The MADIT II trial started in 1997 and ended in 2001 where the safety committee stopped the study because the benefits were already statistically significant.


The study included patients with a prior  myocardial infarction  and an  ejection fraction  less than or equal to 30%.


The results were a reduction in mortality of 31% compared to patients receiving conventional therapy alone.


This  medical treatment –related article is a  stub . You can help Wikipedia by  expanding it .


Myocardial depressant factor  (MDF) or  Myocardial Toxic factor  (MTF) is a low-molecular-weight  peptide [ 1 ]  released from the  pancreas  into the blood in mammals during various  shock  states. [ 2 ]


MDF is a significant mediator of shock pathophysiology, reducing  myocardial  contractility, constricting  splanchnic  arteries and impairing  phagocytosis  by the  reticuloendothelial system . Survival can be improved by preventing its release or blocking its activity, for example using  glucocorticoids ,  prostaglandins ,  aprotinin ,  captopril ,  imidazole  or  lidocaine . [ citation needed ]


This  molecular biology  article is a  stub . You can help Wikipedia by  expanding it .


Myocardial injury after non-cardiac surgery , also known as  MINS , refers to at least one elevated post-operative  troponin  level presumed to be of an ischemic mechanism. [ 1 ] [ 2 ]  There is an absence of any overt non-ischemic causes to explain this elevation.


National Medical Research Center for Cardiology named after academician  Yevgeniy Chazov  of the  Ministry of Health of the Russian Federation  ( Russian :  ФГБУ «Национальный медицинский исследовательский центр кардиологии имени академика Е.И. Чазова» (НМИЦ кардиологии) Министерства здравоохранения Российской Федерации )  is one of the leading and oldest specialized medical institutions in Russia, whose activities are aimed at diagnosing, treating and preventing cardiovascular diseases. [ 1 ]


The history of the cardiological complex dates back to 1945, when the Institute of Experimental and Clinical Therapy of the  USSR Academy of Medical Sciences  was organized on the basis of the clinics of the All-Union Institute of Experimental Medicine. The first director of the institute was the therapist, doctor of medical sciences, academician of the Academy of Medical Sciences V. F. Zelenin. [ 2 ]


Three years later, the Institute of Clinical Therapy was reorganized into the Institute of Therapy, and Academician A. L. Myasnikov was appointed director, who, upon taking office, identified priority areas for study:  hypertension  and atherosclerosis. Soon the institute became the leading institution in the Soviet Union dealing with cardiovascular pathologies. However, for further development, the institute needed to expand its staff and territory. This became possible after moving to Petroverigsky Lane. The priority areas of the Institute's activities include  coronary circulation  and its regulation,  renal circulation  and arterial hypertension; research on  atherosclerosis  has also expanded significantly. [ 2 ]  In 1963, the Institute established the first specialized department in the  Soviet Union  for the treatment of  acute myocardial infarction . [ 2 ]


In 1965, after the death of A. L. Myasnikov,  Yevgeniy Chazov  who worked also in the  Kremlin Hospital  became the director. A year later, the institute received the name of the former director and became known as the Research Institute of Therapy named after. A. L. Myasnikov, and a year later changed the name to the Institute of Cardiology. A. L. Myasnikova. At that time, the institute carried out extensive research on the possibilities of diagnosing and treating secondary forms of arterial hypertension. An experimental laboratory for cardiac electrophysiology was also founded, where two antiarrhythmic drugs, ethmozine and ethacizine, were created. [ 2 ]


On May 16, 1973, the first clinical echocardiographic study was carried out at the institute. Yuri Belenkov, an employee of the institute, becomes a pioneer in the development and implementation of this diagnostic method into wide practice. In 1975, by a decree of the  Council of Ministers of the USSR , the All-Union Cardiology Research Center (VKSC) was created, the composition of which was constantly increasing, and by 1981 it included the Research Institute of Cardiology named after. A. L. Myasnikova, Institute of Experimental Cardiology and Institute of Preventive Cardiology. [ 2 ]  On June 5 of the same year, in the Department of Emergency Cardiology of the VKSC, for the first time in the world, a patient with myocardial infarction underwent thrombolysis using intracoronary administration of fibrinolysin at a dose 10 times lower than with intravenous administration, which led to the creation of a new method of treatment -  thrombolytic therapy .


On August 24, 1982 [ 3 ]  The Institute of Clinical Cardiology and the Institute of Experimental Cardiology move to a new complex of 26 buildings on 3rd Cherepkovskaya Street. The work of a group of architects (I.M. Vinogradsky, V.K. Legoshin and others) on this complex of buildings was awarded the USSR State Prize in Literature, Art and Architecture in 1990.


In 1984, the Department of Cardiac Surgery was opened, headed by Academician R.S. Akchurin. In 1988, the Institute of Preventive Cardiology was withdrawn from the VKSC, which was later transformed into the Center for Preventive Medicine. In 1996, by an  order  of the  Government of Russia , the center received the name of the Russian Cardiology Research and Production Complex (RKNPC) of the Ministry of Health of Russia. [ 2 ]


In 2016, plans were announced for the reconstruction and expansion of building 9b of the RKNPC, which houses the cardio-reanimation ward [ 4 ]  The reconstruction provides for a change in the space-planning decisions of the building, with placement on the first floor of a therapeutic inpatient department for 30 beds. [ 5 ]


On May 1, 2017, in accordance with the order of the  Minister of Health of the Russian Federation , Corresponding Member of the  Russian Academy of Sciences , Doctor of Medical Sciences, Professor Sergey Boytsov was appointed General Director. [ 6 ]


On July 12, 2017, the RKNPC was renamed the National Medical Research Center for Cardiology.


