, this will sever the nervous supply to the diaphragm. The most common damage to the phrenic nerve is by  bronchial cancer , which usually only affects one side of the diaphragm. Other causes include  Guillain–Barré syndrome  and  systemic lupus erythematosus . [ 19 ]


A  hiatus hernia  is a  hernia  common in adults in which parts of the lower esophagus or stomach that are normally in the abdomen pass/bulge abnormally through the diaphragm and are present in the thorax.  Hernias are described as  rolling , in which the hernia is beside the oesophagus, or  sliding , in which the hernia directly involves the esophagus.  These hernias are implicated in the development of reflux, as the different pressures between the thorax and abdomen normally act to keep pressure on the  esophageal hiatus .  With herniation, this pressure is no longer present, and the angle between the  cardia  of the  stomach  and the oesophagus disappear. Not all hiatus hernias cause symptoms however, although almost all people with  Barrett's oesophagus  or  oesophagitis  have a hiatus hernia. [ 19 ]


Hernias may also occur as a result of congenital malformation, a  congenital diaphragmatic hernia . When the  pleuroperitoneal  membranes fail to fuse, the diaphragm does not act as an effective barrier between the abdomen and thorax. Herniation is usually of the left, and commonly through the posterior  lumbocostal triangle , although rarely through the anterior  foramen of Morgagni . The contents of the abdomen, including the  intestines , may be present in the thorax, which may impact development of the growing lungs and lead to  hypoplasia . [ 20 ]  This condition is present in 0.8 - 5/10,000 births. [ 21 ]   A large herniation has high mortality rate, and requires immediate surgical repair. [ 22 ]


Due to its position separating the  thorax  and  abdomen , fluid abnormally present in the thorax, or air abnormally present in the abdomen, may collect on one side of the diaphragm. An  X-ray  may reveal this.  Pleural effusion , in which there is fluid abnormally present between the two  pleurae  of the  lungs , is detected by an  X-ray  of the chest, showing fluid collecting in the  angle between the ribs and diaphragm . [ 19 ]  An X-ray may also be used to reveal a  pneumoperitoneum , in which there is gas in the abdomen.


An X-ray may also be used to check for herniation. [ 20 ]


The adoption of a deeper breathing pattern typically occurs during physical exercise in order to facilitate greater oxygen absorption. During this process the diaphragm more consistently adopts a lower position within the body's core. In addition to its primary role in breathing, the diaphragm also plays a secondary role in strengthening the posture of the core. This is especially evident during deep breathing where its generally lower position increases intra-abdominal pressure, which serves to strengthen the lumbar spine. [ 23 ] [ better source needed ]


The key to real core stabilization is to maintain the increased IAP while going through normal breathing cycles. [...] The diaphragm then performs its breathing function at a lower position to facilitate a higher IAP. [ 23 ]


[ better source needed ]


Therefore, if a person's diaphragm position is lower in general, through deep breathing, then this assists the strengthening of their core during that period. This can be an aid in strength training and other forms of athletic endeavour. For this reason, taking a deep breath or adopting a deeper breathing pattern is typically recommended when lifting heavy weights.


The existence of a membrane separating the pharynx from the stomach can be traced widely among the  chordates .  Thus the  model organism , the marine chordate  lancelet , possesses an atriopore by which water exits the pharynx, which has been claimed (and disputed) to be homologous to structures in  ascidians  and  hagfishes . [ 25 ]   The  tunicate  epicardium separates digestive organs from the pharynx and heart, but the anus returns to the upper compartment to discharge wastes through an outgoing siphon.


Thus the diaphragm emerges in the context of a body plan that separated an upper feeding compartment from a lower digestive tract, but the point at which it originates is a matter of definition.  Structures in fish, amphibians, reptiles, and birds have been called diaphragms, but it has been argued that these structures are not  homologous .  For instance, the alligator diaphragmaticus muscle does not insert on the  esophagus  and does not affect pressure of the lower esophageal sphincter. [ 26 ]   The lungs are located in the abdominal compartment of amphibians and reptiles, so that contraction of the diaphragm expels air from the lungs rather than drawing it into them.  In birds and mammals, lungs are located above the diaphragm.  The presence of an exceptionally well-preserved fossil of  Sinosauropteryx , with lungs located beneath the diaphragm as in crocodiles, has been used to argue that dinosaurs could not have sustained an active warm-blooded physiology, or that birds could not have evolved from dinosaurs. [ citation needed ]   An explanation for this (put forward in 1905), is that lungs originated beneath the diaphragm, but as the demands for respiration increased in warm-blooded birds and mammals, natural selection came to favor the  parallel evolution  of the herniation of the lungs from the abdominal cavity in both lineages. [ 24 ]


However, birds lack diaphragms.  They do not breathe in the same way as mammals and do not rely on creating a negative pressure in the thoracic cavity, at least not to the same extent.  They rely on a rocking motion of the keel of the sternum to create local areas of reduced pressure to supply thin, membranous airsacs cranially and caudally to the fixed-volume, non-expansive lungs.  A complicated system of valves and air sacs cycles air constantly over the absorption surfaces of the lungs so allowing maximal efficiency of gaseous exchange.  Thus, birds do not have the reciprocal tidal breathing flow of mammals.  On careful dissection, around eight air sacs can be clearly seen.  They extend quite far caudally into the abdomen. [ 27 ]


This article incorporates text in the  public domain  from  page 404  of the 20th edition of   Gray's Anatomy   (1918)


This article incorporates text from a publication now in the  public domain :  Chambers, Ephraim , ed. (1728).  Cyclopædia, or an Universal Dictionary of Arts and Sciences  (1st ed.). James and John Knapton, et al.   {{ cite encyclopedia }} :  Missing or empty  |title=  ( help )


The  aortic hiatus  is a midline [ 1 ] : 185   opening in the posterior part of the  diaphragm  giving passage to the  descending aorta  as well as the  thoracic duct , and variably the  azygos  and  hemiazygos  veins. [ 2 ]  It is the lowest and most posterior of the large apertures. [ citation needed ]


It is located at the level of the inferior border of the  twelfth thoracic vertebra (T12) , [ 2 ]  posterior to the  median arcuate ligament [ 2 ] [ 1 ] : 185   between the two  crura of the diaphragm . [ 2 ]


Strictly speaking, it is not an aperture in the diaphragm but an  osseoaponeurotic  opening between it and the  vertebral column , and therefore behind the diaphragm (meaning that diaphragmatic contractions during respiration do not directly affect aortic blood flow [ 3 ] ). [ citation needed ]


The hiatus is situated slightly to the left of the midline, and is bound anteriorly by the crura, and posteriorly by the body of the first  lumbar vertebra . [ citation needed ]


Occasionally some tendinous fibers prolonged across the bodies of the vertebræ from the medial parts of the inferior ends of the  crura  pass posterior to the aorta, and thus convert the hiatus into a fibrous ring. [ citation needed ]


The aorta is situated on the left, the thoracic duct in the middle, and the azygos vein on the right. [ 1 ] : 185   The hemiazygos vein may pass through the aortic hiatus [ 2 ]  or may pass through the diaphragm independently through its own foramen in the left crus. [ 1 ] : 186


The  crus of diaphragm  ( pl. : crura), refers to one of two  tendinous  structures that extends below the  diaphragm  to the  vertebral column . There is a right crus and a left crus, which together form a tether for muscular contraction. They take their name from their leg-shaped appearance –  crus  meaning  leg  in Latin.


