Troponin  is a sensitive  biomarker  for a heart with insufficient blood supply. It is released 4–6 hours after injury and usually peaks at about 12–24 hours. [ 42 ]  Two tests of troponin are often taken—one at the time of initial presentation and another within 3–6 hours, [ 81 ]  with either a high level or a significant rise being diagnostic. A test for  brain natriuretic peptide  (BNP) can be used to evaluate for the presence of heart failure, and rises when there is increased demand on the left ventricle. These tests are considered  biomarkers  because they are highly specific for cardiac disease. [ 82 ]  Testing for the  MB form of creatine kinase  provides information about the heart's blood supply, but is used less frequently because it is less specific and sensitive. [ 83 ]


Other blood tests are often taken to help understand a person's general health and risk factors that may contribute to heart disease. These often include a  full blood count  investigating for  anaemia , and  basic metabolic panel  that may reveal any disturbances in electrolytes. A  coagulation screen  is often required to ensure that the right level of anticoagulation is given.  Fasting lipids  and  fasting blood glucose  (or an  HbA1c  level) are often ordered to evaluate a person's  cholesterol  and diabetes status, respectively. [ 84 ]


Using surface electrodes on the body, it is possible to record the electrical activity of the heart. This tracing of the electrical signal is the electrocardiogram (ECG) or (EKG). An ECG is a  bedside test  and involves the placement of ten leads on the body. This produces a "12 lead" ECG (three extra leads are calculated mathematically, and one lead is  electrically ground , or earthed). [ 85 ]


There are five prominent features on the ECG: the  P wave  (atrial depolarisation), the  QRS complex  (ventricular depolarisation) [ h ]  and the  T wave  (ventricular repolarisation). [ 8 ]  As the heart cells contract, they create a current that travels through the heart. A downward deflection on the ECG implies cells are becoming more positive in charge ("depolarising") in the direction of that lead, whereas an upward inflection implies cells are becoming more negative ("repolarising") in the direction of the lead. This depends on the position of the lead, so if a wave of depolarising moved from left to right, a lead on the left would show a negative deflection, and a lead on the right would show a positive deflection. The ECG is a useful tool in detecting  rhythm disturbances  and in detecting insufficient blood supply to the heart. [ 85 ]  Sometimes abnormalities are suspected, but not immediately visible on the ECG.  Testing when exercising  can be used to provoke an abnormality or an ECG can be worn for a longer period such as a 24-hour  Holter monitor  if a suspected rhythm abnormality is not present at the time of assessment. [ 85 ]


Several  imaging  methods can be used to assess the anatomy and function of the heart, including  ultrasound  ( echocardiography ),  angiography ,  CT ,  MRI , and  PET, scans . An echocardiogram is an ultrasound of the heart used to measure the heart's function, assess for valve disease, and look for any abnormalities. Echocardiography can be conducted by a probe on the chest ( transthoracic ), or by a probe in the  esophagus  ( transesophageal ). A typical echocardiography report will include information about the width of the valves noting any  stenosis , whether there is any backflow of blood ( regurgitation ) and information about the blood volumes at the end of systole and diastole, including an  ejection fraction , which describes how much blood is ejected from the left and right ventricles after systole. Ejection fraction can then be obtained by dividing the volume ejected by the heart (stroke volume) by the volume of the filled heart (end-diastolic volume). [ 86 ]  Echocardiograms can also be conducted under circumstances when the body is more stressed, in order to examine for signs of lack of blood supply. This  cardiac stress test  involves either direct exercise, or where this is not possible, injection of a drug such as  dobutamine . [ 78 ]


CT scans,  chest X-rays  and other forms of imaging can help evaluate the heart's size, evaluate for signs of  pulmonary oedema , and indicate whether there is  fluid around the heart . They are also useful for evaluating the aorta, the major blood vessel which leaves the heart. [ 78 ]


Diseases affecting the heart can be treated by a variety of methods including lifestyle modification, drug treatment, and surgery.


Narrowings of the coronary arteries (ischemic heart disease) are treated to relieve symptoms of chest pain caused by a partially narrowed artery (angina pectoris), to minimise heart muscle damage when an artery is completely occluded ( myocardial infarction ), or to prevent a myocardial infarction from occurring. Medications to improve angina symptoms include  nitroglycerin ,  beta blockers , and calcium channel blockers, while preventative treatments include  antiplatelets  such as  aspirin  and  statins , lifestyle measures such as stopping smoking and weight loss, and treatment of risk factors such as high blood pressure and diabetes. [ 87 ]


In addition to using medications, narrowed heart arteries can be treated by expanding the narrowings or redirecting the flow of blood to bypass an obstruction. This may be performed using a  percutaneous coronary intervention , during which narrowings can be expanded by passing small balloon-tipped wires into the coronary arteries, inflating the balloon to expand the narrowing, and sometimes leaving behind a metal scaffold known as a stent to keep the artery open. [ 88 ]


If the narrowings in coronary arteries are unsuitable for treatment with a percutaneous coronary intervention, open surgery may be required. A  coronary artery bypass graft  can be performed, whereby a blood vessel from another part of the body (the  saphenous vein ,  radial artery , or  internal mammary artery ) is used to redirect blood from a point before the narrowing (typically the  aorta ) to a point beyond the obstruction. [ 88 ] [ 89 ]


Diseased heart valves that have become abnormally narrow or abnormally leaky may require surgery. This is traditionally performed as an open surgical procedure to replace the damaged heart valve with a tissue or metallic  prosthetic valve . In some circumstances, the  tricuspid  or  mitral  valves can be repaired  surgically , avoiding the need for a valve replacement. Heart valves can also be treated percutaneously, using techniques that share many similarities with percutaneous coronary intervention.  Transcatheter aortic valve replacement  is increasingly used for patients consider very high risk for open valve replacement. [ 60 ]


Abnormal heart rhythms ( arrhythmias ) can be treated using antiarrhythmic drugs. These may work by manipulating the flow of electrolytes across the cell membrane (such as  calcium channel blockers ,  sodium channel blockers ,  amiodarone , or  digoxin ), or modify the autonomic nervous system's effect on the heart ( beta blockers  and  atropine ). In some arrhythmias such as atrial fibrillation which increase the risk of stroke, this risk can be reduced using anticoagulants such as  warfarin  or  novel oral anticoagulants . [ 62 ]


If medications fail to control an arrhythmia, another treatment option may be  catheter ablation . In these procedures, wires are passed from a  vein  or  artery  in the leg to the heart to find the abnormal area of tissue that is causing the arrhythmia. The abnormal tissue can be intentionally damaged, or ablated, by  heating  or  freezing  to prevent further heart rhythm disturbances. Whilst the majority of arrhythmias can be treated using minimally invasive catheter techniques, some arrhythmias (particularly  atrial fibrillation ) can also be treated using open or  thoracoscopic  surgery, either at the time of other cardiac surgery or as a standalone procedure. A  cardioversion , whereby an electric shock is used to stun the heart out of an abnormal rhythm, may also be used.


Cardiac devices in the form of  pacemakers  or  implantable defibrillators  may also be required to treat arrhythmias. Pacemakers, comprising a small battery powered generator implanted under the skin and one or more leads that extend to the heart, are most commonly used to treat abnormally  slow heart rhythms . [ 63 ]  Implantable defibrillators are used to treat serious life-threatening rapid heart rhythms. These devices monitor the heart, and if dangerous heart racing is detected can automatically deliver a shock to restore the heart to a normal rhythm. Implantable defibrillators are most commonly used in patients with heart failure,  cardiomyopathies , or inherited arrhythmia syndromes.


As well as addressing the underlying cause for a patient's heart failure (most commonly  ischemic heart disease  or  hypertension ), the mainstay of heart failure treatment is with medication. These include drugs to prevent fluid from accumulating in the lungs by increasing the amount of urine a patient produces ( diuretics ), and drugs that attempt to preserve the pumping function of the heart ( beta blockers ,  ACE inhibitors  and  mineralocorticoid receptor antagonists ). [ 59 ]


In some patients with heart failure, a specialised pacemaker known as  cardiac resynchronisation therapy  can be used to improve the heart's pumping efficiency. [ 63 ]  These devices are frequently combined with a defibrillator. In very severe cases of heart failure, a small pump called a  ventricular assist device  may be implanted which supplements the heart's own pumping ability. In the most severe cases, a  cardiac transplant  may be considered. [ 59 ]


Humans have known about the heart since ancient times, although its precise function and anatomy were not clearly understood. [ 90 ]  From the primarily religious views of earlier societies towards the heart,  ancient Greeks  are considered to have been the primary seat of scientific understanding of the heart in the ancient world. [ 91 ] [ 92 ] [ 93 ]   Aristotle  considered the heart to be the organ responsible for creating blood;  Plato  considered the heart as the source of circulating blood and  Hippocrates  noted blood circulating cyclically from the body through the heart to the lungs. [ 91 ] [ 93 ]   Erasistratos  (304–250 BCE) noted the heart as a pump, causing dilation of blood vessels, and noted that arteries and veins both radiate from the heart, becoming progressively smaller with distance, although he believed they were filled with air and not blood. He also discovered the heart valves. [ 91 ]


The Greek physician  Galen  (2nd century CE) knew blood vessels carried blood and identified venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions. [ 91 ]  Galen, noting the heart as the hottest organ in the body, concluded that it provided heat to the body. [ 93 ]  The heart did not pump blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the arteries themselves. [ 93 ]  Galen believed the arterial blood was created by venous blood passing from the left ventricle to the right through 'pores' between the ventricles. [ 90 ]  Air from the lungs passed from the lungs via the pulmonary artery to the left side of the heart and created arterial blood. [ 93 ]


These ideas went unchallenged for almost a thousand years. [ 90 ] [ 93 ]


The earliest descriptions of the  coronary  and pulmonary circulation systems can be found in the  Commentary on Anatomy in Avicenna's Canon , published in 1242 by  Ibn al-Nafis . [ 94 ]  In his manuscript, al-Nafis wrote that blood passes through the pulmonary circulation instead of moving from the right to the left ventricle as previously believed by Galen. [ 95 ]  His work was later translated into  Latin  by  Andrea Alpago . [ 96 ]


In Europe, the teachings of Galen continued to dominate the academic community and his doctrines were adopted as the official canon of the Church.  Andreas Vesalius  questioned some of Galen's beliefs of the heart in  De humani corporis fabrica  (1543), but his  magnum opus  was interpreted as a challenge to the authorities and he was subjected to a number of attacks. [ 97 ]   Michael Servetus  wrote in  Christianismi Restitutio  (1553) that blood flows from one side of the heart to the other via the lungs. [ 97 ]