In cardiology  neocardiogenesis  is the  homeostatic  regeneration, repair and renewal of sections of malfunctioning adult cardiovascular tissue.  This includes a combination of  cardiomyogenesis  (the regeneration of  cardiac muscle ) and  angiogenesis  (the regeneration of  blood vessels ). [ 1 ]


The term neocardiogenesis comes from  cardiogenesis , which refers to the development of the heart in the embryo; neocardiogenesis, in turn, means the development of the heart in adults.  The heart has mechanisms already in place that are responsible for small scale repair.  However, these repair mechanisms are not sufficient for large scale repair, made necessary by events such as  myocardial infarctions .  Neocardiogenesis replaces dead cardiac muscle cells with living cells so that both the structure and function of the heart are maintained.  This improves myocardial pumping of fluid around the body. [ 2 ]


The human heart has been thought of as a  postmitotic  organ.  Cardiomyocytes  (muscle cells of the heart) were thought to be terminally differentiated cells that were irreplaceable and thus required to maintain cardiac function throughout life. However it is now known that the heart is able to regenerate new small vessels needed to repair an  ischemic  (lacking blood) myocardium. The belief that humans are born with a fixed number of cardiomyocytes, and that the growth of these cells was directly responsible for the growth of the heart, has also been disproven. [ 3 ]  Reports of the heart's ability to repair itself have started to appear in peer reviewed journals [ 4 ]  and a paper has been published that has shown the potential of bone marrow cells to regenerate myocardium (myogenesis). [ 5 ]  Other studies into the regeneration of myocardium have reported evidence of angiogenesis, [ 6 ]  although such studies have been found to contain discrepancies. [ 7 ]


It has been reported that improvement in heart contractility has occurred as a result of the induction of angiogenesis. [ 8 ]


The activation of cardiac  progenitor cells  (a special type of stem cell with long  telomeres  located in the storage areas of the heart) and circulating stem cells induce cardiomyocytes to  proliferate .  These cells are activated by a mixture of transcriptional factors, genes, growth factors, receptors, the  extracellular matrix  and signalling pathways. The cells then move to affected areas where they can reverse some of the damage by generating a new population of cardiomyocytes. [ 9 ]


The heart has the potential to repair itself when damaged using progenitor and  stem cells . [ 10 ]   Clinical trials have shown that heart muscle has not previously been able to regenerate itself.  New noninvasive drugs, which may make this possible in humans, are required to induce the cardiac myocytes to proliferate.  Studies have been done in an attempt to find such a treatment. [ 11 ]


Neurocardiology  is the study of the  neurophysiological ,  neurological  and  neuroanatomical  aspects of  cardiology , including especially the neurological origins of cardiac disorders. [ 1 ]  The effects of stress on the  heart  are studied in terms of the heart's interactions with both the  peripheral nervous system  and the  central nervous system .


Clinical issues in neurocardiology include  hypoxic – ischemic  brain injury, neurogenic  stress cardiomyopathy , cerebral  embolism ,  encephalopathy , neurologic sequelae of cardiac and thoracic surgery and cardiac interventions, and cardiovascular findings in patients with primary neurological disease. [ 2 ]


Neurocardiology refers to the pathophysiological interplays of the nervous and cardiovascular systems. [ 3 ]  The constant communication between the heart and the brain have proved invaluable to the interdisciplinary fields of neurological and cardiac diseases. [ 4 ]


The fundamental understanding of the communication between the heart and the brain via the nervous system has led scientists towards an understanding of its elaborate circuitry. The brain emits neurological signals of oscillating frequencies. The neural rhythms provide information on the steady-state conditions of healthy individuals. Variations in the neural rhythms provide evidence that a problem is present regarding physiologic regulation and help physicians to more quickly determine the underlying condition based on the given symptoms. [ 5 ]


The  neurocardiac axis  links the cardiovascular and nervous systems to physiological problems such as arrhythmias, epilepsy and stroke. These problems are related to the fundamental factor of stress on the body. As stated previously, the changes in neural oscillations can contribute to the knowledge of what a steady state in an individual looks like, especially because it changes based on the person, as well as contributing to the imbalance of the nervous system and physiological function. Moreover, the brain can control the heart rate through the sympathetic nervous system. [ 5 ]


The cardiovascular system is regulated by the autonomic nervous system, which includes the sympathetic and parasympathetic nervous systems. A distinct balance between these systems is crucial for the pathophysiology of cardiovascular disease. An imbalance can be caused by  hormone  levels, lifestyle, environmental stressors and injuries. [ 6 ]


The complicated link between the brain and the heart can be mapped out from the complex of higher nervous system influences descending down to the heart. This complex innervates key autonomic structures from the brain's cortex to the heart along the neurocardiac axis. The heart is both the source of life and a source of cardiac arrhythmias and complications. The information originates in the brain's cortex and descends down to the  hypothalamus . The neural signals are then transferred to the  brainstem , followed by the  spinal cord —the location from which the heart receives all its signals. In further detail, the heart receives its neural input through parasympathetic and sympathetic ganglia and the  lateral grey column  of the spinal cord. [ 7 ]


The neurocardiac axis is the link to many problems regarding the physiological functions of the body. This includes cardiac ischemia, stroke, epilepsy, heart arrhythmias and cardiac myopathies. Many of these problems are due to the imbalance of the nervous system, resulting in symptoms that affect both the heart and the brain. [ 6 ]
 The connection between the cardiovascular and nervous system has raised concerns in the training processes for medical students. Neurocardiology is based on an understanding that systems within the body are interconnected. When training within one specialty, doctors are more likely to associate patients' symptoms with their field. Without taking integration into account, doctors can consequently delay a correct diagnosis and treatment for the patient. [ 7 ]  However, by specializing in a field, advancement in medicine continues as new findings come into perspective. [ citation needed ]


Cardiovascular systems are regulated by the  autonomic nervous system , which includes the sympathetic and  parasympathetic nervous systems . A distinct balance between these two systems is crucial for the pathophysiology of cardiovascular disease.  Chronic stress  has been widely studied for its effects on the body, resulting in an elevated heart rate (HR), reduced HR variability, elevated sympathetic tone and intensified cardiovascular activity. Consequently, stress promotes an autonomic imbalance in favor of the  sympathetic nervous system . The activation of the sympathetic nervous system contributes to  endothelial  dysfunction,  hypertension ,  atherosclerosis , insulin resistance and increased incidence of arrhythmias. [ 6 ]   An imbalance in the autonomic nervous system has been documented in mood disorders; it is commonly regarded as a mediator between mood disorders and cardiovascular disorders. [ citation needed ]


The hypothalamus is the part of the brain that regulates function and responds to stress. When the brain perceives environmental danger, the  amygdala  fires a nerve impulse to the  hypothalamus  to initiate the body's fight-or-flight mode through the sympathetic nervous system. The stress response starts with the hypothalamus stimulating the  pituitary gland , which releases the  adrenocorticotropic hormone . This signals the release of  cortisol , the stress hormone, initiating a multitude of physical effects on the body to aid in survival. A  negative feedback loop  is then needed to return the body to its resting state by signaling the parasympathetic nervous system. [ 8 ]


Prolonged stress leads to many hazards within the nervous system. Various hormones and glands become overworked, and chemical waste is produced, resulting in the degeneration of nerve cells. The result of prolonged stress is the breakdown of the body and the nervous system. Stress alone does not produce potentially deadly arrhythmias in normal healthy hearts; however, studies do appear to show that stress causes cardiac damage that may lead to arrhythmias. [ citation needed ]