The crura originate from the front of the bodies and  intervertebral fibrocartilage  of the  lumbar vertebrae . They are tendinous and blend with the  anterior longitudinal ligament  of the  vertebral column .


The medial tendinous margins of the crura pass anteriorly and medialward, and meet in the middle line to form an arch across the front of the  aorta  known as the  median arcuate ligament ; this arch is often poorly defined.  The area behind this arch is known as the  aortic hiatus .


From this series of origins the fibers of the diaphragm converge to be inserted into the  central tendon .


The fibers arising from the  xiphoid process  are very short, and occasionally  aponeurotic ; those from the medial and  lateral lumbocostal arches , and more especially those from the ribs and their cartilages, are longer, and describe marked curves as they ascend and converge to their insertion. The fibers of the crura diverge as they ascend, the most lateral being directed upward and lateralward to the central tendon.


The medial fibers of the right crus ascend on the left side of the  esophageal hiatus , and occasionally a fasciculus of the left crus crosses the aorta and runs obliquely through the fibers of the right crus toward the  vena caval foramen .


This article incorporates text in the  public domain  from  page 405  of the 20th edition of   Gray's Anatomy   (1918)


In human anatomy, the  esophageal hiatus  is an opening in the  diaphragm  through which the  esophagus  and the  vagus nerve  pass.


The esophageal hiatus is an oval opening [ 1 ]  in (sources differ) the right  crus of the diaphragm [ 1 ] /left crus of the diaphragm, with fibres of the right crus looping around the hiatus to form a sling (upon  inspiration , this sling would constrict the esophagus, forming a functional (not anatomical) sphincter that prevents gastric contents from refluxing up the esophagus when intra-abdominal pressure rises during inspiration [ citation needed ] ). [ 2 ]  Fibers of the right crus  decussate  inferior to the hiatus. [ 1 ]


The esophageal hiatus gives passage to the oesophagus as well as the  anterior  and the  posterior vagal trunk , esophageal branches of the  left gastric artery  and  vein , and some lymphatic vessels. [ 1 ] [ 2 ]  The  transversalis fascia  lining the inferior surface of the diaphragm extends superiorly through the hiatus to blend with the  endothoracic fascia  and attach to the oesophagus 2-3 cm superior to the  phrenoesophageal ligament . [ 2 ]


The esophageal hiatus is located at level of the  tenth thoracic vertebra (T10) , 2.5 cm to the left of the midline, [ 2 ]  and (sources differ) posterior to the 7th left  costal cartilage [ 2 ] /at the level of the 8th or 9th  intercostal spaces . [ 3 ]  It is placed superior, anterior, and slightly left of the  aortic hiatus . [ citation needed ]


Hiatal hernia  occurs when part of the stomach passes through the esophageal hiatus. [ 4 ] [ 5 ]


The  lateral arcuate ligament  (also  lateral lumbocostal arch  and  external arcuate ligament ) is a  ligament  under the  diaphragm  that arches across the upper part of the  quadratus lumborum muscle . It is traversed by the  subcostal nerve ,  artery  and  vein .


The lateral arcuate ligament runs from the front of the transverse process of the first  lumbar vertebra , and, laterally, to the tip and lower margin of the twelfth  rib . [ 1 ]  It forms an arch over the  quadratus lumborum muscle . [ 1 ]


The lateral arcuate ligament is commonly described in anatomy textbooks as attaching at the first lumbar vertebra (L1). [ 2 ]  However, other instances have been found in  cadaver  studies with attachments at either the second (L2) or third (L3) lumbar vertebra. [ 2 ]


In around 5% of people, inferolateral extensions of the lateral arcuate ligaments, such as thickened nodular areas, are found adjacent to the lateral diaphragmatic surface which can be visualized with  computed tomography  (CT) scans. [ 3 ]


The lateral arcuate ligaments were described by  Galen , as early as AD 177. [ 4 ] [ 5 ]  This was found in his animal dissections performed as part of his  Rome  lectures, collected in  De Anatomicus Administrationibus . [ 4 ] [ 5 ]


The  lumbocostal triangle  (also  Bochdalek's foramen ,   Bochdalek's triangle ) is a space between the costal and lumbar parts of the diaphragm. The base of this triangular space is formed by muscle attachments originating from the XII rib and muscle fibers attaching to the  lateral arcuate ligament . The apex of the triangle is oriented towards the tendinous centre of the diaphragm.  Parietal pleura  and  renal capsule  are in contact in this space, so possible infection can be transmitted through this space.


The existence of this foramen might cause a  congenital diaphragmatic hernia ,  Bochdalek hernia .


This condition has also been associated with thoracic kidney, the presence of the kidney in the thorax instead of the usual abdominal position. [ 1 ]


The  medial arcuate ligament  (also  medial lumbocostal arch  and  internal arcuate ligament ) is a tendinous fascia that arches over the  psoas major  muscle as it passes posterior the  diaphragm .
The purpose of the medial arcuate ligament is to attach the diaphragm to the spine (lumbar vertebra L1 - L2)


The medial arcuate ligament is an arch in the fascia covering the upper part of the  psoas major .  It is attached to the side of the body of the first or second  lumbar vertebra , laterally, it is fixed to the front of the transverse process of the first and, sometimes also, to that of the second lumbar vertebra.


It lies between the  lateral arcuate ligament  and the midline  median arcuate ligament .


The sympathetic chain enters the abdomen by passing deep into this ligament of the diaphragm. This is in contrast to the parasympathetic  vagus nerve  which passes through the  esophageal hiatus .


The  median arcuate ligament  is a  ligament  under the  diaphragm  that connects the right and left  crura  of  diaphragm .


The median arcuate ligament is formed by the right and left crura of the  diaphragm . [ 1 ]  The crura connect to form an arch, behind which is the  aortic hiatus , through which pass the  aorta , the  azygos vein , and the  thoracic duct .