A breakthrough in understanding the flow of blood through the heart and body came with the publication of  De Motu Cordis  (1628) by the English physician  William Harvey . Harvey's book completely describes the systemic circulation and the mechanical force of the heart, leading to an overhaul of the Galenic doctrines. [ 93 ]   Otto Frank  (1865–1944) was a German physiologist; among his many published works are detailed studies of this important heart relationship.  Ernest Starling  (1866–1927) was an important English physiologist who also studied the heart. Although they worked largely independently, their combined efforts and similar conclusions have been recognized in the name " Frank–Starling mechanism ". [ 8 ]


Although  Purkinje fibers  and the  bundle of His  were discovered as early as the 19th century, their specific role in the  electrical conduction system of the heart  remained unknown until  Sunao Tawara  published his monograph, titled  Das Reizleitungssystem des Säugetierherzens , in 1906. Tawara's discovery of the  atrioventricular node  prompted  Arthur Keith  and  Martin Flack  to look for similar structures in the heart, leading to their discovery of the  sinoatrial node  several months later. These structures form the anatomical basis of the electrocardiogram, whose inventor,  Willem Einthoven , was awarded the Nobel Prize in Medicine or Physiology in 1924. [ 98 ]


The first  heart transplant  in a human ever performed was by  James Hardy  in 1964, using a chimpanzee heart, but the patient died within 2 hours. [ 99 ]  The first human to human heart transplantation was performed in 1967 by the South African surgeon  Christiaan Barnard  at  Groote Schuur Hospital  in  Cape Town . [ 100 ] [ 101 ]  This marked an important milestone in  cardiac surgery , capturing the attention of both the medical profession and the world at large. However, long-term survival rates of patients were initially very low.  Louis Washkansky , the first recipient of a donated heart, died 18 days after the operation while other patients did not survive for more than a few weeks. [ 102 ]  The American surgeon  Norman Shumway  has been credited for his efforts to improve transplantation techniques, along with pioneers  Richard Lower ,  Vladimir Demikhov  and  Adrian Kantrowitz . As of March 2000, more than 55,000 heart transplantations have been performed worldwide. [ 103 ]  The first successful transplant of a heart from a  genetically modified  pig to a human in which the patient lived for a longer time, was performed January 7, 2022 in  Baltimore  by heart surgeon  Bartley P. Griffith , recipient was David Bennett (57) this successfully extended his life until 8 March 2022 (1 month and 30 days). [ 104 ]


By the middle of the 20th century,  heart disease  had surpassed infectious disease as the leading cause of death in the United States, and it is currently the leading cause of deaths worldwide. Since 1948, the ongoing  Framingham Heart Study  has shed light on the effects of various influences on the heart, including diet, exercise, and common medications such as aspirin. Although the introduction of  ACE inhibitors  and  beta blockers  has improved the management of chronic heart failure, the disease continues to be an enormous medical and societal burden, with 30 to 40% of patients dying within a year of receiving the diagnosis. [ 105 ]


As one of the vital organs, the heart was long identified as the center of the entire body, the seat of life, or emotion, or reason, will, intellect, purpose or the mind. [ 106 ]  The heart is an emblematic symbol in many religions, signifying "truth, conscience or moral courage in many religions—the temple or throne of God in Islamic and  Judeo-Christian  thought; the divine centre, or  atman , and the  third eye  of transcendent wisdom in  Hinduism ; the diamond of purity and essence of the  Buddha ; the  Taoist  centre of understanding." [ 106 ]


In the  Hebrew Bible , the word for heart,  lev , is used in these meanings, as the seat of emotion, the mind, and referring to the anatomical organ. It is also connected in function and symbolism to the stomach. [ 107 ]


An important part of the concept of the  soul  in  Ancient Egyptian religion  was thought to be the heart, or  ib . The  ib  or metaphysical heart was believed to be formed from one drop of blood from the child's mother's heart, taken at conception. [ 108 ]  To ancient Egyptians, the heart was the seat of  emotion ,  thought , will, and  intention . This is evidenced by  Egyptian  expressions which incorporate the word  ib , such as  Awi-ib  for "happy" (literally, "long of heart"),  Xak-ib  for "estranged" (literally, "truncated of heart"). [ 109 ]  In Egyptian religion, the heart was the key to the afterlife. It was conceived as surviving death in the nether world, where it gave evidence for, or against, its possessor. The heart was therefore not removed from the body during mummification, and was believed to be the center of intelligence and feeling, and needed in the afterlife. [ 110 ]  It was thought that the heart was examined by  Anubis  and a variety of  deities  during the  Weighing of the Heart  ceremony. If the heart weighed more than the feather of  Maat , which symbolized the ideal standard of behavior. If the scales balanced, it meant the heart's possessor had lived a just life and could enter the afterlife; if the heart was heavier, it would be devoured by the monster  Ammit . [ 111 ]


The  Chinese  character for "heart", 心, derives from a comparatively realistic depiction of a heart (indicating the heart chambers) in  seal script . [ 112 ]  The Chinese word  xīn  also takes the metaphorical meanings of "mind", "intention", or "core", and is often translated as "heart-mind" as the ancient Chinese believed the heart was the center of human cognition. [ 113 ]   In Chinese medicine , the heart is seen as the center of  神  shén  "spirit, consciousness". [ 114 ]  The heart is associated with the  small intestine ,  tongue , governs the  six organs and five viscera , and belongs to fire in the five elements. [ 115 ]


The Sanskrit word for heart is  hṛd  or  hṛdaya , found in the oldest surviving Sanskrit text, the  Rigveda . In Sanskrit, it may mean both the anatomical object and "mind" or "soul", representing the seat of emotion.  Hrd  may be a cognate of the word for heart in Greek, Latin, and English. [ 116 ] [ 117 ]


Many  classical  philosophers and scientists, including  Aristotle , considered the heart the seat of thought,  reason , or emotion, often disregarding the brain as contributing to those functions. [ 118 ]  The identification of the heart as the seat of  emotions  in particular is due to the  Roman  physician  Galen , who also located the seat of the passions in the  liver , and the seat of reason in the brain. [ 119 ]


The heart also played a role in the  Aztec  system of belief. The most common form of human sacrifice practiced by the Aztecs was heart-extraction. The Aztec believed that the heart ( tona ) was both the seat of the individual and a fragment of the Sun's heat ( istli ). To this day, the Nahua consider the Sun to be a heart-soul ( tona-tiuh ): "round, hot, pulsating". [ 120 ]


Indigenous leaders from Alaska to Australia came together in 2020 to deliver a message to the world that humanity needs to shift from the mind to the heart, and let our heart be in charge of what we do. [ 121 ]  The message was made into a film, which highlighted that humanity must open their hearts to restore balance to the world. [ 122 ]  Kumu Sabra Kauka, a Hawaiian studies educator and tradition bearer summed up the message of the film saying "Listen to your heart. Follow your path. May it be clear, and for the good of all." [ 121 ]   The film was led by Illarion Merculieff from the  Aleut  (Unangan) tribe. Merculieff has written that Unangan Elders referred to the heart as a "source of wisdom", "a deeper portal of profound interconnectedness and awareness that exists between humans and all living things". [ 123 ] [ 124 ]


In  Catholicism , there has been a long tradition of veneration of the heart, stemming from worship of the wounds of  Jesus Christ  which gained prominence from the mid sixteenth century. [ 125 ]  This tradition influenced the development of the medieval Christian  devotion  to the  Sacred Heart of Jesus  and the parallel veneration of the  Immaculate Heart of Mary , made popular by  John Eudes . [ 126 ]  There are also many references to the heart in the Christian Bible, including "Blessed are the pure in heart, for they will see God", [ 127 ]  "Above all else, guard your heart, for everything you do flows from it", [ 128 ]  "For where your treasure is, there your heart will be also", [ 129 ]  "For as a man thinks in his heart, so shall he be." [ 130 ]


The expression of a  broken heart  is a cross-cultural reference to  grief  for a lost one or to unfulfilled  romantic love .


The notion of " Cupid 's arrows" is ancient, due to  Ovid , but while Ovid describes Cupid as wounding his victims with his arrows, it is not made explicit that it is the  heart  that is wounded. The familiar iconography of Cupid shooting little  heart symbols  is a  Renaissance  theme that became tied to  Valentine's Day . [ 106 ]


In certain  Trans-New Guinea languages , such as  Foi  and Momoona, the heart and seat of emotions are  colexified , meaning they share the same word. [ 131 ]


Animal hearts are widely consumed as a type of  offal . As they are almost entirely muscle, they are high in protein. They are often included in dishes with other internal organs, for example in the  pan-Ottoman   kokoretsi .


Chicken  hearts are considered to be  giblets , and are often grilled on skewers; examples of this are  Japanese   hāto yakitori ,  Brazilian   churrasco de coração , and  Indonesian   chicken heart satay . [ 132 ]  They can also be pan-fried, as in  Jerusalem mixed grill . In  Egyptian cuisine , they can be used, finely chopped, as part of  stuffing  for chicken. [ 133 ]  Many recipes combined them with other giblets, such as the  Mexican   pollo en menudencias [ 134 ]  and the  Russian   ragu iz kurinyikh potrokhov . [ 135 ]


The hearts of beef, pork, and mutton can generally be interchanged in recipes. [ citation needed ]  As heart is a hard-working muscle, it makes for "firm and rather dry" meat, [ 136 ]  so is generally slow-cooked. Another way of dealing with toughness is to  julienne  the meat, as in  Chinese  stir-fried heart. [ 137 ]


Beef  heart is valued for its high meat quality and low price, being commonly disregarded in conventional meat pricing. It can be cut into  steaks , comparable in quality to the more expensive cuts of meat from the same animal, though it is distinguished by a lack of a discernible grain. It was historically eaten in the United States as a cost-saving measure, but is today also eaten as an independently desirable ingredient. [ 138 ]  Beef heart may be grilled or braised. [ 139 ]  In the  Peruvian   anticuchos de corazón , barbecued beef hearts are grilled after being tenderized through long  marination  in a spice and vinegar mixture. An  Australian  recipe for "mock goose" is actually braised stuffed beef heart. [ 140 ]


Pork  heart can be stewed, poached, braised, [ 141 ]  or made into sausage. The  Balinese   oret  is a sort of  blood sausage  made with pig heart and blood. A  French  recipe for  cœur de porc à l'orange  is made of braised heart with an orange sauce.