In a study relating to the relationship between neurocardiology and  arrhythmias  and sudden cardiac death, the authors hypothesized that an individual with a diseased heart has a greater likelihood of experiencing cardiac arrhythmias and sudden cardiac death when the neurocardiac axis is activated. [ 7 ]  An arrhythmia is defined as any disturbance in the cardiac activation sequence or any deviation from accepted limits for the rate or regularity of the normal impulse. The main types of arrhythmias leading to sudden cardiac death are tachyarrhythmias and bradyarrhythmia. Tachyarrhythmias are associated with ventricular fibrillation and  ventricular tachycardia . Bradyarrhythmias are associated with complete atrioventricular blockage and sudden asystole. The underlying cause of sudden cardiac death is unclear, despite the understanding that heart disease causes arrhythmias, which in turn produce sudden cardiac death. [ 7 ]  Lown describes the heart as the target, and the brain as the trigger. If a sudden cardiac death is triggered by an electrical accident, it can be treated with ventricular defibrillation. [ 9 ]


Stroke activates the neurocardiac axis, producing arrhythmias, cardiac damage, and sudden death. In a recent study on patients with already diseased hearts and  electrocardiographic  abnormalities, there was evidence of lost hypothalamic–medullary integration at the midbrain. This resulted in the observation that overactivity in the parasympathetic nervous system may also cause sudden death with  asystole  after stroke.  Catecholamine  medications have been studied for their ability to mediate the effects of electrocardiographic changes and heart damage. [ 7 ]


Sudden death from epilepsy is not very common, with a rate of approximately two cases in every thousand. The present understanding about how sudden cardiac death can result from epilepsy is that the brain stimulates an arrhythmia. Recordings during seizures report that the onset of tachycardia just prior to the seizure is common, with both atrial and ventricular ectopy. [ 7 ]  A sudden epileptic death may be a result of the sympathetic activation or autonomic imbalance of the nervous system, as described earlier. [ citation needed ]


The relationship between emotions and their effect on the destabilization of the heart continues to be a mystery. It is considered that both the spatial and temporal patterns of autonomic input to the heart play a key role in altered electrophysiological parameters. The body continually attempts to maintain homeostasis through the  baroreflex . This balance in the autonomic neural input to the heart in response to the pressure and volume changes leads to alterations in the  baroreceptors . [ 10 ]


Drugs with both antidepressant and cardiometabolic actions are in the process of being studied. Most medications work on stressors of the heart and some also work to treat neuropsychiatric diseases. Antidepressant medications have shown to be insufficient to induce the normalization of cardiovascular dysfunctions, which are associated with psychiatric conditions. [ 11 ]


Lifestyle modifications play a crucial role in the management of cardiovascular and neurological diseases. Physical activity and a well-balanced diet favor cardiovascular conditioning and improve performance and capacity. Exercise has a positive effect on the metabolism, which controls glucose levels, especially for stress-related pathology and brain disorders such as depression, which impose a heavy burden on the cardiovascular system. Many studies are currently being conducted to gather more information regarding the common mediators of cardiovascular disease and the central nervous system. The brain–heart interaction is considered bidirectional; however, the central nervous system is often regulated more strongly than the heart and blood vessels. [ 6 ]


Pacemaker crosstalk  results when the  pacemaker -generated electrical event in one  heart chamber  is sensed by the lead in another chamber, resulting in inappropriate inhibition of the pacing artifact in the second chamber. [ 1 ]


Crosstalk can only occur in a dual chamber or  biventricular pacemaker . It happens less often in more recent models of dual chamber pacemakers due to the addition of a  ventricular  blanking period, which coincides with the  atrial  stimulus. This helps to prevent ventricular channel oversensing of atrial output. Newer dual chamber pacemakers also use  bipolar  leads with a smaller pacing spike, and  steroid  eluting leads with lower pacing thresholds. Crosstalk is more common in unipolar systems since they require a larger pacing spike. Crosstalk is sometimes referred to as crosstalk inhibition, far-field sensing, or self-inhibition. In some cases, crosstalk can occur in the  pulse generator   circuit  itself, though more common causes include atrial lead dislodgement into the ventricle, ventricular lead dislodgement into the atrium, high atrial output current, high ventricular sensitivity, and short ventricular blanking period. [ 1 ]


In general, the treatment of crosstalk includes decreasing atrial pacing output, decreasing atrial  pulse width , decreasing ventricular sensitivity, increasing the ventricular blanking period, activating ventricular safety pacing, and new atrial lead  implant  if insulation failure mandates unipolar programming. [ 1 ]


Parachute mitral valve  (or  PMV ) is a rare  congenital heart disease  where the  mitral valve  only has a single papillary muscle from which all  chordae tendineae  originate. It is caused by an embryologic failure of papillary muscles to divide into two normally distinct columns, giving the mitral valve orifice and chordea an irregular, parachute-like appearance. Due to the abnormal anatomy, there are almost always associated mitral valve disorders, and because of its abnormal embryologic origin, PMV almost always coincides in a complex of other congenital heart defects. [ 1 ]  PMV is usually identified during infancy or childhood due to its symptomatic nature, and hardly ever diagnosed during adulthood.


As a result of the thickened and shortened chordae, there is a restriction of the inflow of blood to mitral valve annulus and subannulus causing a narrowing known as  mitral stenosis  which increases the pressure gradient through the valve. Also, abnormal closure of the mitral valve leaflets or  mitral valve prolapse  will cause the valve significantly leak during closure known as  mitral valve insufficiency .


Parachute mitral valve is commonly associated with other congenital heart disease.  A 2004 study finds that children with PMV are 68% likely to have aortic coarctation, 54% likely to have an atrial septal defect, 46% likely to have a ventricular septal defect, and 19% likely to have left ventricular hypoplasia. [ 2 ]  Parachute mitral valve is also a part of the congenital complex of  Shone's Syndrome . [ 3 ]


Unfortunately, the overall outcome of the children diagnosed with parachute mitral valve especially with the other likely multilevel left-heart diseases is only somewhat satisfactory. [ 4 ]  However, with increasingly improved technology for mitral valve reconstructions, repairs and replacements procedures, outcomes are expected to improve in the future.