In between 10% and 24% of people, the median arcuate ligament occurs very low. [ 2 ]


Compression of  celiac artery  and  celiac ganglia  by the median arcuate ligament being too low in some individuals; [ 3 ]  can lead to the  median arcuate ligament syndrome , which is characterized by abdominal pain, weight loss, and an epigastric  bruit . [ 4 ]


The  sternocostal triangle  (foramina of Morgagni, Larrey's space, sternocostal hiatus, etc. [ 1 ] ) are small zones lying between the  costal  and  sternal  attachments of the  thoracic diaphragm . No vascular elements are present within this space. [ 2 ]  The borders of this space are:


Medial: the lateral border of the sternal part of the  diaphragm


Lateral: the medial border of the costal part of the  diaphragm


Anterior: the musculoaponeurotic plane formed by a confluence of the  transversus thoracis  superiorly and the  transversus abdominis  inferiorly


The  superficial epigastric artery  passes in front of the aponeurotic plane that forms the anterior border and enters the abdomen anterior to the  diaphragm . [ 2 ]


It is named for  Giovanni Battista Morgagni . [ 3 ]


It can be a site of  Morgagni's hernia .


The  caval opening of diaphragm [ 2 ]  (also  foramen of vena cava , [ 1 ]   vena caval foramen [ 3 ] [ 1 ] ) is an opening in the  central tendon of diaphragm  giving passage to the  inferior vena cava [ 2 ] [ 3 ]  as well as to some terminal [ 2 ]  branches of [ 2 ] [ 1 ]  the  right phrenic nerve , [ 2 ] [ 3 ]  and some lymphatic vessels en route to middle phrenic and  mediastinal lymph nodes . [ 2 ]  The foramen occurs between the middle leaf and the right leaf of the  central tendon of diaphragm , [ 2 ] [ 3 ]  with the fibres of the central tendon uniting vigorously with the  adventitia  of the inferior vena cava (resulting in dilation of the IVC with contraction of the diaphragm during inspiration so as to facilitate venous return to the heart [ 2 ] ). [ 3 ]


It is the superior-most of the three large diaphragmatic openings [ 2 ]  and is situated at the level of (sources differ) the 8th  thoracic vertebra  (T8) [ 3 ] /the intervertebral disc between T8 and T9 vertebrae. [ 2 ]  It is situated slightly to the right of the midline. [ 2 ]


The  heart  is a muscular  organ  found in  humans  and other  animals . This organ pumps  blood  through the  blood vessels . [ 1 ]  Heart and blood vessels together make the  circulatory system . [ 2 ]  The pumped blood carries  oxygen  and  nutrients  to the tissue, while carrying  metabolic waste  such as  carbon dioxide  to the  lungs . [ 3 ]  In  humans , the heart is approximately the size of a closed  fist  and is located between the lungs, in the middle compartment of the  chest , called the  mediastinum . [ 4 ]


In humans, the heart is divided into four chambers: upper left and right  atria  and lower left and right  ventricles . [ 5 ] [ 6 ]  Commonly, the right atrium and ventricle are referred together as the  right heart  and their left counterparts as the  left heart . [ 7 ]  In a healthy heart, blood flows one way through the heart due to  heart valves , which prevent  backflow . [ 4 ]  The heart is enclosed in a protective sac, the  pericardium , which also contains a small amount of  fluid . The wall of the heart is made up of three layers:  epicardium ,  myocardium , and  endocardium . [ 8 ]


The heart pumps blood with a  rhythm  determined by a group of  pacemaker cells  in the  sinoatrial node . These generate an electric current that causes the heart to contract, traveling through the  atrioventricular node  and along the  conduction system of the heart . In humans, deoxygenated blood enters the heart through the right atrium from the  superior  and  inferior venae cavae  and passes to the right ventricle. From here, it is pumped into  pulmonary circulation  to the  lungs , where it receives oxygen and gives off carbon dioxide. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the  aorta  into  systemic circulation , traveling through  arteries ,  arterioles , and  capillaries —where  nutrients  and other substances are exchanged between blood vessels and cells, losing oxygen and gaining carbon dioxide—before being returned to the heart through  venules  and  veins . [ 9 ]  The heart beats at a  resting rate  close to 72 beats per minute. [ 10 ]   Exercise  temporarily increases the rate, but lowers it in the long term, and is good for heart health. [ 11 ]


Cardiovascular diseases  are the most common cause of death globally as of 2008, accounting for 30% of all human deaths. [ 12 ] [ 13 ]  Of these more than three-quarters are a result of  coronary artery disease  and  stroke . [ 12 ]  Risk factors include:  smoking , being  overweight , little exercise,  high cholesterol ,  high blood pressure , and poorly controlled  diabetes , among others. [ 14 ]  Cardiovascular diseases do not frequently have symptoms but may cause  chest pain  or  shortness of breath . Diagnosis of heart disease is often done by the taking of a  medical history ,  listening  to the  heart-sounds  with a  stethoscope , as well as with  ECG , and  echocardiogram  which uses  ultrasound . [ 4 ]  Specialists who focus on diseases of the heart are called  cardiologists , although many specialties of medicine may be involved in treatment. [ 13 ]


The human heart is situated in the  mediastinum , at the level of  thoracic vertebrae   T5 – T8 . A double-membraned sac called the  pericardium  surrounds the heart and attaches to the mediastinum. [ 16 ]  The back surface of the heart lies near the  vertebral column , and the front surface, known as the sternocostal surface, sits behind the  sternum  and  rib cartilages . [ 8 ]  The upper part of the heart is the attachment point for several large blood vessels—the  venae cavae ,  aorta  and  pulmonary trunk . The upper part of the heart is located at the level of the third costal cartilage. [ 8 ]  The lower tip of the heart, the  apex , lies to the left of the sternum (8 to 9 cm from the  midsternal line ) between the junction of the fourth and fifth ribs near their  articulation  with the costal cartilages. [ 8 ]


The largest part of the heart is usually slightly offset to the left side of the chest ( levocardia ). In a rare congenital disorder ( dextrocardia ) the heart is offset to the right side and is felt to be on the left because the  left heart  is stronger and larger, since it pumps to all body parts. Because the heart is between the  lungs , the left lung is smaller than the right lung and has a cardiac notch in its border to accommodate the heart. [ 8 ]
The heart is cone-shaped, with its  base  positioned upwards and tapering down to the apex. [ 8 ]  An adult heart has a mass of 250–350 grams (9–12 oz). [ 17 ]  The heart is often described as the size of a fist: 12 cm (5 in) in length, 8 cm (3.5 in) wide, and 6 cm (2.5 in) in thickness, [ 8 ]  although this description is disputed, as the heart is likely to be slightly larger. [ 18 ]  Well-trained  athletes  can have much larger hearts due to the effects of exercise on the heart muscle, similar to the response of skeletal muscle. [ 8 ]


The heart has four chambers, two upper  atria , the receiving chambers, and two lower  ventricles , the discharging chambers. The atria open into the ventricles via the  atrioventricular valves , present in the  atrioventricular septum . This distinction is visible also on the surface of the heart as the  coronary sulcus . [ 19 ]  There is an ear-shaped structure in the upper right atrium called the  right atrial appendage , or auricle, and another in the upper left atrium, the  left atrial appendage . [ 20 ]  The right atrium and the right ventricle together are sometimes referred to as the  right heart . Similarly, the left atrium and the left ventricle together are sometimes referred to as the  left heart . [ 7 ]  The ventricles are separated from each other by the  interventricular septum , visible on the surface of the heart as the  anterior longitudinal sulcus  and the  posterior interventricular sulcus . [ 19 ]