The size of the heart varies among the different animal  groups , with hearts in  vertebrates  ranging from those of the smallest mice (12 mg) to the blue whale (600 kg). [ 142 ]  In vertebrates, the heart lies in the middle of the ventral part of the body, surrounded by a  pericardium . [ 143 ]  which in some fish may be connected to the  peritoneum . [ 144 ]  In all vertebrates, the heart has an asymmetric orientation, almost always on the left side. According to one theory, this is caused by a  developmental axial twist  in the early embryo. [ 145 ] [ 146 ]


The sinoatrial node is found in all  amniotes  but not in more primitive vertebrates. In these animals, the muscles of the heart are relatively continuous, and the sinus venosus coordinates the beat, which passes in a wave through the remaining chambers. Since the sinus venosus is incorporated into the right atrium in amniotes, it is likely  homologous  with the SA node. In teleosts, with their vestigial sinus venosus, the main centre of coordination is, instead, in the atrium. The rate of heartbeat varies enormously between different species, ranging from around 20 beats per minute in  codfish  to around 600 in  hummingbirds [ 147 ]  and up to 1,200 bpm in the  ruby-throated hummingbird . [ 148 ]


Adult  amphibians  and most  reptiles  have a  double circulatory system , meaning a circulatory system divided into arterial and venous parts. However, the heart itself is not completely separated into two sides. Instead, it is separated into three chambers—two atria and one ventricle. Blood returning from both the systemic circulation and the lungs is returned, and blood is pumped simultaneously into the systemic circulation and the lungs. The double system allows blood to circulate to and from the lungs which deliver oxygenated blood directly to the heart. [ 149 ]


In reptiles, other than  snakes , the heart is usually situated around the middle of the thorax. In terrestrial and arboreal snakes, it is usually located nearer to the head; in aquatic species the heart is more centrally located. [ 150 ]  There is a heart with three chambers: two atria and one ventricle. The form and function of these hearts are different from mammalian hearts due to the fact that snakes have an elongated body, and thus are affected by different environmental factors. In particular, the snake's heart relative to the position in their body has been influenced greatly by gravity. Therefore, snakes that are larger in size tend to have a higher  blood pressure  due to gravitational change. [ 150 ]  The ventricle is incompletely separated into two-halves by a wall ( septum ), with a considerable gap near the pulmonary artery and aortic openings. In most reptilian species, there appears to be little, if any, mixing between the bloodstreams, so the aorta receives, essentially, only oxygenated blood. [ 147 ] [ 149 ]  The exception to this rule is  crocodiles , which have a four-chambered heart. [ 151 ]


In the heart of  lungfish , the septum extends partway into the ventricle. This allows for some degree of separation between the de-oxygenated bloodstream destined for the lungs and the oxygenated stream that is delivered to the rest of the body. The absence of such a division in living amphibian species may be partly due to the amount of respiration that occurs through the skin; thus, the blood returned to the heart through the venae cavae is already partially oxygenated. As a result, there may be less need for a finer division between the two bloodstreams than in lungfish or other  tetrapods . Nonetheless, in at least some species of amphibian, the spongy nature of the ventricle does seem to maintain more of a separation between the bloodstreams. Also, the original valves of the  conus arteriosus  have been replaced by a spiral valve that divides it into two parallel parts, thereby helping to keep the two bloodstreams separate. [ 147 ]


Archosaurs  ( crocodilians  and  birds ) and  mammals  show complete separation of the heart into two pumps for a total of four heart chambers; it is thought that the four-chambered heart of archosaurs evolved independently from that of mammals. In crocodilians, there is a small opening, the  foramen of Panizza , at the base of the arterial trunks and there is some degree of mixing between the blood in each side of the heart, during a dive underwater; [ 152 ] [ 153 ]  thus, only in birds and mammals are the two streams of blood—those to the pulmonary and systemic circulations—permanently kept entirely separate by a physical barrier. [ 147 ]


The heart evolved no less than 380 million years ago in  fish . [ 154 ]  Fish have what is often described as a two-chambered heart, [ 155 ]  consisting of one atrium to receive blood and one ventricle to pump it. [ 156 ]  However, the fish heart has entry and exit compartments that may be called chambers, so it is also sometimes described as three-chambered [ 156 ]  or four-chambered, [ 157 ]  depending on what is counted as a chamber. The atrium and ventricle are sometimes considered "true chambers", while the others are considered "accessory chambers". [ 158 ]


Primitive fish have a four-chambered heart, but the chambers are arranged sequentially so that this primitive heart is quite unlike the four-chambered hearts of mammals and birds. The first chamber is the  sinus venosus , which collects deoxygenated blood from the body through the  hepatic  and  cardinal veins . From here, blood flows into the atrium and then to the powerful muscular ventricle where the main pumping action will take place. The fourth and final chamber is the  conus arteriosus , which contains several valves and sends blood to the  ventral aorta . The ventral aorta delivers blood to the gills where it is oxygenated and flows, through the  dorsal aorta , into the rest of the body. (In  tetrapods , the ventral aorta has divided in two; one half forms the  ascending aorta , while the other forms the pulmonary artery). [ 147 ]


In the adult fish, the four chambers are not arranged in a straight row but instead form an S-shape, with the latter two chambers lying above the former two. This relatively simple pattern is found in  cartilaginous fish  and in the  ray-finned fish . In  teleosts , the conus arteriosus is very small and can more accurately be described as part of the aorta rather than of the heart proper. The conus arteriosus is not present in any  amniotes , presumably having been absorbed into the ventricles over the course of evolution. Similarly, while the sinus venosus is present as a vestigial structure in some reptiles and birds, it is otherwise absorbed into the right atrium and is no longer distinguishable. [ 147 ]


Arthropods  and most  mollusks  have an open circulatory system. In this system, deoxygenated blood collects around the heart in cavities ( sinuses ). This blood slowly permeates the heart through many small one-way channels. The heart then pumps the blood into the  hemocoel , a cavity between the organs. The heart in arthropods is typically a muscular tube that runs the length of the body, under the back and from the base of the head. Instead of blood the circulatory fluid is  haemolymph  which carries the most commonly used  respiratory pigment , copper-based  haemocyanin  as the oxygen transporter. Haemoglobin is only used by a few arthropods. [ 159 ]


In some other invertebrates such as  earthworms , the circulatory system is not used to transport oxygen and so is much reduced, having no veins or arteries and consisting of two connected tubes. Oxygen travels by diffusion and there are five small muscular vessels that connect these vessels that contract at the front of the animals that can be thought of as "hearts". [ 159 ]


Squids and other cephalopods  have two "gill hearts" also known as  branchial hearts , and one "systemic heart". [ 160 ]  The branchial hearts have two atria and one ventricle each, and pump to the  gills , whereas the systemic heart pumps to the body. [ 161 ] [ 162 ]


Only the  chordates  (including vertebrates) and the  hemichordates  have a central "heart", which is a vesicle formed from the thickening of the  aorta  and contracts to pump blood. This suggests a presence of it in the last  common ancestor of these groups  (may have been lost in the  echinoderms ).


This article incorporates text from the  CC BY  book:  OpenStax College,  Anatomy & Physiology. OpenStax CNX. 30 July 2014.


In  cardiology , an  accessory pathway  is an additional electrical connection between two parts of the  heart . [ 1 ]  These pathways can lead to abnormal heart rhythms ( arrhythmias ) associated with symptoms of  palpitations . Some pathways may activate a region of  ventricular  muscle earlier than would normally occur, referred to as pre-excitation, and this may be seen on an  electrocardiogram .   The combination of an accessory pathway that causes pre-excitation with arrhythmias is known as  Wolff–Parkinson–White syndrome . [ 2 ]


Accessory pathways are often diagnosed using an electrocardiogram, but characterisation and location of the pathway may require an  electrophysiological study .  Accessory pathways may not require any treatment, but those causing symptoms may be treated with medication including  calcium channel antagonists ,  beta blockers  or  flecainide . [ 3 ]   Alternatively, the electrical conduction through an accessory pathways can be abolished using  catheter ablation , potentially offering a permanent cure. [ 3 ]


The most common sites for accessory pathways are connections between muscle tissue in the  atria  and the ventricles (atrio-ventricular pathways), bypassing the  atrioventricular node .  Rarer sites include connections between atrial muscle and the  conducting tissue  within the ventricles (atrio-fascicular pathways), between the atrioventricular node and the muscle tissue of the ventricle (nodo-ventricular pathways), and between the conducting tissue of the ventricle and the ventricular muscle (fasciculo-ventricular pathways).  These rarer accessory pathways are sometimes collectively referred to as Mahaim pathways or Mahaim fibres. [ 4 ]


Mahaim pathways are typically seen on the right side of the heart, with their ventricular connection lying within or close to the right bundle branch. [ 4 ]   The fibres often conduct slowly and in one direction only - from the atria to the ventricles (antegrade conduction); not from the ventricles to the atria (retrograde conduction). Unlike most atrio-ventricular accessory pathways which conduct electrical impulses at a relatively fixed speed, conduction through a Mahaim pathway varies according to how rapidly it is stimulated. More frequent stimulation leads to slower conduction, known as decremental conduction. [ 4 ]  If conduction to the ventricles occurs solely through the pathway (maximal pre-excitation), as occurs during arrhythmias like antidromic  atrioventricular re-entrant tachycardia , the ECG appearance is of  QRS complexes  with a  left bundle branch block  morphology which can be mistaken for  ventricular tachycardia .   However, due to their slow decremental conduction, during sinus rhythm the 12-lead ECG will often show little pre-excitation. [ 4 ]


The  heart  is a muscular organ situated in the  mediastinum . It consists of four chambers, four valves, two main arteries (the coronary arteries), and the conduction system. The left and right sides of the heart have different functions: the right side receives de-oxygenated blood through the  superior  and  inferior   venae cavae  and pumps blood to the lungs through the  pulmonary artery , and the left side receives saturated blood from the lungs.