ParvE101Q  is an experimental modification of  parvalbumin , designed to delay  calcium  sequestration in heart muscles to enhance contraction. [ 1 ]  The protein parvalbumin has  EF hand  motifs used for calcium binding. [ 2 ]  EF hands are structural helix-loop-helix protein subunits that have a high affinity for calcium ions, and a moderate affinity for  magnesium  ions. [ 3 ]  In muscle, the binding of Ca 2+  by parvalbumin efficiently sequesters it following contraction. This increases the speed of muscle relaxation, allowing the muscle to contract again sooner. [ 1 ]  Although parvalbumin is classified as a  delayed calcium buffer , it quickly sequesters Ca 2+ , usually before the muscle is done fully contracting. [ 4 ]  Large amounts of parvalbumin allow rapid contractions of muscles at a high contractile speed with the trade-off of having relatively lower contraction force. [ 4 ]  This decreased force of contraction is due to the rapid sequestration of Ca 2+ , preventing prolonged contraction which is required for greater force.


It has been theorized that expressing a modified version of parvalbumin in the  heart  could have therapeutic use to aid heart contraction, and treat relaxation disorders. [ 5 ]  ParvE101Q is optimized so that relaxation is rapid, but contraction lasts for a sufficient time to fully eject blood. [ 1 ]   Amino acid  substitutions of  glutamine  for  glutamate  on the protein’s 101st amino acid were introduced, followed immediately by a  tryptophan  replacing a  phenylalanine  at site 102, as well as  alanine  replacing  aspartate  at site 51. By introducing these changes, the preferential binding of Ca 2+  and Mg 2+  were reversed. Instead of having high preference for Ca 2+  like parvalbumin, ParvE101Q has a preference for Mg 2+  first, and Ca 2+  second. [ 1 ]  This reversed binding preference allows the normal presence of Mg 2+  to delay the Ca 2+  sequestration of ParvE101Q. This delay allows heart contraction to last long enough to preserve blood ejection, then have the excess Ca 2+  bound and sequestered by ParvE101Q. The resulting increase in contractility is speculated to be due to the increased Mg 2+  binding affinity. By binding Mg 2+  first, ParvE101Q allows more Ca 2+  binding to  Troponin C , which is required for  myocyte  contraction. [ 1 ]  The result of the modification is an increased contractility and quicker relaxation in myocytes with no reported side-effects. [ 1 ]  This modified protein retains the heart’s ability to store calcium in the  sarcoplasmic reticulum , even under the added stress of  caffeine . Additionally, when treated with ParvE101Q,  calcium sparks  (spontaneous releases of Ca 2+  from the sarcoplasmic reticulum) are not different from normal. Other Ca 2+  handling proteins used for sequestration are not affected by ParvE101Q, and the effects are not dependent on temperature changes. [ 1 ]


Clinically, ParvE101Q shows promise in correcting  diastolic heart failure . Diastolic heart failure is a condition where the heart has trouble relaxing efficiently. As a result, less blood is pumped out of the ventricles and the blood trying to enter the heart can back up in the circulation to cause  hypertension , often in the lungs, and  congestive heart failure  develops. [ 6 ]  Additionally, the decreased ability of the heart to eject blood leads to perfusion problems to vital organs such as the heart’s  coronary arteries  and the  brain . ParvE101Q is being investigated for side effects, and optimal delivery mechanisms before moving on to experimental trials to treat conditions such as diastolic heart failure. Parvalbumin has diverse effects on  cell cycles ,  second messengers ,  microtubule  organization, cardiac muscle contraction, and the  nervous system . [ 7 ] [ 8 ]


Pathophysiology  is a study which explains the function of the body as it relates to diseases and conditions. The  pathophysiology of hypertension  is an area which attempts to explain mechanistically the causes of  hypertension , which is a chronic disease characterized by elevation of  blood pressure . Hypertension can be classified by cause as either  essential  (also known as primary or  idiopathic ) or  secondary . About 90–95% of hypertension is essential hypertension. [ 1 ] [ 2 ] [ 3 ] [ 4 ]   Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium.  Secondary hypertension  indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess  aldosterone ,  cortisol , or  catecholamines . Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease. [ 5 ]


Cardiac output  and  peripheral resistance  are the two determinants of  arterial pressure . [ 6 ]  Cardiac output is determined by  stroke volume  and  heart rate ; stroke volume is related to  myocardial contractility  and to the size of the  vascular compartment . Peripheral resistance is determined by functional and anatomic changes in small  arteries  and  arterioles .


Single gene mutations can cause  Mendelian  forms of  high blood pressure ; [ 7 ]  ten genes have been identified which cause these monogenic forms of  hypertension . [ 7 ] [ 8 ]  These mutations affect blood pressure by altering  kidney salt handling . [ 9 ] [ 10 ]  There is greater similarity in  blood pressure  within families than between families, which indicates a form of  inheritance , [ 11 ]  and this is not due to shared environmental factors. [ 12 ]  With the aid of  genetic analysis   techniques , a  statistically significant  linkage of blood pressure to several  chromosomal regions , including regions linked to familial combined  hyperlipidemia , was found. [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]  These findings suggest that there are many  genetic loci , in the general population, each with small effects on blood pressure. Overall, however, identifiable single-gene causes of hypertension are uncommon, consistent with a multifactorial cause of essential hypertension. [ 2 ] [ 10 ] [ 18 ] [ 19 ]


The  autonomic nervous system  plays a central role in maintaining cardiovascular homeostasis via  pressure ,  volume , and  chemoreceptor  signals. It does this by regulating the peripheral vasculature, and kidney function, which in turn affect  cardiac output ,  vascular resistance , and  fluid retention . Excess activity of the  sympathetic nervous system  increases blood pressure and contributes to hypertension. [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]


The mechanisms of increased sympathetic nervous system activity in hypertension involve alterations in  baroreflex  and  chemoreflex  pathways at both peripheral and central levels.  Arterial baroreceptors  are reset to a higher pressure in hypertensive patients, and this peripheral resetting reverts to normal when arterial pressure is normalized. [ 25 ] [ 26 ] [ 27 ]  Furthermore, there is  central  resetting of the  aortic baroreflex  in hypertensive patients, resulting in suppression of sympathetic inhibition after activation of aortic baroreceptor nerves. This baroreflex resetting seems to be mediated, at least partly, by a central action of  angiotensin II . [ 28 ] [ 29 ] [ 30 ]  Additional small-molecule  mediators  that suppress baroreceptor activity and contribute to exaggerated sympathetic drive in hypertension include  reactive oxygen species  and  endothelin . [ 31 ] [ 32 ]  Some studies have shown that hypertensive patients manifest greater  vasoconstrictor  responses to infused  norepinephrine  than  normotensive  controls. [ 33 ]  And that hypertensive patients do not show the normal response to increased circulating norepinephrine
levels which generally induces downregulation of  noradrenergic receptor , and it is believed that this abnormal response is  genetically   inherited . [ 34 ]