The  fibrous   cardiac skeleton  gives structure to the heart. It forms the atrioventricular septum, which separates the atria from the ventricles, and the fibrous rings, which serve as bases for the four  heart valves . [ 21 ]  The cardiac skeleton also provides an important boundary in the heart's electrical conduction system since collagen cannot conduct  electricity . The interatrial septum separates the atria, and the interventricular septum separates the ventricles. [ 8 ]  The interventricular septum is much thicker than the interatrial septum since the ventricles need to generate greater pressure when they contract. [ 8 ]


The heart has four valves, which separate its chambers. One valve lies between each atrium and ventricle, and one valve rests at the exit of each ventricle. [ 8 ]


The valves between the atria and ventricles are called the atrioventricular valves. Between the right atrium and the right ventricle is the  tricuspid valve . The tricuspid valve has three cusps, [ 22 ]  which connect to  chordae tendinae  and three  papillary muscles  named the anterior, posterior, and septal muscles, after their relative positions. [ 22 ]  The  mitral valve  lies between the left atrium and left ventricle. It is also known as the bicuspid valve due to its having two cusps, an anterior and a posterior cusp. These cusps are also attached via chordae tendinae to two papillary muscles projecting from the ventricular wall. [ 23 ]


The papillary muscles extend from the walls of the heart to valves by cartilaginous connections called chordae tendinae. These muscles prevent the valves from falling too far back when they close. [ 24 ]  During the relaxation phase of the cardiac cycle, the papillary muscles are also relaxed and the tension on the chordae tendineae is slight. As the heart chambers contract, so do the papillary muscles. This creates tension on the chordae tendineae, helping to hold the cusps of the atrioventricular valves in place and preventing them from being blown back into the atria. [ 8 ]   [ g ] [ 22 ]


Two additional semilunar valves sit at the exit of each of the ventricles. The  pulmonary valve  is located at the base of the  pulmonary artery . This has three cusps which are not attached to any papillary muscles. When the ventricle relaxes blood flows back into the ventricle from the artery and this flow of blood fills the pocket-like valve, pressing against the cusps which close to seal the valve. The semilunar  aortic valve  is at the base of the  aorta  and also is not attached to papillary muscles. This too has three cusps which close with the pressure of the blood flowing back from the aorta. [ 8 ]


The right heart consists of two chambers, the right atrium and the right ventricle, separated by a valve, the  tricuspid valve . [ 8 ]


The right atrium receives blood almost continuously from the body's two major  veins , the  superior  and  inferior   venae cavae . A small amount of blood from the coronary circulation also drains into the right atrium via the  coronary sinus , which is immediately above and to the middle of the opening of the inferior vena cava. [ 8 ]  In the wall of the right atrium is an oval-shaped depression known as the  fossa ovalis , which is a remnant of an opening in the fetal heart known as the  foramen ovale . [ 8 ]  Most of the internal surface of the right atrium is smooth, the depression of the fossa ovalis is medial, and the anterior surface has prominent ridges of  pectinate muscles , which are also present in the  right atrial appendage . [ 8 ]


The right atrium is connected to the right ventricle by the tricuspid valve. [ 8 ]  The walls of the right ventricle are lined with  trabeculae carneae , ridges of cardiac muscle covered by endocardium. In addition to these muscular ridges, a band of cardiac muscle, also covered by endocardium, known as the  moderator band  reinforces the thin walls of the right ventricle and plays a crucial role in cardiac conduction. It arises from the lower part of the interventricular septum and crosses the interior space of the right ventricle to connect with the inferior papillary muscle. [ 8 ]  The right ventricle tapers into the  pulmonary trunk , into which it ejects blood when contracting. The pulmonary trunk branches into the left and right pulmonary arteries that carry the blood to each lung. The pulmonary valve lies between the right heart and the pulmonary trunk. [ 8 ]


The left heart has two chambers: the left atrium and the left ventricle, separated by the  mitral valve . [ 8 ]


The left atrium receives oxygenated blood back from the lungs via one of the four  pulmonary veins . The left atrium has an outpouching called the  left atrial appendage . Like the right atrium, the left atrium is lined by  pectinate muscles . [ 25 ]  The left atrium is connected to the left ventricle by the mitral valve. [ 8 ]


The left ventricle is much thicker as compared with the right, due to the greater force needed to pump blood to the entire body. Like the right ventricle, the left also has  trabeculae carneae , but there is no  moderator band . The left ventricle pumps blood to the body through the aortic valve and into the aorta. Two small openings above the aortic valve carry blood to the  heart muscle ; the  left coronary artery  is above the left cusp of the valve, and the  right coronary artery  is above the right cusp. [ 8 ]


The heart wall is made up of three layers: the inner  endocardium , middle  myocardium  and outer  epicardium . These are surrounded by a double-membraned sac called the pericardium.


The innermost layer of the heart is called the endocardium. It is made up of a lining of  simple squamous epithelium  and covers heart chambers and valves. It is continuous with the  endothelium  of the veins and arteries of the heart, and is joined to the myocardium with a thin layer of connective tissue. [ 8 ]  The endocardium, by secreting  endothelins , may also play a role in regulating the contraction of the myocardium. [ 8 ]


The middle layer of the heart wall is the myocardium, which is the  cardiac muscle —a layer of involuntary  striated muscle tissue  surrounded by a framework of  collagen . The cardiac muscle pattern is elegant and complex, as the muscle cells swirl and spiral around the chambers of the heart, with the outer muscles forming a figure 8 pattern around the atria and around the bases of the great vessels and the inner muscles, forming a figure 8 around the two ventricles and proceeding toward the apex. This complex swirling pattern allows the heart to pump blood more effectively. [ 8 ]


There are two types of cells in cardiac muscle:  muscle cells  which have the ability to contract easily, and  pacemaker cells  of the conducting system. The muscle cells make up the bulk (99%) of cells in the atria and ventricles. These contractile cells are connected by  intercalated discs  which allow a rapid response to impulses of  action potential  from the pacemaker cells. The intercalated discs allow the cells to act as a  syncytium  and enable the contractions that pump blood through the heart and into the  major arteries . [ 8 ]  The pacemaker cells make up 1% of cells and form the conduction system of the heart. They are generally much smaller than the contractile cells and have few  myofibrils  which gives them limited contractibility. Their function is similar in many respects to  neurons . [ 8 ]  Cardiac muscle tissue has  autorhythmicity , the unique ability to initiate a cardiac action potential at a fixed rate—spreading the impulse rapidly from cell to cell to trigger the contraction of the entire heart. [ 8 ]