The heart has the shape of a pyramid, with its apex pointing towards the left nipple while its base forms the posterior surface of the heart. Other surfaces are the anterior, inferior (or diaphragmatic), and two pulmonary surfaces facing the lungs. Its longest dimension (apical to base) is broadly 12–13 cm, while the average weight is 250 grams in females and 300 grams in males. [ 1 ]  Its primary role is to receive the blood from the body, pump it to the lungs to be oxygenated, and receive it once more to pump it again to the rest of the human body tissues. Heart rate, defined as the number of times the heart beats per minute, can fluctuate due to the body's varying needs for oxygen and nutrients. [ 2 ]  In addition, heart rates can increase when the sympathetic nervous system is activated but decrease when the parasympathetic nervous system is activated. [ 3 ]  The sympathetic nervous system can prepare the body for stressful situations by defaulting to “fight or flight”. The parasympathetic nervous system on the other hand regulates “rest and digest” when at ease or safe. [ 4 ]  Although the parasympathetic nervous system prevails, specific mental, physical, or environmental stressors trigger the sympathetic nervous system, and thus, increase heart rate. [ 5 ]  The right side of the heart (which consists of the  right atrium  and the  right ventricle ) receives the desaturated blood, while the left side (consisting of the  left atrium  and  left ventricle ) receives the oxygenated blood.


The  pericardium  is a thick membrane that covers the heart. It consists of two layers: the fibrous pericardium and the serous pericardium. It forms two recesses: the transverse recess and oblique recess. The transverse recess lies behind the  aorta  and  pulmonary trunk , while the oblique recess lies behind the left atrium. [ 6 ]  The serous pericardium is thin and covers the heart. It is also called the epicardium. The fibrous pericardium is much thicker. Together they form the pericardial cavity, a thin sac hosting a small amount of fluid. [ 7 ]


The four cardiac valves are kept in their place partly because of the  fibrous skeleton  of the heart, which is a collection of  connective tissue . It consists of the right fibrous trigone (which along with the membranous  septum  forms the  central fibrous body ), the left right fibrous trigone, and the conus tendon. The right fibrous trigone is the strongest part of the skeleton. It lies to the right of the  aortic valve  and connects it with the  mitral  and  tricuspid  valves. It is pierced by the  bundle of His . Lastly, the aortomitral curtain is also a part of the fibrous skeleton; it is formed by fibrous tissue connecting two of three of the aortic valve leaflets (the right and non-coronary leaflet) with anterior leaflet of the mitral valve. [ 8 ]


The heart has four chambers: the  left and right atriums  and the  left and right ventricles . They form a shallow groove at the line of their junction, which form the atrioventricular groove. The  atrioventricular groove  hosts major  coronary arteries  while they travel along to the line of attachment of  atrioventricular valves . The right and left ventricles are separated by a  septum , which corresponds to the  interventricular grooves  that travel from the  posterior  to the anterior surface of the heart.


The right atrium lies among the two  venae cavae , behind and somewhat right of the  sternum . It is right and anterior to the left atrium. [ 9 ]  It consists of the venous component (or sina venarum), which is the main, smooth part of the right atrium (auricula or atrium proper). This venous component includes the right appendage, the front and lateral wall of right atrium, and the vestibule of the  tricuspid valve . [ 10 ] [ 11 ]  The venous component receives the blood from superior and inferior venae cavae. [ 12 ]  What separates the two components is the inside appearance of the wall. While the sina venarum has smooth walls, the characteristic of the auricula are the thick muscle bundles that make it appear somewhat rough. [ 11 ]  Sina venarum corresponds to the  right horn of sinus venosus  of the  embryonic heart . [ 12 ]


Externally, the most prominent features of the heart are the right appendage (or right auricle), the  sulcus terminalis , and the  coronary sulcus . [ 12 ]  The right appendage is pyramidal in shape, with its base opening at the sina venarum. [ 12 ]  The sulcus terminalis, or terminal groove, is a shallow groove that travels from the IVC to the SVC and separates the right appendage from the venous compartment of the right ventricle. [ 12 ] [ 10 ]  At the upper end of sulcus terminalis lies the  sinoatrial node . [ 13 ]  The sinoatrial node receives blood supply from a branch of the right coronary artery or circumflex artery in 55% and 45% of people respectively. This artery is called the sinus nodal artery, and it is sometimes visible through the open sternum. [ 13 ]  Another groove, which runs somewhat parallel and posterior to sulcus terminalis, is Waterstone's groove (also known as Sondergaard's groove). [ 10 ]


Internally, the  crista terminalis  is a prominent muscle bundle from which the  pectinate muscles  of the right atrium originate. The terminal crest corresponds to the external sulcus terminalis. [ 14 ] [ 12 ]  The  fossa ovalis  lies on the interatrial wall and is the remnant of the prenatal atrial communication. [ 12 ]  The opening of the inferior vena cava is guarded by the  Eustachian valve , while next to it lies the  Thebesian valve  that guards the  orifice  of the  coronary sinus . [ 15 ]  The thebesian veins also drain into the right atrium. [ 16 ]  Most of the right atrium is  trabeculated , as it is covered with pectinate muscles that run parallel to one another. [ 17 ]


The right ventricle receives blood from the right atrium through the tricuspid valve and pumps it to the lungs. [ 18 ]  The right ventricle lies behind the sternum and forms a large part of the sternodiaphragmatical surface of the heart. Its inferior surface lies over the central tendon of the diaphragm. The right ventricle consists of an inlet portion that receives blood from the right atrium through the tricuspid valve. There is an apical portion that approaches- but does not reach- the apex of the heart; this apical portion is packed with rough trabeculations. The last portion is a muscular outlet portion (infudibulum) that pumps the blood to the pulmonary artery. [ 17 ] The atrioventricular groove, a groove that harbors the right coronary artery of the heart, marks the separation of the atrium and the ventricle. Internally, the  crista supraventricularis , a muscular thickener, separates the right ventricle into two spaces.


The left atrium lies to the left and slightly posterior of the right atrium. The pulmonary artery and aorta are located in front of the left atrium. The left atrium is slightly smaller than the right atrium and consists of the venous component, which receives saturated blood from the lungs via four pulmonary veins, the vestibule, and a narrow appendage. The venous component forms a large part of the posterior wall of the heart and the anterior wall of the  oblique pericardial sinus . [ 19 ] The appendage of the left atrium is a narrow, finger-like entity that contains small pectinate muscles. Its small orifice lies anterior of the left superior pulmonary vein and lateral to the mitral valve. The tip of the appendage can be found in various positions. [ 20 ]


The left ventricle is made of thick muscle walls because a lot of power is needed to push blood to the arterial system of the body. It is conical in shape and it is longer than the right ventricle in length, it also occupies part of the anterior (sternocostal), inferior (diaphragmatical), and left wall of heart. The left ventricle forms the apex of the heart and it receives blood from the left atrium through the mitral valve and pumps it to the body through the aortic valve. It consists of an inlet portion (ostium venosum), an outlet portion (ostium arteriosum), and an apical portion. [ 21 ]  The anterolateral and posteromedial papillary muscles are two strong papillary muscles within the left ventricle that anchor the two leaflets of the mitral valve (the valve between left atrium and ventricle consists of two leaflets). While these two muscles have a thick muscular base, they separate into various tendinous cords before entering the leaflets of the mitral valve. [ 22 ]  The apical portion is conical and consists of fine trabeculations. [ 23 ]


The heart is supplied blood from two arterial systems: left and right. The major arteries of the two systems travel within the atrioventricular groove and form a crown shape, thus they are named "coronary arteries". There is significant variation of which system provides blood to the inferior surface of the heart. If the PDA starts from the right coronary artery, then the coronary circulation is named as "right dominance", which is the case with 60% of the general population. The arteries are located in the subepicardium, so they are easily visible in the human eye, but in some cases, especially at their initial course, may be sited within the myocardium. [ 24 ]


The right coronary artery usually lies just above the aortic valve, within the aortic root, in the right coronary sinus that is the anterior surface of the aortic root. It travels anteriorly and slightly to the right to reach the atrioventricular groove; it enters the groove and follows it path to reach the cardiac crux, the place where atrioventricular groove meets the interatrial and interventricular grooves at the posterior surface of the heart. The right coronary artery provides blood to the wall of the right heart and some areas of the left heart though its branches. [ 24 ]  The right coronary system mostly supplies the right ventricle and atrium, apart from the anterior interventricular septum and a small area neighboring the course of the left anterior descending artery. [ 27 ]


The left main coronary artery begins at the posterior sinus of the aortic root. It is the largest coronary artery, as the myocardium supplied by this artery is larger than the coronary artery, although it becomes short as soon as it separates in the anterior interventricular (also known as  left anterior descending  or LAD) and circumflex artery. [ 27 ]  The LAD travels within the interventricular groove and gives of diagonal and septal branches. Diagonal branches supply the anterior surface of the heart while septal branches supply the muscle mass of the  interventricular septum ; the first one supplies the atrioventricular bundle at the point of its bifurcation. [ 27 ]  The circumflex artery is embedded within the atrioventricular groove, travels laterally to the left and curves to the posterior surface of the heart, where it usually diminishes at the crux area (where it sometimes supplies the posterior descending artery (in case of left dominance)). [ 27 ]  The left coronary system mainly supplies the left heart and a large part of the interventricular septum. [ 27 ]


Two separate systems of returning blood from the myocardial mass to the cardiac cavities. The major system consists of the coronary sinus, a wide vessel that collects blood from smaller veins and drains it to the right atrium. The smaller system consists of smaller veins that are draining the inner part of cardiac mass directly to cardiac cavities, most commonly to right atrium. [ 28 ]  There are three distinct lymphatic drainage plexuses in the heart; after  anastomosing  each other, they end up in a  brachiocephalic  node. [ 29 ]


In approximately 1% of humans, coronary arteries originate in a not typical position. Among that 1%, the most common abnormality is circumflex arising from right coronary artery, instead of left main artery and usually does not pose any problem. Other abnormalities are coronary arteries originating from a not typical sinus and then traveling either between the aorta and pulmonary artery, or intramural. In both cases, outside pressure causes ischaemia and thus angina. [ 30 ]


There are four major  valves in the heart , two  atrioventricular valves  (connecting one atrium to a ventricle) and two arterial (or  semilunar ) valves guarding the outflow of blood from the human heart. Each atrioventricular valve (tricuspid and mitral valves) consists of the leaflets, the annulus, the tendinous cords, the papillary muscles, and the supporting muscle mass. Semilunar valves (pulmonary and aortic valves) consists of leaflets, the sinuses and the interleaflet triangles. [ 31 ]


Aortic valve is in between the muscular left ventricle and the fibroelastic aorta, the biggest artery of the human body. Its three leaflet close when hydrostatic pressure applies over the valve, while kept open during the ejection phase of the cardiac cycle, when blood is pushed out of the heart by the contracting musculare of the left ventricle. [ 32 ]  Histologically, the leaflets are fibrous in their core, covered with endothelium; [ 33 ] [ 34 ]   a thickening at their free edge, is named  node of Arantius . The aortic leaflets are hinged at the beginning of the aorta, at very first part of aortic sinus. Their line of attachement is not circular, it rather creates a corona, nonetheless it is commonly named as " aortic ring ". [ 33 ]