Exposure to  stress  increases sympathetic outflow, and repeated stress-induced vasoconstriction may result in  vascular hypertrophy , leading to progressive increases in  peripheral resistance  and blood pressure. [ 2 ]  This could partly explain the greater incidence of hypertension in  lower socioeconomic groups , since they must endure greater levels of stress associated with daily living. Persons with a family history of hypertension manifest augmented vasoconstrictor and sympathetic responses to laboratory stressors, such as  cold pressor testing  and  mental  stress, that may predispose them to hypertension. This is particularly true of young African Americans. Exaggerated stress responses may contribute to the increased incidence of hypertension in this group. [ 35 ]  For patients having hypertension, higher  heart rate variability  (HRV) is a risk factor for  atrial fibrillation . [ 36 ]


Resistant hypertension can be treated by electrically stimulating the  baroreflex  with a pacemaker-like device. [ 37 ]


Another system maintaining the  extracellular fluid volume ,  peripheral resistance , and that if disturbed may lead to hypertension, is the  renin–angiotensin–aldosterone system .  Renin  is a circulating  enzyme  that participates in maintaining  extracellular  volume and arterial  vasoconstriction , therefore contributing to regulation of  blood pressure . It performs this function by breaking down ( hydrolysing )  angiotensinogen , secreted from the liver, into the peptide  angiotensin I . Angiotensin I is further cleaved by an enzyme that is located primarily but not exclusively in the  pulmonary circulation  bound to  endothelium ; that enzyme is  angiotensin converting enzyme  (ACE). This cleavage produces  angiotensin II , the most vasoactive peptide. [ 38 ] [ 39 ]  Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature of arteries, raising peripheral resistance and thereby elevating blood pressure. Angiotensin II also causes the adrenal glands to release  aldosterone , which stimulates the epithelial cells of the kidneys to increase re-absorption of salt and water, leading to raised blood volume and raised blood pressure. So elevated  renin  levels in the blood (normally 1.98-2.46 ng/ml in the upright position) [ 40 ]  leads to hypertension. [ 2 ] [ 41 ]


Recent studies claim that obesity is a risk factor for hypertension because of activation of the  renin–angiotensin system  (RAS) in  adipose tissue , [ 42 ] [ 43 ]  and also linked  renin–angiotensin system  with  insulin resistance , and claims that anyone can cause the other. [ 44 ]  Local production of  angiotensin II  in various tissues, including the  blood vessels ,  heart ,  adrenals , and  brain , is controlled by  ACE  and other  enzymes , including the  serine protease   chymase . The activity of local renin–angiotensin systems and alternative pathways of angiotensin II formation may make an important contribution to remodeling of resistance  vessels  and the development of target organ damage (i.e.  left ventricular hypertrophy ,  congestive heart failure ,  atherosclerosis ,  stroke ,  end-stage kidney disease ,  myocardial infarction , and  arterial aneurysm ) in hypertensive persons. [ 41 ]


The  endothelium  of blood vessels produces an extensive range of substances that influence  blood flow  and, in turn, is affected by changes in the blood and the pressure of blood flow. For example, local  nitric oxide  and  endothelin , which are secreted by the endothelium, are the major regulators of vascular tone and blood pressure. In patients with essential hypertension, the balance between the  vasodilators  and the  vasoconstrictors  is upset, which leads to changes in the endothelium and sets up a " vicious cycle " that contributes to the maintenance of high blood pressure. In patients with hypertension,  endothelial activation  and damage also lead to changes in  vascular tone , vascular reactivity, and  coagulation  and  fibrinolytic pathways . Alterations in endothelial function are a reliable indicator of target organ damage and atherosclerotic disease, as well as prognosis. [ 45 ]


Evidence suggests that  oxidant stress  alters many functions of the  endothelium , including modulation of  vasomotor tone . Inactivation of  nitric oxide  ( NO ) by  superoxide  and other  reactive oxygen species  ( ROS ) seems to occur in conditions such as  hypertension . [ 46 ] [ 47 ] [ 48 ]  Normally  nitric oxide  is an important regulator and mediator of numerous processes in the  nervous ,  immune  and  cardiovascular systems , including  smooth muscle  relaxation thus resulting in  vasodilation  of the  artery  and increasing  blood flow , suppressor of migration and proliferation of vascular smooth-muscle cells. [ 2 ]  It has been suggested that  angiotensin II  enhances formation of the oxidant superoxide at concentrations that affect blood pressure minimally. [ 49 ]


Endothelin  is a potent vasoactive peptide produced by endothelial cells that has both  vasoconstrictor  and vasodilator properties. Circulating endothelin levels are increased in some hypertensive patients, [ 50 ] [ 51 ]  particularly  African Americans  and persons with hypertension. [ 50 ] [ 52 ] [ 53 ] [ 54 ]


A 2007 review article states that while excessive sodium consumption has long been recognized as contributing to the risk of hypertension, "potassium, the main intracellular cation, has usually been viewed as a minor factor in the pathogenesis of hypertension. However, abundant evidence indicates that a potassium deficit has a critical role in hypertension and its cardiovascular sequelae." The authors state that modern, western, high sodium, low potassium diets result in corresponding changes in intracellular concentration of these, the two most important cations in animal cells.  This imbalance leads to contraction of vascular smooth muscle, restricting blood flow and so driving up blood pressure.  The authors cite studies which show that potassium supplementation is effective in reducing hypertension. [ 55 ]


Epidemiological support for this hypothesis can be found in a 2014 meta-analysis which states that "the sodium-to-potassium ratio appears to be more strongly associated with blood pressure outcomes than either sodium or potassium alone in hypertensive adult populations.". [ 56 ]


Basic science discoveries have implicated the immune system as in the development of hypertension in animal models. [ 57 ]  Population studies in humans have reported that higher levels of certain inflammatory cytokines are associated with greater risk of hypertension development. [ 58 ] [ 59 ] [ 60 ]


Phidippides cardiomyopathy  refers to the  cardiomyopathic  changes that occur after long periods of  endurance training . This term was coined by Justin E. Trivax, MD, MPH, FACC, FSCAI, FSVM and his colleague  Peter A. McCullough  in 2012 following Dr. Trivax's research of marathon runners.  [ 1 ] [ 2 ]


In 490 BC, during the Greco-Persian War, Persian King Darius I launched an attack on the outnumbered Greeks, prompting the legendary Greek herald,  Phidippides  to run nearly 75 miles to Sparta for military support. Although the Spartans agreed to help, they could not leave immediately due to religious obligations, so Phidippides returned to Marathon, where he learned that the Greeks had defeated the Persians. After running another 26.2 miles to Athens to announce the victory, he collapsed and died after exclaiming, "We are victorious!" This was the first account of long-distance running resulting in mortality.