There are specific  proteins expressed  in cardiac muscle cells. [ 26 ] [ 27 ]  These are mostly associated with muscle contraction, and bind with  actin ,  myosin ,  tropomyosin , and  troponin . They include  MYH6 ,  ACTC1 ,  TNNI3 ,  CDH2  and  PKP2 . Other proteins expressed are  MYH7  and  LDB3  that are also expressed in skeletal muscle. [ 28 ]


The pericardium is the sac that surrounds the heart. The tough outer surface of the pericardium is called the fibrous membrane. This is lined by a double inner membrane called the serous membrane that produces  pericardial fluid  to lubricate the surface of the heart. [ 29 ]  The part of the serous membrane attached to the fibrous membrane is called the parietal pericardium, while the part of the serous membrane attached to the heart is known as the visceral pericardium. The pericardium is present in order to lubricate its movement against other structures within the chest, to keep the heart's position stabilised within the chest, and to protect the heart from infection. [ 30 ]


Heart tissue, like all cells in the body, needs to be supplied with  oxygen ,  nutrients  and a way of removing  metabolic wastes . This is achieved by the coronary circulation, which includes  arteries ,  veins , and  lymphatic vessels . Blood flow through the coronary vessels occurs in peaks and troughs relating to the heart muscle's relaxation or contraction. [ 8 ]


Heart tissue receives blood from two arteries which arise just above the aortic valve. These are the  left main coronary artery  and the  right coronary artery . The left main coronary artery splits shortly after leaving the aorta into two vessels, the  left anterior descending  and the  left circumflex artery . The left anterior descending artery supplies heart tissue and the front, outer side, and septum of the left ventricle. It does this by branching into smaller arteries—diagonal and septal branches. The left circumflex supplies the back and underneath of the left ventricle. The right coronary artery supplies the right atrium, right ventricle, and lower posterior sections of the left ventricle. The right coronary artery also supplies blood to the atrioventricular node (in about 90% of people) and the sinoatrial node (in about 60% of people). The right coronary artery runs in a groove at the back of the heart and the left anterior descending artery runs in a groove at the front. There is significant variation between people in the anatomy of the arteries that supply the heart  [ 31 ]  The arteries divide at their furthest reaches into smaller branches that join at the edges of each arterial distribution. [ 8 ]


The  coronary sinus  is a large vein that drains into the right atrium, and receives most of the venous drainage of the heart. It receives blood from the  great cardiac vein  (receiving the left atrium and both ventricles), the  posterior cardiac vein  (draining the back of the left ventricle), the  middle cardiac vein  (draining the bottom of the left and right ventricles), and  small cardiac veins . [ 32 ]  The  anterior cardiac veins  drain the front of the right ventricle and drain directly into the right atrium. [ 8 ]


Small lymphatic networks called  plexuses  exist beneath each of the three layers of the heart. These networks collect into a main left and a main right trunk, which travel up the groove between the ventricles that exists on the heart's surface, receiving smaller vessels as they travel up. These vessels then travel into the atrioventricular groove, and receive a third vessel which drains the section of the left ventricle sitting on the diaphragm. The left vessel joins with this third vessel, and travels along the pulmonary artery and left atrium, ending in the  inferior tracheobronchial node . The right vessel travels along the right atrium and the part of the right ventricle sitting on the diaphragm. It usually then travels in front of the ascending aorta and then ends in a brachiocephalic node. [ 33 ]


The heart receives nerve signals from the  vagus nerve  and from nerves arising from the  sympathetic trunk . These nerves act to influence, but not control, the heart rate.  Sympathetic nerves  also influence the force of heart contraction. [ 34 ]  Signals that travel along these nerves arise from two paired  cardiovascular centres  in the  medulla oblongata . The vagus nerve of the  parasympathetic nervous system  acts to decrease the heart rate, and nerves from the  sympathetic trunk  act to increase the heart rate. [ 8 ]  These nerves form a network of nerves that lies over the heart called the  cardiac plexus . [ 8 ] [ 33 ]


The vagus nerve is a long, wandering nerve that emerges from the  brainstem  and provides parasympathetic stimulation to a large number of organs in the thorax and abdomen, including the heart. [ 35 ]  The nerves from the sympathetic trunk emerge through the T1–T4  thoracic ganglia  and travel to both the sinoatrial and atrioventricular nodes, as well as to the atria and ventricles. The ventricles are more richly innervated by sympathetic fibers than parasympathetic fibers. Sympathetic stimulation causes the release of the neurotransmitter  norepinephrine  (also known as  noradrenaline ) at the  neuromuscular junction  of the cardiac nerves [ citation needed ] . This shortens the repolarisation period, thus speeding the rate of depolarisation and contraction, which results in an increased heart rate. It opens chemical or ligand-gated sodium and calcium ion channels, allowing an influx of  positively charged ions . [ 8 ]  Norepinephrine binds to the  beta–1 receptor . [ 8 ]


The heart is the first functional organ to develop and starts to beat and pump blood at about three weeks into  embryogenesis . This early start is crucial for subsequent embryonic and  prenatal development .


The heart derives from  splanchnopleuric mesenchyme  in the neural plate which forms the  cardiogenic region . Two  endocardial tubes  form here that fuse to form a primitive heart tube known as the  tubular heart . [ 36 ]  Between the third and fourth week, the heart tube lengthens, and begins to fold to form an S-shape within the pericardium. This places the chambers and major vessels into the correct alignment for the developed heart. Further development will include the formation of the septa and the valves and the remodeling of the heart chambers. By the end of the fifth week, the septa are complete, and by the ninth week, the heart valves are complete. [ 8 ]


Before the fifth week, there is an opening in the fetal heart known as the  foramen ovale . The foramen ovale allowed blood in the fetal heart to pass directly from the right atrium to the left atrium, allowing some blood to bypass the lungs. Within seconds after birth, a flap of tissue known as the  septum primum  that previously acted as a valve closes the foramen ovale and establishes the typical cardiac circulation pattern. A depression in the surface of the right atrium remains where the foramen ovale was, called the fossa ovalis. [ 8 ]


The  embryonic  heart begins beating at around 22 days after conception (5 weeks after the last normal menstrual period, LMP). It starts to beat at a rate near to the mother's which is about 75–80  beats per minute  (bpm). The embryonic heart rate then accelerates and reaches a peak rate of 165–185 bpm early in the early 7th week (early 9th week after the LMP). [ 37 ] [ 38 ]  After 9 weeks (start of the  fetal  stage) it starts to decelerate, slowing to around 145 (±25) bpm at birth. There is no difference in female and male heart rates before birth. [ 39 ]


The heart functions as a pump in the  circulatory system  to provide a continuous  flow of blood  throughout the body. This circulation consists of the  systemic circulation  to and from the body and the  pulmonary circulation  to and from the lungs. Blood in the pulmonary circulation exchanges  carbon dioxide  for oxygen in the lungs through the process of  respiration . The systemic circulation then transports oxygen to the body and returns carbon dioxide and relatively deoxygenated blood to the heart for transfer to the lungs. [ 8 ]