Each of the three aortic valve leaflets is named after the orifice of the coronary artery located above the leaflet- one is named non-coronary leaflet as it lacks a coronary ostium. [ 34 ]  Left and right leaflet originate from the muscle fibers of left ventricle, [ 35 ]  while non coronary leaflet is in continuation with mitral valve's anterior leaflet forming the  aortic-mitral curtain . [ 34 ]


Mitral valve separates left atrium with left ventricle. It consists of the two mitral leaflets, (anterior and posterior) sited within the mitral annulus.  Chordae tendineae  are attached to the ventricular surfaces and the free edges of the two leaflets. Chordae are also attached to the two papillary muscles of left ventricle. Anterior leaflet is much larger than the posterior leaflet but posterior has a broader base, approaching two thirds of circumflex  [ 36 ]


Tricuspid valve separates right chambers- atrium from ventricle. As its name suggest, it has 3 leaflets (anterior, posterior and septal), all attached at the annulus of the leaflet that notably lacks any fibrotic tissue. [ 37 ]  Apart from the leaflets and annulus, it also consists of three papillary muscles and three sets of chordae tendineae. [ 38 ]


Conduction system is a network of  cardiac muscle fibers  aiming to generate and transduce signals in the heart, so to produce  contraction of the heart  and thus  pulse . Normally, the signal is generated at  sinus node , also known as sinoatrial node, since it lies on the right atrial wall, near the orifice of  superior vena cava . Usually, a rather large artery, named sinus artery, supplies the node. Various pathways initiate from sinus node, and carry the signal through the wall of both right and left atrium. They all end in  atrioventricular node . This latter node lies on the floor of atrioventricular septum, just above the orifice of Coronary Sinus. From the atrioventricular node, the buddle of His, that travels along the interventricular septum and spits the to left and right buddle branches. They supply left and right ventricle respectively. [ 39 ]


The  Caerphilly Heart Disease Study , also known as the  Caerphilly Prospective Study  (CaPS), is an  epidemiological  prospective  cohort , set up in 1979 in a representative population sample drawn from  Caerphilly , a typical small town in  South Wales , UK. [ 1 ]


The initial aim was to examine relationships between a wide range of social, lifestyle,  dietary  and other factors with incident  vascular disease . Opportunity was also taken, in collaboration with a range of clinical and laboratory colleagues, to collect data on a wide range of factors with possible relevance to diseases other than vascular, and at the same time to collect clinical information on  incident  disease events.
The study was initiated by Professor  Peter Elwood , Director of the  Medical Research Council  (MRC) Epidemiology Unit for South Wales.  The work has so far led to over 400 publications in the  medical press .


In 1948, an MRC epidemiological unit was set up in  Cardiff , South Wales, under  Professor Archie Cochrane .  Peter Elwood  joined Cochrane in 1963 and together they promoted long-term studies of representative population samples. They also conducted  randomised controlled trials  to test a variety of clinical hypotheses. Undoubtedly, the most important of their joint studies was a randomised controlled trial of  aspirin  showing a reduction of vascular mortality. [ 2 ]


Reported in the  British Medical Journal  in 1974, this was the first study to demonstrate a protective role for aspirin in the reduction of death and  reinfarction . [ 3 ]  The British Medical Journal recognised this article as one of the 50 most frequently cited papers published between 1945 and 1989. [ 4 ]


Following this trial, Elwood and his research team set up the Caerphilly Heart Disease Study, [ 1 ]  with their primary focus on vascular disease, and the identification of predictors for  platelet activity  and  thrombosis . Caerphilly was chosen for the work because the population was fairly stable, it had age and social class structures similar to that of the whole UK population, and there was a high incidence of  ischaemic heart disease  compared with the rest of the UK.


In 1979, all men aged between 45 and 59 years, who were on the  electoral registers  and/or general practice lists for Caerphilly and the adjoining villages of  Abertridwr ,  Senghenydd ,  Trethomas ,  Bedwas  and  Machen  were invited to co-operate in a long-term health study.  2,512 subjects (89% of the total eligible population) agreed to participate and were examined in Phase 1 (baseline) between July 1979 and September 1983. [ 1 ]


Since then, the men have been re-examined seven times (at five-year intervals) with approximately 95% of the surviving men co-operating in each re-examination. Many questions and tests have been repeated, but the opportunity has also been taken to include new questionnaires and tests.  In the early phases of the study, samples of  fasting blood  were collected for extensive testing and long-term storage, and on occasions urine and other biological samples were also taken, and aliquots stored.  Thus, while the initial aims of the study focused upon vascular disease, the wealth of data collected has enabled the testing of a large number of hypotheses relevant to other diseases too. [ citation needed ]


From the start of the study, the term ' Collaborative ' was usually added to the title, paying tribute to the many physicians, laboratory technicians and other colleagues, expert in a wide range of clinical and metabolic disciplines, who were actively involved in the work. [ citation needed ]


Heart disease  prevalence  is far greater in men than women – therefore women were not included in the study.  A far larger sample size would have been required if women had been the focus of the study, and unfortunately, the available resources were not sufficient for this. [ citation needed ]


The work in Caerphilly was often linked with the Speedwell Study, a similar study operating in nearby  Bristol , 60 km away. The survey techniques were similar and a number of questionnaires and biological tests were used in both the studies. This enabled a number of joint reports on vascular disease, and in particular on the relevance of  blood lipids , to be based on the five thousand subjects within the two cohorts together.


Initially, the study was funded by the Medical Research Council and led by Peter Elwood.  Following Elwood's retirement in 1995 the study continued under the leadership of Dr John Gallacher ( Cardiff University ) and Professor Yoav Ben-Shlomo ( Bristol University ), together with Dr John Yarnell ( Queen's University ) and Professor Tony Bayer (Cardiff University).  Financial support was obtained from the  British Heart Foundation  and the  Alzheimer's Society . [ citation needed ]


The Caerphilly Study's research strategy was to identify factors showing an association with vascular disease (and other diseases), and then to test these associations in randomised controlled trials and statistical analysis.


The  Framingham Heart Study , a much earlier cohort study in the US, had already shown that  cholesterol  is an important predictive factor for heart disease, [ 5 ]  and studies of US Veterans had shown that  raised blood pressure  is a major factor in stroke. [ 6 ]  The Caerphilly Study re-tested these predictors together with  lipid fractions  and high-density  lipoproteins  (total  HDL , HDL2 and HDL3). [ 7 ]  More recently,  arterial resistance  and its contribution to  blood pressure  has also been studied within the cohort. [ 8 ]


The randomised controlled trial of  aspirin  had shown that blood  platelets  play a key role in vascular disease. [ 2 ]  The Caerphilly Study focused on this by developing a large data-bank of platelet testing during the early phases of the study. Platelet collection and analysis was undertaken in close collaboration with Dr John O'Brien, Consultant Haematologist in St Mary's Hospital, Portsmouth, Professor Serge Renaud, a Director of Research in the  French National Institute of Health and Medical Research  in  Lyon , and Professor  Rod Flower  FRS, then at the  University of Bath . The work was done in a specially equipped mobile platelet laboratory, lent to the Caerphilly team by Serge Renaud, and towed by him from INSERM in Lyon, France, to the  Miners' Hospital . [ 9 ]


Detailed work was also completed on thrombosis and  haemostatic  factors with the active involvement of John O'Brien and in collaboration with Professor Gordon Lowe, in the  Institute of Cardiovascular and Medical Sciences . [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]


At baseline, a 1:3 sample (668 men) completed a 7-day weighed dietary intake record.  Data on the dietary intake of each subject in the cohort was collected during each phase of the study.


Ten years into the study a detailed package of  cognitive function  tests were performed by each subject. These tests have been repeated several times [ 15 ]  and later enabled the evaluation of factors with possible relevance to  cognitive decline  and  dementia .


The Caerphilly Study gave opportunity to study the relationship between lifestyle choices and health in a representative population sample drawn from a typical small town in the UK. [ 16 ]
The participants were asked detailed questions at baseline and at subsequent examinations about lifestyle behaviours, enabling the men to be classified in terms of five healthy behaviours:


These healthy behaviours displayed significant negative associations with cognitive impairment and dementia, with participant disease outcomes falling as the number of healthy behaviours followed increased. Men who followed four or five of the healthy behaviours during 30 years of follow-up experienced on average a 73% reduction in diabetes, a 67% reduction in vascular disease, a 35% reduction in cancer (attributable to non-smoking alone) and a 64% reduction in cognitive impairment and dementia. [ 16 ]


Healthy behaviours are the responsibility of each individual, [ 17 ]  and <1% of the men in the Caerphilly Study followed all five, with only 5% following four consistently. [ 16 ]  Comparisons with data collected in the 2009 Welsh Health Survey indicate that while the pattern of behaviours has changed, the proportions of subjects following four or five of the healthy behaviours has scarcely altered over the past 30 years. [ 18 ]


The Caerphilly Study estimated the likely effect of increased healthy living within the community by supposing that each man in the Caerphilly cohort had each been urged at the start of the study in 1979 to adopt just one additional healthy behaviour. If only half of them had complied, then over the following 30 years 12% fewer would have developed diabetes; 6% fewer would have had a vascular disease event; 13% fewer would have developed dementia; and there would have been 5% fewer deaths. [ 16 ]  A video summarising this work is available on YouTube. [ 19 ]


Participants were asked to obtain from a close female relative the details of their own  birth weight  and how they had been fed as infants.  Over half of the men obtained these details, and results showed that having been  breast fed  conferred some protection against the loss of cognitive function later in life, particularly in those whose birth weight had been low. [ 20 ]


Smoking, alcohol intake and leisure activities are lifestyle factors which were found to be predictive of cognitive function. [ 21 ]  Significant associations were also between cognitive function and  blood rheology  and negative associations with both  haematocrit  and plasma viscosity, but not with the thrombotic potential of blood, as indicated by  fibrinogen  level. [ 22 ]  These relationships appear to be direct, and not through underlying long-term disease processes. Sleep pattern, and in particular severe daytime sleepiness, was also predictive of vascular dementia. [ 23 ]