It has been proposed by Trivax et al. that strenuous exercise results in a cascade of events starting with the effects of training for long-distance events which may result in left ventricular dilation, left ventricular hypertrophy, and increased left ventricular mass. The acute effects of exercise including increased catecholamines, increased oxygen demand, increased preload and afterload, metabolic derangements, acute kidney injury, dehydration, elevation of troponin, CK, CK-MB, and natriuretic peptides. This results in right atrial and right ventricular strain and dilation, right ventricular hypokinesis and marked diastolic dysfunction. Subacute effects of exercise include increased expression of cardiac fibrotic markers including TGF, fibronectin-1, collagens, MMP-2 and TIMP1. Chronic effects include increased cardiac chamber sizes, patchy areas of fibrosis, atrial and ventricular arrhythmias and increased risk of sudden cardiac death.


This has been quoted in the literature multiple times and has been inaccurately thought that Dr. James O'Keefe had coined the term. [ 3 ]  He was speaking about the sudden death of  Micah True , a 58-year-old ultrarunner and cult hero a.k.a. Caballo Blanco who died on a 12-mile training jog in the rugged Gila Wilderness of southwest New Mexico. After an autopsy, the Albuquerque coroner wrote that “Micah True died as a result of cardiomyopathy during exertion”. Since then, multiple websites have warned their readers on the possible damage from prolonged endurance training. [ 4 ]


The suggested etiology for Phidippides cardiomyopathy is the cardiac remodeling from prolonged strenuous exercises. [ citation needed ]


The repeated prolonged states of volume overload in the right  atrium  and right  ventricle  from endurance training will lead to chronic structural changes. Long term changes include patches of  cardiac fibrosis  which can allow zones of re-entry for  cardiac arrhythmias . [ 2 ]


It is suggested that  Cardiac MRI  is the best imaging modality [ 1 ]  to investigate this condition.


There is not much evidence describing this condition and other than a case report, [ 1 ]  no other studies have corroborated the pathophysiological changes suggested by McCullough.


Not all experts agree with Trivax and McCullough.  Many feel that further research is necessary to understand this condition better. [ citation needed ]


The  photoplethysmogram  (PPG) measurement made at a peripheral site, such as the finger, ear or forehead represents the volume of blood in the vessel at the site of measurement. The PPG signal consists of pulses that reflect the change in vascular blood volume with each  cardiac  beat. Beat-to-beat fluctuations, known as  photoplethysmogram variability (PPGV)  are found in the signal baseline and  amplitude  which reflects various physiological influences such as  respiration  and regulation of vascular tone by the sympathetic nervous system.


The beat-to-beat variation of the PPG in time domain can be represented in the  frequency domain  by means of signal transformation methods, such as  fast Fourier transform  or autoregressive model. The spectrum can be divided into two main bands, that is, low frequency (LF) band ranging from 0.04 to 0.15 Hz and high frequency (HF) band between 0.15 and 0.6 Hz. The LF band can be subdivided into a mid-frequency (MF) band from 0.09 Hz to 0.15 Hz. [ 1 ]  The integration of the power  spectral density  over the frequency range will give the spectral power.
Low-frequency oscillation in the PPG is found to reflect the sympathetic control over the peripheral circulation, whilst the high frequency component is related to the mechanical consequence of respiration on venous return. [ 1 ] [ 2 ]


The PPGV was found to be useful in detecting blood loss by observing the spectral features of the PPGV. [ 3 ] [ 4 ] [ 5 ]
LF power, together with other features derived from the PPG waveform, was used to classify patients into different ranges of systemic vascular resistance, which may be used as an indicator of critical illness. [ 6 ]
It has been proposed that the PPGV can also be used as an indicator of peripheral circulatory abnormalities in  sepsis  patients. [ 7 ]  The application of PPGV as an indicator of sepsis has been extended by using spectral analysis of the PPGV to classify patients into different severity of sepsis. [ 1 ]


Portsmouth sign  refers to a situation in which the  systolic blood pressure  (SBP) reading (measured in  mmHg ) falls below that of the  heart rate  (HR) (measured in beats per minute). It typically signifies a worrying clinical prognosis, specifically caused by  shock . The sign takes its name from physicians working at  Portsmouth University  who first described the sign in the context of  hypotension . [ 1 ]


Portsmouth sign is most often noted clinically when reviewing observations charts which often plot SBP and HR on the same axis, allowing direct observation of situations in which SBP falls below HR. Patients exhibiting this sign are likely to be significantly fluid depleted and in urgent need of aggressive fluid resuscitation. This sign is part of a number of 'early warning' signs that can be used to promptly detect abnormal physiological states. [ 2 ]


Potassium-sparing diuretics  or  antikaliuretics [ 1 ]  refer to drugs that cause  diuresis  without causing  potassium  loss in the  urine . [ 2 ]  They are typically used as an  adjunct  in management of  hypertension ,  cirrhosis , and  congestive heart failure . [ 3 ]  The steroidal  aldosterone antagonists  can also be used for treatment of  primary hyperaldosteronism .  Spironolactone , a  steroidal   aldosterone antagonist , is also used in management of female  hirsutism  and  acne  from  PCOS  or  other causes . [ 4 ] [ 5 ]


Normally, sodium is reabsorbed in the  collecting tubules  of a renal  nephron . This occurs via epithelial sodium channels or ENaCs, located on the luminal surface of principal cells that line the collecting tubules. Positively-charged Na+ entering the cells during reabsorption leads to an electronegative luminal environment causing the secretion of potassium (K + ) into the lumen/ urine in exchange. [ 2 ]  Sodium reabsorption also causes water retention. [ 8 ] [ 9 ]


When the kidneys detect low blood pressure, the  renin–angiotensin–aldosterone system  (RAAS) is activated and eventually, aldosterone is secreted. Aldosterone binds to aldosterone receptors (mineralocorticoid receptors) increasing sodium reabsorption in an effort to increase blood pressure and improve fluid status in the body. When excessive sodium reabsorption occurs, there is an increasing loss of K +  in the urine and can lead to clinically significant decreases, termed  hypokalemia . Increased sodium reabsorption also increases water retention. [ 8 ] [ 9 ]