The  right heart  collects deoxygenated blood from two large veins, the  superior  and  inferior   venae cavae . Blood collects in the right and left atrium continuously. [ 8 ]  The superior vena cava drains blood from above the  diaphragm  and empties into the upper back part of the right atrium. The inferior vena cava drains the blood from below the diaphragm and empties into the back part of the atrium below the opening for the superior vena cava. Immediately above and to the middle of the opening of the inferior vena cava is the opening of the thin-walled coronary sinus. [ 8 ]  Additionally, the  coronary sinus  returns deoxygenated blood from the myocardium to the right atrium. The blood collects in the right atrium. When the right atrium contracts, the blood is pumped through the  tricuspid valve  into the right ventricle. As the right ventricle contracts, the tricuspid valve closes and the blood is pumped into the pulmonary trunk through the pulmonary valve. The pulmonary trunk divides into pulmonary arteries and progressively smaller arteries throughout the lungs, until it reaches  capillaries . As these pass by  alveoli  carbon dioxide is  exchanged  for oxygen. This happens through the passive process of  diffusion .


In the  left heart , oxygenated blood is returned to the left atrium via the pulmonary veins. It is then pumped into the left ventricle through the  mitral valve  and into the aorta through the aortic valve for systemic circulation. The aorta is a large artery that branches into many smaller arteries,  arterioles , and ultimately capillaries. In the capillaries, oxygen and nutrients from blood are supplied to body cells for metabolism, and exchanged for carbon dioxide and waste products. [ 8 ]  Capillary blood, now deoxygenated, travels into  venules  and veins that ultimately collect in the superior and inferior vena cavae, and into the right heart.


The cardiac cycle is the sequence of events in which the heart contracts and relaxes with every heartbeat. [ 10 ]  The period of time during which the ventricles contract, forcing blood out into the aorta and main pulmonary artery, is known as  systole , while the period during which the ventricles relax and refill with blood is known as  diastole . The atria and ventricles work in concert, so in systole when the ventricles are contracting, the atria are relaxed and collecting blood. When the ventricles are relaxed in diastole, the atria contract to pump blood to the ventricles. This coordination ensures blood is pumped efficiently to the body. [ 8 ]


At the beginning of the cardiac cycle, the ventricles are relaxing. As they do so, they are filled by blood passing through the open  mitral  and  tricuspid  valves. After the ventricles have completed most of their filling, the atria contract, forcing further blood into the ventricles and priming the pump. Next, the ventricles start to contract. As the pressure rises within the cavities of the ventricles, the mitral and tricuspid valves are forced shut. As the pressure within the ventricles rises further, exceeding the pressure with the aorta and pulmonary arteries, the aortic and pulmonary valves open. Blood is ejected from the heart, causing the pressure within the ventricles to fall. Simultaneously, the atria refill as blood flows into the right atrium through the superior and  inferior vena cavae , and into the left atrium through the pulmonary veins. Finally, when the pressure within the ventricles falls below the pressure within the aorta and pulmonary arteries, the aortic and pulmonary valves close. The ventricles start to relax, the mitral and tricuspid valves open, and the cycle begins again. [ 10 ]


Cardiac output (CO) is a measurement of the amount of blood pumped by each ventricle (stroke volume) in one minute. This is calculated by multiplying the stroke volume (SV) by the beats per minute of the heart rate (HR). So that: CO = SV x HR. [ 8 ]
The cardiac output is normalized to body size through  body surface area  and is called the  cardiac index .


The average cardiac output, using an average stroke volume of about 70mL, is 5.25 L/min, with a normal range of 4.0–8.0 L/min. [ 8 ]  The stroke volume is normally measured using an  echocardiogram  and can be influenced by the size of the heart, physical and mental condition of the individual,  sex ,  contractility , duration of contraction,  preload  and  afterload . [ 8 ]


Preload  refers to the filling pressure of the atria at the end of diastole, when the ventricles are at their fullest. A main factor is how long it takes the ventricles to fill: if the ventricles contract more frequently, then there is less time to fill and the preload will be less. [ 8 ]  Preload can also be affected by a person's blood volume. The force of each contraction of the heart muscle is proportional to the preload, described as the  Frank-Starling mechanism . This states that the force of contraction is directly proportional to the initial length of muscle fiber, meaning a ventricle will contract more forcefully, the more it is stretched. [ 8 ] [ 40 ]


Afterload , or how much pressure the heart must generate to eject blood at systole, is influenced by  vascular resistance . It can be influenced by narrowing of the heart valves ( stenosis ) or contraction or relaxation of the peripheral blood vessels. [ 8 ]


The strength of heart muscle contractions controls the stroke volume. This can be influenced positively or negatively by agents termed  inotropes . [ 41 ]  These agents can be a result of changes within the body, or be given as drugs as part of treatment for a medical disorder, or as a form of  life support , particularly in  intensive care units . Inotropes that increase the force of contraction are "positive" inotropes, and include  sympathetic  agents such as  adrenaline ,  noradrenaline  and  dopamine . [ 42 ]  "Negative" inotropes decrease the force of contraction and include  calcium channel blockers . [ 41 ]


The normal rhythmical heart beat, called  sinus rhythm , is established by the heart's own pacemaker, the  sinoatrial node  (also known as the sinus node or the SA node). Here an electrical signal is created that travels through the heart, causing the heart muscle to contract. The sinoatrial node is found in the upper part of the  right atrium  near to the junction with the superior vena cava. [ 43 ]  The electrical signal generated by the sinoatrial node travels through the right atrium in a radial way that is not completely understood. It travels to the left atrium via  Bachmann's bundle , such that the muscles of the left and right atria contract together. [ 44 ] [ 45 ] [ 46 ]  The signal then travels to the  atrioventricular node . This is found at the bottom of the right atrium in the  atrioventricular septum , the boundary between the right atrium and the left ventricle. The septum is part of the  cardiac skeleton , tissue within the heart that the electrical signal cannot pass through, which forces the signal to pass through the atrioventricular node only. [ 8 ]  The signal then travels along the  bundle of His  to left and right  bundle branches  through to the ventricles of the heart. In the ventricles the signal is carried by specialized tissue called the  Purkinje fibers  which then transmit the electric charge to the heart muscle. [ 47 ]


The normal  resting heart rate  is called the  sinus rhythm , created and sustained by the  sinoatrial node , a group of pacemaking cells found in the wall of the right atrium. Cells in the sinoatrial node do this by creating an  action potential . The  cardiac action potential  is created by the movement of specific  electrolytes  into and out of the pacemaker cells. The action potential then spreads to nearby cells. [ 48 ]