In diabetic subjects, it was found that poor control of blood sugar was associated with a lower cognitive function, and diabetes per se, but none of the components of  metabolic syndrome , other than high blood pressure, were predictive of worse cognition. [ 24 ]  Hearing loss was also found to be predictive of later cognitive impairment and incident dementia. [ 25 ]


The main objective of the work on  platelets  was to identify an aspect of platelet morphology or activity with predictive power for incident vascular disease, which could be developed as a  screening test  to identify subjects at high risk of a vascular event. In addition to number and size of the platelets, three tests of platelet aggregation were performed, several being repeated after five years. A stressed template bleeding time test was also performed on each man. [ citation needed ]


No prediction for heart disease was shown by any aspect of platelet morphology nor any platelet test, nor by the bleeding time test.  An unexpected finding was that the men who had had the most active platelets in two tests, based on platelet rich plasma and whole blood, had the lowest subsequent risk of an incident ischaemic stroke. [ 26 ]


Detailed analyses of the dietary data identified a number of food items related to vascular disease risk. The consumption of fatty fish was associated with lower levels of  blood lipids , [ 27 ]  and a reduction in vascular disease mortality was confirmed in a randomised trial. [ 28 ]


Milk consumption was found to be associated with a small reduction in the metabolic syndrome, [ 29 ]  and reductions in ischaemic heart disease, ischaemic stroke and diabetes, [ 30 ]  and these findings were confirmed in later overviews and meta-analyses. [ 31 ]  A reduction in blood pressure associated with milk consumption is well recognised, but new work in Caerphilly also identified a reduction in arterial stiffness associated with milk consumption. [ 8 ]


The consumption of fruit and vegetables was shown to be positively associated with blood antioxidant levels. [ 32 ]  Detailed work with Serge Renaud on platelet activity showed a beneficial relationship between a low alcohol consumption and platelet aggregation, but an enhanced response to  thrombin  with binge drinking, confirming previous work in animals. [ 33 ]


A detailed questionnaire of sleep pattern was included in one of the re-examinations of the men. In addition to the association with cognitive function already mentioned, [ 23 ]  there was evidence of an increase in ischaemic stroke in men whose sleep is frequently disturbed, and an association between daytime sleepiness and a significant increase in ischaemic heart disease. [ 34 ]


Many analyses of foods and dietary factors were conducted, as well as an examination of  Helicobacter pylori  and other infections, and vascular disease risk. [ 35 ] [ 36 ] [ 37 ]  A reduction in vascular disease mortality was found in those subjects most sexually active. [ 38 ]  Relationships between vascular disease and psychiatric symptoms, [ 39 ] [ 40 ]  noise exposure, [ 41 ] [ 42 ]  and hearing loss [ 25 ]  were also identified.


Cardiac excitation-contraction coupling  ( Cardiac   EC coupling )  describes the series of events, from the production of an  electrical impulse (action potential)  to the  contraction  of  muscles  in the  heart . [ 1 ]  This process is of vital importance as it allows for the  heart  to beat in a controlled manner, without the need for conscious input. EC coupling results in the sequential  contraction  of the  heart muscles  that allows  blood  to be pumped, first to the  lungs  ( pulmonary circulation ) and then around the rest of the body ( systemic circulation ) at a rate between 60 and 100 beats every minute, when the body is at rest. [ 2 ]  This rate can be altered, however, by  nerves  that work to either increase heart rate ( sympathetic nerves ) or decrease it ( parasympathetic nerves ), as the body's  oxygen  demands change. Ultimately,  muscle contraction  revolves around a  charged atom (ion) ,  calcium (Ca 2+ ) , [ 3 ]  which is responsible for converting the electrical energy of the  action potential  into mechanical energy (contraction) of the muscle. This is achieved in a region of the muscle cell, called the  transverse tubule  during a process known as  calcium induced calcium release . [ 4 ]


Located in the wall of the  right atrium  is a group of specialised cells, called the  Sinoatrial node (SAN) .  These cells, unlike most other  cells  within the  heart , can spontaneously produce  action potentials . [ 5 ]  These  action potentials  travel along the  cell membrane (sarcolemma) , as impulses, passing from one cell to the next through channels, in structures known as  gap junctions . [ 6 ]


Certain regions of the  sarcolemma  penetrate deep into the  cell . These are known as  transverse-tubules (t-tubules) ; which are also found in  skeletal muscle cells  and allow for the  action potential  to travel into the centre of the cell. [ 7 ]  Special  proteins  called  L-type calcium channels (also known as dihydropyridine receptors (DHPR))  are located on the  t-tubule membrane , and are activated by the action potential. Activated DHPRs open, forming a  channel , that allows Ca 2+  to pass into the cell. This increase in Ca 2+ , then binds to and activates another  receptor , called a  type 2 ryanodine receptor (RyR2) , located on the membrane of a structure known as the  sarcoplasmic reticulum (SR) . The  SR  is a  Ca 2+  stored within the cell and is located very close to the T-tubule. Activation of  RyR2  causes it to open, releasing even more  Ca 2+  into the  cell , this release of calcium is called a  calcium spark . This means that the initial flow of Ca 2+  into the  cell , causes a larger release of  Ca 2+  within the  cell , therefore the process is called  calcium induced calcium release (CICR) . [ 8 ]


The increase in Ca 2+ , produced by CICR, now does two things. Firstly, it binds to the intracellular side of the DHPR, signalling the channels to close and preventing further influx of Ca 2+  into the cell. Secondly Ca 2+  indirectly activates  proteins , called  myofilaments , resulting in  muscle contraction . The two main myofilaments in  cardiac  (and  skeletal )  muscle  are  actin  and  myosin . Ca 2+  binds to a protein called  troponin , which is bound to the actin filament. This binding causes a shape change in the troponin which exposes areas on the  actin , to which the head of the  myosin  filament binds. The binding of the  myosin head  to  actin  is known as a cross-bridge. A  molecule , called   adenosine triphosphate (ATP)  which is produced by an intracellular structure called a  mitochondrion , is then used, as a source of energy, to help move the myosin head, carrying the actin. As a result, the actin slides across the myosin filament shortening the muscle. This is called a power stroke.  Myosin  then detaches from the  actin  and resets itself back to its original position, binding to another part of the  actin  and producing another power stroke, shortening the  muscle  further. This process continues, with the myosin head moving in a motion similar to that of an oar rowing a boat, until the  Ca 2+  level within the cell decreases (see figure 1). [ 9 ]


Contraction ends when the Ca 2+  is removed from the cell. When this happens, the troponin changes back to its original shape, blocking the binding sites on  actin  and preventing the formation of crossbridges. This decrease in  Ca 2+  within the  cell  is brought about by a variety of  proteins , known collectively as  ion transporters . The main pumps involved are: the  sarcoplasmic reticulum Ca 2+ -ATPase , which pumps  Ca 2+  back into the SR, the  Sarcolemmal sodium-calcium exchanger , which pumps one  Ca 2+  out of the cell, in exchange for 3 sodium ions being pumped into the cell,  the  Sarcolemmal Ca 2+ -ATPase , which uses ATP to pump  Ca 2+  directly out of the cell and the  Mitochondrial Ca 2+  Uniport system , which pumps  Ca 2+  into the mitochondria. [ 10 ]


Sympathetic nerves work by releasing a protein ( neurotransmitter ) called  noradrenaline  which binds to a specific receptor ( beta 1 adrenoceptor ) located in the  sarcolemma  and the  t-tubule membrane  of  cardiac cells . This activates a protein, called a G-protein and results in a series of reactions (known as a  cyclic AMP pathway ) that leads to the production of a  molecule  called  cAMP  ( cyclic adenosine monophosphate ). In the SAN  cAMP  binds to an  ion channel  involved in action potential initiation, speeding up the production of the  action potential  (see  sinoatrial node  for more detail). cAMP also, activates a  protein  called  protein kinase A  ( PKA ). PKA affects both the  L-type calcium channels (also known as dihydropyridine receptors (DHPR))  and  RyR , increasing the rise in Ca  2+  within the contractile  cells  and therefore increasing rate of  muscle contraction . PKA also affects the  myofilaments  as well as a  protein  called  phospholamban  (PLB; see  sarcoplasmic reticulum  for more details), speeding up the rate of  Ca 2+ decline  in the cell and so speeding up  muscle relaxation . [ 2 ]


Parasympathetic nerves work by releasing a neurotransmitter called acetylcholine (ACh) which binds to specific receptor ( M2 muscarinic receptor ) on the sarcolemma of both SAN cells and ventricular cells. This again activates a  G-protein . However this G-protein works by inhibiting, the cAMP pathway, therefore, preventing the sympathetic nervous system from increasing heart rate. As well as this, in the SAN, the G-protein activates specific potassium channel, that opposes action potential initiation (see  SAN  for more details), thus slowing heart rate. [ 2 ]


Cardiac physiology  or  heart function  is the study of healthy, unimpaired function of the  heart : involving blood flow;  myocardium  structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.


The heart functions as a pump and acts as a double pump in the  cardiovascular system  to provide a continuous circulation of blood throughout the body. This circulation includes the  systemic circulation  and the  pulmonary circulation . Both circuits transport blood but they can also be seen in terms of the gases they carry. The pulmonary circulation collects oxygen from the lungs and delivers carbon dioxide for exhalation. The systemic circuit transports oxygen to the body and returns relatively de-oxygenated blood and carbon dioxide to the pulmonary circuit. [ 1 ]


Blood flows through the heart in one direction, from the atria to the ventricles, and out through the  pulmonary artery  into the pulmonary circulation, and the  aorta  into the systemic circulation. The pulmonary artery (also trunk) branches into the left and right  pulmonary arteries  to supply each lung. Blood is prevented from flowing backwards ( regurgitation ) by the tricuspid, bicuspid, aortic, and pulmonary valves. [ citation needed ]


The function of the  right heart , is to collect de-oxygenated blood, in the right atrium, from the body via the superior vena cava, inferior vena cava and from the coronary sinus and pump it, through the tricuspid valve, via the  right ventricle , through the semilunar  pulmonary valve  and into the pulmonary artery in the pulmonary circulation where carbon dioxide can be  exchanged  for oxygen in the lungs. This happens through the passive process of  diffusion . In the  left heart  oxygenated blood is returned to the left atrium via the pulmonary vein. It is then pumped into the left ventricle through the bicuspid valve and into the aorta for systemic circulation. Eventually in the systemic capillaries exchange with the tissue fluid and cells of the body occurs; oxygen and nutrients are supplied to the cells for their metabolism and exchanged for carbon dioxide and waste products [ 1 ]  In this case, oxygen and nutrients exit the systemic capillaries to be used by the cells in their metabolic processes, and carbon dioxide and waste products will enter the blood. [ 1 ]


The ventricles are stronger and thicker than the atria, and the muscle wall surrounding the left ventricle is thicker than the wall surrounding the right ventricle due to the higher force needed to pump the blood through the  systemic circulation .  Atria  facilitate circulation primarily by allowing uninterrupted venous flow to the heart, preventing the inertia of interrupted venous flow that would otherwise occur at each ventricular systole. [ 2 ]


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. This autorhythmicity is still modulated by the  endocrine  and  nervous systems . [ 1 ]


There are two types of cardiac muscle cell:  cardiomyocytes  which have the ability to contract easily, and modified cardiomyocytes the  pacemaker cells  of the conducting system. The cardiomyocytes make up the bulk (99%) of cells in the atria and ventricles. These contractile cells respond to impulses of  action potential  from the pacemaker cells and are responsible for the contractions that pump blood through the body. The pacemaker cells make up just (1% of cells) and form the conduction system of the heart. They are generally much smaller than the contractile cells and have few of the  myofibrils  or  myofilaments  which means that they have limited contractibility. Their function is similar in many respects to  neurons . [ 1 ]  The  bundle of His  and  Purkinje fibres  are specialised cardiomyocytes that function in the conduction system.