Potassium-sparing diuretics act to prevent sodium reabsorption in the collecting tubule by either binding ENaCs (amiloride, triamterene) or by inhibiting aldosterone receptors (spironolactone, eplerenone). This prevents excessive excretion of K +  in urine and decreased retention of water, preventing hypokalemia. [ 10 ]


Because these diuretics are weakly  natriuretic , they do not cause clinically significant blood pressure changes and thus, are not used as primary therapy for hypertension. [ 11 ]  They can be used in combination with other  anti-hypertensives  or drugs that cause hypokalemia to help maintain a  normal range  for potassium. For example, they are often used as an adjunct to  loop diuretics  (usually  furosemide ) to treat fluid retention in  congestive heart failure  and  ascites  in  cirrhosis . [ 11 ]


On their own this group of drugs may raise potassium levels beyond the normal range, termed  hyperkalemia , which risks potentially fatal  arrhythmias . Triamterene, specifically, is a potential nephrotoxin and up to half of the patients on it can have  crystalluria  or  urinary casts . [ 12 ] [ 13 ]  Due to its activity as an androgen receptor antagonist and progesterone receptor agonist, spironolactone causes adverse effects, including gynecomastia or decreased libido in males and menstrual abnormalities in females. [ 14 ]  Spironolactone also causes hyperkalemia [ 15 ]  and renal insufficiency. [ 16 ]


Spironolactone interacts with the following medications: [ 17 ]


- ACE inhibitors/ARBs: increases hyperkalemia risk


- Alcohol: risk of orthostatic hypotension


- Barbiturates: risk of orthostatic hypotension


- Narcotics: risk of orthostatic hypotension


- NSAIDs: increases hyperkalemia risk and decreases diuretic effect of potassium-sparing diuretics


- Digoxin: increases digoxin plasma concentrations, leading to increased toxicity


In  medicine , the  cardiac examination , also  precordial exam , is performed as part of a  physical examination , or when a patient presents with  chest pain  suggestive of a cardiovascular  pathology . It would typically be modified depending on the  indication  and integrated with other examinations especially the  respiratory examination . [ 1 ]


Like all medical examinations, the cardiac examination follows the standard structure of inspection, palpation and auscultation.


The patient is positioned in the  supine position  tilted up at 45 degrees if the patient can tolerate this. The head should rest on a pillow and the arms by their sides. The level of the jugular venous pressure (JVP) should only be commented on in this position as flatter or steeper angles lead to artificially elevated or reduced level respectively. Also, left ventricular failure leads to  pulmonary edema  which increases and may impede breathing if the patient is laid flat.


Lighting should be adjusted so that it is not obscured by the examiner who will approach from the right hand side of the patient as is medical custom.


The torso and neck should be fully exposed and access should be available to the legs.


General Inspection:


Inspect the hands for:


Inspect the head for:


Then inspect the precordium for:


The pulses should be palpated, first the  radial pulse  commenting on rate and rhythm then the brachial pulse commenting on character and finally the  carotid pulse  again for character.
The pulses may be:


The valve areas are palpated for abnormal pulsations (palpable  heart murmurs  known as  thrills ) and precordial movements (known as  heaves ).  Heaves are best felt with the heel of the hand at the  sternal  border.


The  apex beat  is found approximately in the fifth left  intercostal space  in the  mid-clavicular line . It can be impalpable for a variety of reasons including  obesity ,  emphysema ,  effusion  and rarely  dextrocardia . The apex beat is assessed for size, amplitude, location, impulse and duration. There are specific terms to describe the sensation such as tapping, heaving and thrusting.


Often the apex beat is felt diffusely over a large area, in this case the most inferior and lateral position it can be felt in should be described as well as the location of the largest amplitude.


Finally the  sacrum  and  ankles  are checked for  pitting edema  which is caused by  right ventricular failure  in isolation or as part of  congestive cardiac failure .


One should comment on


To complete the exam blood pressure should be checked, an  ECG  recorded,  funduscopy  performed to assess for  Roth spots  or  papilledema . A full peripheral circulation exam should be performed.


A plot of a system's  pressure versus volume  has long been used to measure the work done by the system and its efficiency. This analysis can be applied to  heat engines  and  pumps , including the  heart . A considerable amount of information on cardiac performance can be determined from the  pressure vs. volume  plot ( pressure–volume diagram ). A number of  methods  have been determined for measuring PV-loop values experimentally.


Real-time  left ventricular  (LV) pressure–volume loops provide a framework for understanding cardiac mechanics in experimental animals and humans. Such loops can be generated by real-time measurement of pressure and volume within the left ventricle. Several physiologically relevant  hemodynamic  parameters such as  stroke volume ,  cardiac output ,  ejection fraction ,  myocardial contractility , etc. can be determined from these loops.


To generate a PV loop for the left ventricle, the LV pressure is plotted against LV volume at multiple time points during a single  cardiac cycle .


Afterload  is the mean tension produced by a chamber of the heart in order to contract. It can also be considered as the ‘load’ that the heart must eject blood against. Afterload is, therefore, a consequence of aortic large vessel compliance, wave reflection, and small vessel resistance (LV afterload) or similar pulmonary artery parameters (RV afterload).


Left ventricular afterload is affected by various disease conditions.  Hypertension  increases the afterload, since the LV has to work harder to overcome the elevated arterial peripheral resistance and decreased compliance.  Aortic valve  diseases like  aortic stenosis  and  insufficiency  also increase the afterload, whereas  mitral valve regurgitation  decreases the afterload.


Preload  is described as the stretching of a single  cardiac myocyte  immediately prior to contraction and is, therefore, related to the  sarcomere  length. Since sarcomere length cannot be determined in the intact heart, other indices of preload such as ventricular  end-diastolic volume  or pressure are used.


As an example, preload increases when venous return is increased. This is because the end-diastolic pressure and volume of the ventricle are increased, which stretches the sarcomeres.
Preload can be calculated as


Stroke volume  (SV) is the volume of blood ejected by the right/left ventricle in a single contraction. It is the difference between the  end-diastolic volume  (EDV) and the  end-systolic volume  (ESV).


In mathematical terms,

 SV

 =

 EDV

 −

 ESV

 {\displaystyle {\text{SV}}={\text{EDV}}-{\text{ESV}}}


The stroke volume is affected by changes in preload, afterload, and inotropy (contractility). In normal hearts, the SV is not strongly influenced by afterload, whereas, in failing hearts, the SV is highly sensitive to afterload changes.
Stroke volume relative to EDV is  Ejection Fraction .