When the sinoatrial cells are resting, they have a negative charge on their membranes. A rapid influx of  sodium  ions causes the membrane's charge to become positive; this is called  depolarisation  and occurs spontaneously. [ 8 ]  Once the cell has a sufficiently high charge, the sodium channels close and  calcium  ions then begin to enter the cell, shortly after which  potassium  begins to leave it. All the ions travel through  ion channels  in the membrane of the sinoatrial cells. The potassium and calcium start to move out of and into the cell only once it has a sufficiently high charge, and so are called  voltage-gated . Shortly after this, the calcium channels close and  potassium channels  open, allowing potassium to leave the cell. This causes the cell to have a negative resting charge and is called  repolarisation . When the membrane potential reaches approximately −60 mV, the potassium channels close and the process may begin again. [ 8 ]


The ions move from areas where they are concentrated to where they are not. For this reason sodium moves into the cell from outside, and potassium moves from within the cell to outside the cell. Calcium also plays a critical role. Their influx through slow channels means that the sinoatrial cells have a prolonged "plateau" phase when they have a positive charge. A part of this is called the  absolute refractory period . Calcium ions also combine with the regulatory protein  troponin C  in the  troponin complex  to enable  contraction  of the cardiac muscle, and separate from the protein to allow relaxation. [ 49 ]


The adult resting heart rate ranges from 60 to 100 bpm. The resting heart rate of a  newborn  can be 129 beats per minute (bpm) and this gradually decreases until maturity. [ 50 ]  An athlete's heart rate can be lower than 60 bpm. During exercise the rate can be 150 bpm with maximum rates reaching from 200 to 220 bpm. [ 8 ]


The normal  sinus rhythm  of the heart, giving the resting heart rate, is influenced by a number of factors. The  cardiovascular centres  in the brainstem control the sympathetic and parasympathetic influences to the heart through the vagus nerve and sympathetic trunk. [ 51 ]  These cardiovascular centres receive input from a series of receptors including  baroreceptors , sensing the stretching of blood vessels and  chemoreceptors , sensing the amount of oxygen and carbon dioxide in the blood and its pH. Through a series of reflexes these help regulate and sustain blood flow. [ 8 ]


Baroreceptors are stretch receptors located in the  aortic sinus ,  carotid bodies , the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Baroreceptors fire at a rate determined by how much they are stretched, [ 52 ]  which is influenced by blood pressure, level of physical activity, and the relative distribution of blood. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers increase sympathetic stimulation and decrease parasympathetic stimulation. [ 8 ]  There is a similar reflex, called the atrial reflex or  Bainbridge reflex , associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialized baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac center responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase heart rate. The opposite is also true. [ 8 ]  Chemoreceptors present in the carotid body or adjacent to the aorta in an aortic body respond to the blood's oxygen, carbon dioxide levels. Low oxygen or high carbon dioxide will stimulate firing of the receptors. [ 53 ]


Exercise and fitness levels, age, body temperature,  basal metabolic rate , and even a person's emotional state can all affect the heart rate. High levels of the hormones  epinephrine , norepinephrine, and  thyroid hormones  can increase the heart rate. The levels of electrolytes including calcium, potassium, and sodium can also influence the speed and regularity of the heart rate;  low blood oxygen , low  blood pressure  and  dehydration  may increase it. [ 8 ]


Cardiovascular diseases , which include diseases of the heart, are the leading cause of death worldwide. [ 54 ]  The majority of cardiovascular disease is noncommunicable and related to lifestyle and other factors, becoming more prevalent with ageing. [ 54 ]  Heart disease is a major cause of death, accounting for an average of 30% of all deaths in 2008, globally. [ 12 ]  This rate varies from a lower 28% to a high 40% in  high-income countries . [ 13 ]  Doctors that specialise in the heart are called  cardiologists . Many other medical professionals are involved in treating diseases of the heart, including  doctors ,  cardiothoracic surgeons ,  intensivists , and  allied health practitioners  including  physiotherapists  and  dieticians . [ 55 ]


Coronary artery disease, also known as ischemic heart disease, is caused by  atherosclerosis —a build-up of fatty material along the inner walls of the arteries. These fatty deposits known as atherosclerotic plaques  narrow  the coronary arteries, and if severe may reduce blood flow to the heart. [ 56 ]  If a narrowing (or stenosis) is relatively minor then the patient may not experience any symptoms. Severe narrowings may cause chest pain ( angina ) or breathlessness during exercise or even at rest. The thin covering of an atherosclerotic plaque can rupture, exposing the fatty centre to the circulating blood. In this case a clot or thrombus can form, blocking the artery, and restricting blood flow to an area of heart muscle causing a myocardial infarction (a heart attack) or  unstable angina . [ 57 ]  In the worst case this may cause  cardiac arrest , a sudden and utter loss of output from the heart. [ 58 ]   Obesity ,  high blood pressure , uncontrolled  diabetes , smoking and high  cholesterol  can all increase the risk of developing atherosclerosis and coronary artery disease. [ 54 ] [ 56 ]


Heart failure is defined as a condition in which the heart is unable to pump enough blood to meet the demands of the body. [ 59 ]  Patients with  heart failure  may experience breathlessness especially when lying flat, as well as ankle swelling, known as  peripheral oedema . Heart failure is the result of many diseases affecting the heart, but is most commonly associated with  ischemic heart disease ,  valvular heart disease , or high blood pressure. Less common causes include various  cardiomyopathies . Heart failure is frequently associated with weakness of the heart muscle in the ventricles (systolic heart failure), but can also be seen in patients with heart muscle that is strong but stiff (diastolic heart failure). The condition may affect the left ventricle (causing predominantly breathlessness), the right ventricle (causing predominantly swelling of the legs and an elevated  jugular venous pressure ), or both ventricles. Patients with heart failure are at higher risk of developing dangerous heart rhythm disturbances or  arrhythmias . [ 59 ]


Cardiomyopathies are diseases affecting the muscle of the heart. Some cause abnormal thickening of the heart muscle ( hypertrophic cardiomyopathy ), some cause the heart to abnormally expand and weaken ( dilated cardiomyopathy ), some cause the heart muscle to become stiff and unable to fully relax between contractions ( restrictive cardiomyopathy ) and some make the heart prone to abnormal heart rhythms ( arrhythmogenic cardiomyopathy ). These conditions are often genetic and can be  inherited , but some such as dilated cardiomyopathy may be caused by damage from toxins such as alcohol. Some cardiomyopathies such as hypertrophic cardiomopathy are linked to a higher risk of sudden cardiac death, particularly in athletes. [ 8 ]  Many cardiomyopathies can lead to heart failure in the later stages of the disease. [ 59 ]


Healthy heart valves allow blood to flow easily in one direction, and prevent it from flowing in the other direction. A diseased heart valve may have a narrow opening ( stenosis ), that restricts the flow of blood in the forward direction. A valve may otherwise be leaky, allowing blood to leak in the reverse direction ( regurgitation ). Valvular heart disease may cause breathlessness, blackouts, or chest pain, but may be asymptomatic and only detected on a routine examination by hearing abnormal heart sounds or a  heart murmur . In the developed world, valvular heart disease is most commonly caused by degeneration secondary to old age, but may also be caused by infection of the heart valves ( endocarditis ). In some parts of the world  rheumatic heart disease  is a major cause of valvular heart disease, typically leading to mitral or aortic stenosis and caused by the body's immune system reacting to a  streptococcal  throat infection. [ 60 ] [ 61 ]