Cardiomyocytes , are considerably shorter and have smaller diameters than skeletal  myocytes . Cardiac muscle (like skeletal muscle) is characterized by  striations  – the stripes of dark and light bands resulting from the organised arrangement of myofilaments and  myofibrils  in the  sarcomere  along the length of the cell.  T (transverse) tubules  are deep invaginations from the  sarcolemma  (cell membrane) that penetrate the cell, allowing the electrical impulses to reach the interior. In cardiac muscle the T-tubules are only found at the  Z-lines . [ 1 ]  When an  action potential  causes cells to contract,  calcium  is released from the  sarcoplasmic reticulum  of the cells as well as the T tubules. The calcium release triggers sliding of the  actin  and  myosin  fibrils leading to contraction. [ 3 ]  A plentiful supply of  mitochondria  provide the energy for the contractions. Typically, cardiomyocytes have a single, central nucleus, but can also have two or more. [ 1 ]


Cardiac muscle cells branch freely and are connected by junctions known as  intercalated discs  which help the synchronized contraction of the muscle. [ 4 ]  The  sarcolemma  (membrane) from adjacent cells bind together at the intercalated discs. They consist of  desmosomes , specialized linking  proteoglycans ,  tight junctions , and large numbers of  gap junctions  that allow the passage of ions between the cells and help to synchronize the contraction. Intercellular  connective tissue  also helps to strongly bind the cells together, in order to withstand the forces of contraction. [ 1 ]


Cardiac muscle undergoes  aerobic respiration  patterns, primarily metabolizing lipids and carbohydrates. Oxygen from the lungs attaches to  haemoglobin  and is also stored in the  myoglobin , so that a plentiful supply of oxygen is available.  Lipids , and  glycogen  are also stored within the  sarcoplasm  and these are broken down by mitochondria to release  ATP . The cells undergo  twitch-type contractions  with long  refractory periods  followed by brief relaxation periods when the heart fills with blood for the next cycle. [ 1 ]


It is not very well known how the electric signal moves in the atria. It seems that it moves in a radial way, but  Bachmann's bundle  and  coronary sinus  muscle play a role in conduction between the two atria, which have a nearly simultaneous  systole . [ 5 ] [ 6 ] [ 7 ]  While in the ventricles, the signal is carried by specialized tissue called the  Purkinje fibers  which then transmit the electric charge to the  myocardium . [ 8 ]


If embryonic heart cells are separated into a Petri dish and kept alive, each is capable of generating its own electrical impulse followed by contraction. When two independently beating embryonic cardiac muscle cells are placed together, the cell with the higher inherent rate sets the pace, and the impulse spreads from the faster to the slower cell to trigger a contraction. As more cells are joined, the fastest cell continues to assume control of the rate. A fully developed adult heart maintains the capability of generating its own electrical impulse, triggered by the fastest cells, as part of the cardiac conduction system. The components of the cardiac conduction system include the  atrial  and  ventricular syncytium , the sinoatrial node, the atrioventricular node, the  bundle of His  (atrioventricular bundle), the  bundle branches , and the Purkinje cells. [ 1 ]


Normal  sinus rhythm  is established by the  sinoatrial (SA) node , the heart's  pacemaker . The SA node is a specialized grouping of cardiomyocytes in the upper and back walls of the right atrium very close to the opening of the  superior vena cava . The SA node has the highest rate of  depolarization . [ 1 ]


This impulse spreads from its initiation in the SA node throughout the atria through specialized internodal pathways, to the atrial myocardial contractile cells and the atrioventricular node. The internodal pathways consist of three bands (anterior, middle, and posterior) that lead directly from the SA node to the next node in the conduction system, the atrioventricular node. The impulse takes approximately 50 ms (milliseconds) to travel between these two nodes. The relative importance of this pathway has been debated since the impulse would reach the atrioventricular node simply following the cell-by-cell pathway through the contractile cells of the myocardium in the atria. In addition, there is a specialized pathway called Bachmann's bundle or the interatrial band that conducts the impulse directly from the right atrium to the left atrium. Regardless of the pathway, as the impulse reaches the atrioventricular septum, the connective tissue of the cardiac skeleton prevents the impulse from spreading into the myocardial cells in the ventricles except at the atrioventricular node. [ 1 ]  The electrical event, the wave of depolarization, is the trigger for muscular contraction. The wave of depolarization begins in the right atrium, and the impulse spreads across the superior portions of both atria and then down through the contractile cells. The contractile cells then begin contraction from the superior to the inferior portions of the atria, efficiently pumping blood into the ventricles. [ 1 ]


The atrioventricular (AV) node is a second cluster of specialized myocardial conductive cells, located in the inferior portion of the right atrium within the atrioventricular septum. The septum prevents the impulse from spreading directly to the ventricles without passing through the AV node. There is a critical pause before the AV node depolarizes and transmits the impulse to the atrioventricular bundle. This delay in transmission is partially attributable to the small diameter of the cells of the node, which slow the impulse. Also, conduction between nodal cells is less efficient than between conducting cells. These factors mean that it takes the impulse approximately 100 ms to pass through the node. This pause is critical to heart function, as it allows the atrial cardiomyocytes to complete their contraction that pumps blood into the ventricles before the impulse is transmitted to the cells of the ventricle itself. With extreme stimulation by the SA node, the AV node can transmit impulses maximally at 220 per minute. This establishes the typical maximum heart rate in a healthy young individual. Damaged hearts or those stimulated by drugs can contract at higher rates, but at these rates, the heart can no longer effectively pump blood. [ 1 ]


Arising from the AV node, the bundle of His, proceeds through the interventricular septum before dividing into two  bundle branches , commonly called the left and right bundle branches. The left bundle branch has two fascicles. The left bundle branch supplies the left ventricle, and the right bundle branch the right ventricle. Since the left ventricle is much larger than the right, the left bundle branch is also considerably larger than the right. Portions of the right bundle branch are found in the moderator band and supply the right papillary muscles. Because of this connection, each papillary muscle receives the impulse at approximately the same time, so they begin to contract simultaneously just prior to the remainder of the myocardial contractile cells of the ventricles. This is believed to allow tension to develop on the chordae tendineae prior to right ventricular contraction. There is no corresponding moderator band on the left. Both bundle branches descend and reach the apex of the heart where they connect with the Purkinje fibers. This passage takes approximately 25 ms. [ 1 ]


The Purkinje fibers are additional myocardial conductive fibers that spread the impulse to the myocardial contractile cells in the ventricles. They extend throughout the myocardium from the apex of the heart toward the atrioventricular septum and the base of the heart. The Purkinje fibers have a fast inherent conduction rate, and the electrical impulse reaches all of the ventricular muscle cells in about 75 ms. Since the electrical stimulus begins at the apex, the contraction also begins at the apex and travels toward the base of the heart, similar to squeezing a tube of toothpaste from the bottom. This allows the blood to be pumped out of the ventricles and into the aorta and pulmonary trunk. The total time elapsed from the initiation of the impulse in the SA node until depolarization of the ventricles is approximately 225 ms. [ 1 ]


Action potentials are considerably different between conductive and contractive cardiomyocytes. While sodium  Na +  and potassium  K +  ions play essential roles,  calcium ions  Ca 2+  are also critical for both types of cell. Unlike skeletal muscles and neurons, cardiac conductive cells do not have a stable resting potential. Conductive cells contain a series of sodium  ion channels  that allow a normal and slow influx of sodium ions that causes the membrane potential to rise slowly from an initial value of −60 mV up to about –40 mV. The resulting movement of sodium ions creates spontaneous  depolarization  (or prepotential depolarization). [ 1 ]


At this point,  calcium channels  open and Ca 2+  enters the cell, further depolarizing it at a more rapid rate until it reaches a value of approximately +5 mV. At this point, the calcium ion channels close and  potassium channels  open, allowing outflux of K +  and resulting in repolarization. When the membrane potential reaches approximately −60 mV, the K +  channels close and Na +  channels open, and the prepotential phase begins again. This process gives the autorhythmicity to cardiac muscle. [ 1 ]


There is a distinctly different electrical pattern involving the contractile cells. In this case, there is a rapid depolarization, followed by a plateau phase and then repolarization. This phenomenon accounts for the long  refractory periods  required for the cardiac muscle cells to pump blood effectively before they are capable of firing for a second time. These cardiac myocytes normally do not initiate their own electrical potential, although they are capable of doing so, but rather wait for an impulse to reach them. [ 1 ]


Contractile cells demonstrate a much more stable resting phase than conductive cells at approximately −80 mV for cells in the atria and −90 mV for cells in the ventricles. Despite this initial difference, the other components of their action potentials are virtually identical. In both cases, when stimulated by an action potential, voltage-gated channels rapidly open, beginning the positive-feedback mechanism of depolarization. This rapid influx of positively charged ions raises the membrane potential to approximately +30 mV, at which point the sodium channels close. The rapid depolarization period typically lasts 3–5 ms. Depolarization is followed by the plateau phase, in which membrane potential declines relatively slowly. This is due in large part to the opening of the slow Ca 2+  channels, allowing Ca 2+  to enter the cell while few K +  channels are open, allowing K +  to exit the cell. The relatively long plateau phase lasts approximately 175 ms. Once the membrane potential reaches approximately zero, the Ca 2+  channels close and K +  channels open, allowing K +  to exit the cell. The repolarization lasts approximately 75 ms. At this point, membrane potential drops until it reaches resting levels once more and the cycle repeats. The entire event lasts between 250 and 300 ms. [ 1 ]


The absolute refractory period for cardiac contractile muscle lasts approximately 200 ms, and the relative refractory period lasts approximately 50 ms, for a total of 250 ms. This extended period is critical, since the heart muscle must contract to pump blood effectively and the contraction must follow the electrical events. Without extended refractory periods, premature contractions would occur in the heart and would not be compatible with life. [ 1 ]


Calcium ions play two critical roles in the physiology of cardiac muscle. Their influx through slow calcium channels accounts for the prolonged plateau phase and absolute refractory period. Calcium ions also combine with the regulatory protein  troponin  in the  troponin complex . Both roles enabling the myocardium to function properly. [ 1 ]


Approximately 20 percent of the calcium required for contraction is supplied by the influx of Ca 2+  during the plateau phase. The remaining Ca 2+  for contraction is released from storage in the sarcoplasmic reticulum. [ 1 ]


The pattern of prepotential or spontaneous depolarization, followed by rapid depolarization and repolarization just described, are seen in the SA node and a few other conductive cells in the heart. Since the SA node is the pacemaker, it reaches threshold faster than any other component of the conduction system. It will initiate the impulses spreading to the other conducting cells. The SA node, without nervous or endocrine control, would initiate a heart impulse approximately 80–100 times per minute. Although each component of the conduction system is capable of generating its own impulse, the rate progressively slows from the SA node to the Purkinje fibers. Without the SA node, the AV node would generate a heart rate of 40–60 beats per minute. If the AV node were blocked, the atrioventricular bundle would fire at a rate of approximately 30–40 impulses per minute. The bundle branches would have an inherent rate of 20–30 impulses per minute, and the Purkinje fibers would fire at 15–20 impulses per minute. While a few exceptionally trained aerobic athletes demonstrate resting heart rates in the range of 30–40 beats per minute (the lowest recorded figure is 28 beats per minute for  Miguel Indurain , a cyclist)–for most individuals, rates lower than 50 beats per minute would indicate a condition called bradycardia. Depending upon the specific individual, as rates fall much below this level, the heart would be unable to maintain adequate flow of blood to vital tissues, initially resulting in decreasing loss of function across the systems, unconsciousness, and ultimately death. [ 1 ]


The period of time that begins with contraction of the atria and ends with ventricular relaxation is known as the cardiac cycle. The period of contraction that the heart undergoes while it pumps blood into circulation is called systole. The period of relaxation that occurs as the chambers fill with blood is called diastole. Both the atria and ventricles undergo systole and diastole, and it is essential that these components be carefully regulated and coordinated to ensure blood is pumped efficiently to the body. [ 1 ]


Fluids, move from regions of high pressure to regions of lower pressure. Accordingly, when the heart chambers are relaxed (diastole), blood will flow into the atria from the higher pressure of the veins. As blood flows into the atria, the pressure will rise, so the blood will initially move passively from the atria into the ventricles. When the action potential triggers the muscles in the atria to contract (atrial systole), the pressure within the atria rises further, pumping blood into the ventricles. During ventricular systole, pressure rises in the ventricles, pumping blood into the pulmonary trunk from the right ventricle and into the aorta from the left ventricle. [ 1 ]


At the beginning of the cardiac cycle, both the atria and ventricles are relaxed (diastole). Blood is flowing into the right atrium from the superior and inferior venae cavae and the coronary sinus. Blood flows into the left atrium from the four pulmonary veins. The two atrioventricular valves, the tricuspid and mitral valves, are both open, so blood flows unimpeded from the atria and into the ventricles. Approximately 70–80 percent of ventricular filling occurs by this method. The two semilunar valves, the pulmonary and aortic valves, are closed, preventing backflow of blood into the right and left ventricles from the pulmonary trunk on the right and the aorta on the left. [ 1 ]


Contraction of the atria follows depolarization, represented by the  P wave  of the ECG. As the atrial muscles contract from the superior portion of the atria toward the atrioventricular septum, pressure rises within the atria and blood is pumped into the ventricles through the open atrioventricular (tricuspid, and mitral or bicuspid) valves. At the start of atrial systole, the ventricles are normally filled with approximately 70–80 percent of their capacity due to inflow during diastole. Atrial contraction, also referred to as the "atrial kick," contributes the remaining 20–30 percent of filling. Atrial systole lasts approximately 100 ms and ends prior to ventricular systole, as the atrial muscle returns to diastole. [ 1 ]   hala' Bold text'


Ventricular systole follows the depolarization of the ventricles and is represented by the  QRS complex  in the ECG. It may be conveniently divided into two phases, lasting a total of 270 ms. At the end of atrial systole and just prior to ventricular contraction, the ventricles contain approximately 130 mL blood in a resting adult in a standing position. This volume is known as the end diastolic volume (EDV) or preload. [ 1 ]


Initially, as the muscles in the ventricle contract, the pressure of the blood within the chamber rises, but it is not yet high enough to open the semilunar (pulmonary and aortic) valves and be ejected from the heart. However, blood pressure quickly rises above that of the atria that are now relaxed and in diastole. This increase in pressure causes blood to flow back toward the atria, closing the tricuspid and mitral valves. Since blood is not being ejected from the ventricles at this early stage, the volume of blood within the chamber remains constant. Consequently, this initial phase of ventricular systole is known as isovolumic contraction, also called isovolumetric contraction. [ 1 ]


In the second phase of ventricular systole, the ventricular ejection phase, the contraction of the ventricular muscle has raised the pressure within the ventricle to the point that it is greater than the pressures in the pulmonary trunk and the aorta. Blood is pumped from the heart, pushing open the pulmonary and aortic semilunar valves. Pressure generated by the left ventricle will be appreciably greater than the pressure generated by the right ventricle, since the existing pressure in the aorta will be so much higher. Nevertheless, both ventricles pump the same amount of blood. This quantity is referred to as  stroke volume . Stroke volume will normally be in the range of 70–80 mL. Since ventricular systole began with an EDV of approximately 130 mL of blood, this means that there is still 50–60 mL of blood remaining in the ventricle following contraction. This volume of blood is known as the end systolic volume (ESV). [ 1 ]


Ventricular relaxation, or diastole, follows repolarization of the ventricles and is represented by the  T wave  of the ECG. It too is divided into two distinct phases and lasts approximately 430 ms. [ 1 ]


During the early phase of ventricular diastole, as the ventricular muscle relaxes, pressure on the remaining blood within the ventricle begins to fall. When pressure within the ventricles drops below pressure in both the pulmonary trunk and aorta, blood flows back toward the heart, producing the dicrotic notch (small dip) seen in blood pressure tracings. The semilunar valves close to prevent backflow into the heart. Since the atrioventricular valves remain closed at this point, there is no change in the volume of blood in the ventricle, so the early phase of ventricular diastole is called the isovolumic ventricular relaxation phase, also called isovolumetric ventricular relaxation phase. [ 1 ]


In the second phase of ventricular diastole, called late ventricular diastole, as the ventricular muscle relaxes, pressure on the blood within the ventricles drops even further. Eventually, it drops below the pressure in the atria. When this occurs, blood flows from the atria into the ventricles, pushing open the tricuspid and mitral valves. As pressure drops within the ventricles, blood flows from the major veins into the relaxed atria and from there into the ventricles. Both chambers are in diastole, the atrioventricular valves are open, and the semilunar valves remain closed. The cardiac cycle is complete. [ 1 ]


One of the simplest methods of assessing the heart's condition is to  listen  to it using a  stethoscope . [ 1 ]  In a healthy heart, there are 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". [ 1 ]  Each sound consists of two components, reflecting the slight difference in time as the two valves close. [ 9 ]  S2 may  split  into two distinct sounds, either as a result of inspiration or different valvular or cardiac problems. [ 9 ]  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. [ 1 ]


Heart murmurs  are abnormal heart sounds which can be either pathological or benign and there are numerous kinds. [ 10 ]  Murmurs are graded by volume, from 1) the quietest, to 6) the loudest, and evaluated by their relationship to the heart sounds and position in the cardiac cycle. [ 9 ]   Phonocardiograms  can record these sounds. [ 1 ]  Murmurs can result from narrowing (stenosis), regurgitation or insufficiency of any of the main heart valves but they can also result from a number of other disorders, including  atrial  and  ventricular septal defects . [ 9 ]  One example of a murmur is  Still's murmur , which presents a musical sound in children, has no symptoms and disappears in adolescence. [ 11 ]


A different type of sound, a  pericardial friction rub  can be heard in cases of pericarditis where the inflamed membranes can rub together. [ 12 ]


The resting heart rate of a newborn can be 120 beats per minute (bpm) and this gradually decreases until maturity and then gradually increases again with age. The adult resting heart rate ranges from 60 to 100 bpm. Exercise and fitness levels, age and  basal metabolic rate  can all affect the heart rate. 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 and 220 bpm. [ 1 ]


The normal  sinus rhythm  of the heart rate is generated by the  SA node . It is also influenced by  central  factors through  sympathetic  and  parasympathetic  nerves [ 3 ] : 116–22   of the two paired  cardiovascular centres  of the  medulla oblongata . Activity is increased via sympathetic stimulation of the cardioaccelerator nerves, and inhibited via parasympathetic stimulation by the  vagus nerve . During rest vagal stimulation normally predominates as, left unregulated, the SA node would initiate a  sinus rhythm  of approximately 100 bpm. [ 1 ]


Both sympathetic and parasympathetic stimuli flow through the paired  cardiac plexus  near the base of the heart. Without any nervous stimulation, the SA node would establish a sinus rhythm of approximately 100 bpm. Since resting rates are considerably less than this, it becomes evident that parasympathetic stimulation normally slows HR. [ 1 ]  The cardioaccelerator center also sends additional fibers, forming the cardiac nerves via sympathetic ganglia (the cervical ganglia plus superior thoracic ganglia T1–T4) to both the SA and AV nodes, plus additional fibers 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. This shortens the repolarization period, thus speeding the rate of depolarization and contraction, which results in an increased heartrate. It opens chemical or ligand-gated sodium and calcium ion channels, allowing an influx of positively charged ions. [ 1 ]  Norepinephrine binds to the beta–1 receptor.  High blood pressure  medications are used to block these receptors and so reduce the heart rate. [ 1 ]