While in the healthy heart, waves of electrical impulses originate in the  sinus node  before spreading to the rest of the atria, the  atrioventricular node , and finally the ventricles (referred to as a  normal sinus rhythm ), this normal rhythm can be disrupted. Abnormal heart rhythms or arrhythmias may be asymptomatic or may cause palpitations, blackouts, or breathlessness. Some types of arrhythmia such as  atrial fibrillation  increase the long term risk of  stroke . [ 62 ]


Some arrhythmias cause the heart to beat abnormally slowly, referred to as a  bradycardia  or bradyarrhythmia. This may be caused by an  abnormally slow sinus node  or damage within the cardiac conduction system ( heart block ). [ 63 ]  In other arrhythmias the heart may beat abnormally rapidly, referred to as a  tachycardia  or tachyarrhythmia. These arrhythmias can take many forms and can originate from different structures within the heart—some arise from the atria (e.g.  atrial flutter ), some from the atrioventricular node (e.g.  AV nodal re-entrant tachycardia ) whilst others arise from the ventricles (e.g.  ventricular tachycardia ). Some tachyarrhythmias are caused by scarring within the heart (e.g. some forms of  ventricular tachycardia ), others by an irritable focus (e.g. focal  atrial tachycardia ), while others are caused by additional abnormal conduction tissue that has been present since birth (e.g.  Wolff-Parkinson-White syndrome ). The most dangerous form of heart racing is  ventricular fibrillation , in which the ventricles quiver rather than contract, and which if untreated is rapidly fatal. [ 64 ]


The sac which surrounds the heart, called the pericardium, can become inflamed in a condition known as  pericarditis . This condition typically causes chest pain that may spread to the back, and is often caused by a viral infection ( glandular fever ,  cytomegalovirus , or  coxsackievirus ). Fluid can build up within the pericardial sac, referred to as a  pericardial effusion . Pericardial effusions often occur secondary to pericarditis, kidney failure, or tumours, and frequently do not cause any symptoms. However, large effusions or effusions which accumulate rapidly can compress the heart in a condition known as  cardiac tamponade , causing breathlessness and potentially fatal low blood pressure. Fluid can be removed from the pericardial space for diagnosis or to relieve tamponade using a syringe in a procedure called  pericardiocentesis . [ 65 ]


Some people are born with hearts that are abnormal and these abnormalities are known as congenital heart defects. They may range from the relatively minor (e.g.  patent foramen ovale , arguably a variant of normal) to serious life-threatening abnormalities (e.g.  hypoplastic left heart syndrome ). Common abnormalities include those that affect the heart muscle that separates the two side of the heart (a "hole in the heart", e.g.  ventricular septal defect ). Other defects include those affecting the heart valves (e.g.  congenital aortic stenosis ), or the main blood vessels that lead from the heart (e.g.  coarctation of the aorta ). More complex syndromes are seen that affect more than one part of the heart (e.g.  Tetralogy of Fallot ).


Some congenital heart defects allow blood that is low in oxygen that would normally be returned to the lungs to instead be pumped back to the rest of the body. These are known as  cyanotic congenital heart defects  and are often more serious. Major congenital heart defects are often picked up in childhood, shortly after birth, or even before a child is born (e.g.  transposition of the great arteries ), causing breathlessness and a lower rate of growth. More minor forms of congenital heart disease may remain undetected for many years and only reveal themselves in adult life (e.g.,  atrial septal defect ). [ 66 ] [ 67 ]


Channelopathies  can be categorized based on the organ system they affect. In the cardiovascular system, the electrical impulse required for each heart beat is provided by the  electrochemical gradient  of each heart cell. Because the beating of the heart depends on the proper movement of ions across the surface membrane, cardiac ion channelopathies form a major group of heart diseases. [ 68 ] [ 69 ]  Cardiac ion channelopathies may explain some of the cases of  sudden death syndrome  and  sudden arrhythmic death syndrome . [ 70 ]  Long QT syndrome is the most common form of cardiac channelopathy.


Heart disease is diagnosed by the taking of a  medical history , a  cardiac examination , and further investigations, including  blood tests ,  echocardiograms ,  electrocardiograms , and  imaging . Other invasive procedures such as  cardiac catheterisation  can also play a role. [ 76 ]


The cardiac examination includes inspection, feeling the chest with the hands ( palpation ) and listening with a stethoscope ( auscultation ). [ 77 ] [ 78 ]  It involves assessment of  signs  that may be visible on a person's hands (such as  splinter haemorrhages ), joints and other areas. A person's pulse is taken, usually at the  radial artery  near the wrist, in order to assess for the rhythm and strength of the pulse. The  blood pressure  is taken, using either a manual or automatic  sphygmomanometer  or using  a more invasive measurement  from within the artery. Any elevation of the  jugular venous pulse  is noted. A person's  chest  is felt for any transmitted vibrations from the heart, and then listened to with a stethoscope.


Typically, healthy hearts have only two audible  heart sounds , called S1 and S2. The  first heart sound  S1, is the sound created by the closing of the atrioventricular valves during ventricular contraction and is normally described as "lub". The  second heart sound , S2, is the sound of the semilunar valves closing during ventricular diastole and is described as "dub". [ 8 ]  Each sound consists of two components, reflecting the slight difference in time as the two valves close. [ 79 ]  S2 may  split  into two distinct sounds, either as a result of inspiration or different valvular or cardiac problems. [ 79 ]  Additional heart sounds may also be present and these give rise to  gallop rhythms . A  third heart sound , S3 usually indicates an increase in ventricular blood volume. A  fourth heart sound  S4 is referred to as an atrial gallop and is produced by the sound of blood being forced into a stiff ventricle. The combined presence of S3 and S4 give a quadruple gallop. [ 8 ]
 Heart murmurs  are abnormal heart sounds which can be either related to disease or benign, and there are several kinds. [ 80 ]  There are normally two heart sounds, and abnormal heart sounds can either be extra sounds, or "murmurs" related to the flow of blood between the sounds. Murmurs are graded by volume, from 1 (the quietest), to 6 (the loudest), and evaluated by their relationship to the heart sounds, position in the cardiac cycle, and additional features such as their radiation to other sites, changes with a person's position, the frequency of the sound as determined by the side of the  stethoscope  by which they are heard, and site at which they are heard loudest. [ 80 ]  Murmurs may be caused by  damaged heart valves  or congenital heart disease such as  ventricular septal defects , or may be heard in normal hearts. A different type of sound, a  pericardial friction rub  can be heard in cases of pericarditis where the inflamed membranes can rub together.


Blood tests play an important role in the diagnosis and treatment of many cardiovascular conditions.