Ventricular stroke work (SW) is defined as the work performed by the left or right ventricle to eject the stroke volume into the  aorta  or  pulmonary artery , respectively. The area enclosed by the PV loop is a measure of the ventricular stroke work, which is a product of the stroke volume and the mean aortic or pulmonary artery pressure (afterload), depending on whether one is considering the left or the right ventricle.


Cardiac output  (CO) is defined as the amount of blood pumped by the ventricle in unit time.


In mathematical terms,

 CO

 =

 SV

 ×

 Heart Rate

 {\displaystyle {\text{CO}}={\text{SV}}\times {\text{Heart Rate}}}

 .


CO is an indicator of how well the heart is performing its function of transporting blood to deliver oxygen, nutrients, and chemicals to various cells of the body and to remove the cellular wastes. CO is regulated principally by the demand for oxygen by the cells of the body.


Diseases of the cardiovascular system, such as  hypertension  and  heart failure , are often associated with changes in CO.  Cardiomyopathy  and  heart failure  cause a reduction in cardiac output, whereas infection and  sepsis  are known to increase cardiac output. Hence, the ability to accurately measure CO is important in physiology, as it provides for improved diagnosis of abnormalities, and can be used to guide the development of new treatment strategies. However, CO is dependent upon loading conditions and is inferior to hemodynamic parameters defined by the PV plane.
Further reading: Bramwel's book of physiology


Ejection fraction  (EF) is defined as the fraction of  end-diastolic volume  that is ejected out of the ventricle during each contraction.


In mathematical terms,

 EF

 =

 SV
 EDV

 {\displaystyle {\text{EF}}={\frac {\text{SV}}{\text{EDV}}}}


Healthy ventricles typically have ejection fractions greater than 0.55. However, EF is also dependent on loading conditions and inferior to hemodynamic parameters defined by the PV plane.


Myocardial infarction  or  cardiomyopathy  causes damage to the  myocardium , which impairs the heart's ability to eject blood and, therefore, reduces ejection fraction. This reduction in the ejection fraction can manifest itself as heart failure.


Low EF usually indicates  systolic dysfunction , and severe heart failure can result in EF lower than 0.2. EF is also used as a clinical indicator of the inotropy (contractility) of the heart. Increasing inotropy leads to an increase in EF, whereas decreasing inotropy decreases EF.


These represent the minimum and maximum rate of pressure change in the ventricle. Peak dP/dt has historically been used as an index of ventricular performance. However, it is known to be load-dependent and inferior to hemodynamic parameters defined by the PV plane.


An increase in contractility is manifested as an increase in dP/dt max  during isovolumic contraction. However, dP/dt max  is also influenced by preload, afterload, heart rate, and myocardial hypertrophy. Hence, the relationship between ventricular end-diastolic volume and dP/dt is a more accurate index of contractility than dP/dt alone.


Likewise, an increase in diastolic function or an increase in relaxation ( lusitropy ) causes increased dP/dt min  during  isovolumic relaxation . Hence, dP/dt min  has been used as a valuable tool in the analysis of isovolumic relaxation. However, studies have shown that this parameter may not be a valid measure of LV relaxation rate, especially during acute alterations in contractility or afterload.


Tau represents the exponential decay of the ventricular pressure during  isovolumic relaxation . Several studies have shown that Tau is a preload-independent measure of isovolumic relaxation.


The accurate estimation of Tau is highly dependent on the accuracy of ventricular pressure measurements. Thus, high fidelity pressure transducers are required to obtain real time instantaneous ventricular pressures.


Calculation of Tau (Glantz method)


P

 (

 t

 )
 =

 P

 0

 e

 −

 t

 τ

 E

 +

 P

 α

 {\displaystyle {\text{P}}({\text{t}})={\text{P}}_{0}e^{\frac {-{\text{t}}}{\tau _{E}}}+{\text{P}}_{\alpha }}


Due to the load dependency of the previous parameters, more accurate measures of ventricular function are available in the PV plane.


End- systolic  pressure volume relationship (ESPVR) describes the maximal pressure that can be developed by the ventricle at any given LV volume. This implies that the PV loop cannot cross over the line defining ESPVR for any given contractile state.


The slope of ESPVR (Ees) represents the end-systolic elastance, which provides an index of myocardial contractility. The ESPVR is relatively insensitive to changes in preload, afterload, and  heart rate . This makes it an improved index of systolic function over other hemodynamic parameters like ejection fraction, cardiac output, and stroke volume.


The ESPVR becomes steeper and shifts to the left as inotropy (contractility) increases. The ESPVR becomes flatter and shifts to the right as inotropy decreases.


End- diastolic  pressure volume relationship (EDPVR) describes the passive filling curve for the ventricle and thus the passive properties of the myocardium. The slope of the EDPVR at any point along this curve is the reciprocal of ventricular compliance (or ventricular stiffness).


For example, if ventricular compliance is decreased (such as in  ventricular hypertrophy ), the ventricle is stiffer. This results in higher ventricular end-diastolic pressures (EDP) at any given end-diastolic volume (EDV). Alternatively, for a given EDP, a less compliant ventricle would have a smaller EDV due to impaired filling.


If ventricular compliance increases (such as in  dilated cardiomyopathy  where the ventricle becomes highly dilated without appreciable thickening of the wall), the EDV may be very high but the EDP may not be greatly elevated.


The Pressure-volume area (PVA) represents the total  mechanical energy  generated by ventricular contraction. This is equal to the sum of the stroke work (SW), encompassed within the PV loop, and the elastic potential energy (PE).


In mathematical terms,

 PVA

 =

 PE

 +

 SW

 {\displaystyle {\text{PVA}}={\text{PE}}+{\text{SW}}}


also,


PE

 =

 PES

 (

 VES

 −

 V

 0

 )

 2

 −

 PED

 (

 VED

 −

 V

 0

 )

 4

 {\displaystyle {\text{PE}}={\frac {{\text{PES}}({\text{VES}}-{\text{V}}_{0})}{2}}-{\frac {{\text{PED}}({\text{VED}}-{\text{V}}_{0})}{4}}}


There is a highly linear correlation between the PVA and cardiac oxygen consumption per beat. This relationship holds true under a variety of loading and contractile conditions. This estimation of myocardial oxygen consumption (MVO 2 ) is used to study the  coupling of mechanical work  and the energy requirement of the heart in various disease states, such as  diabetes ,  ventricular hypertrophy , and  heart failure . MVO 2  is also used in the calculation of cardiac efficiency, which is the ratio of cardiac stroke work to MVO 2 .


Preload recruitable stroke work (PRSW) is determined by the linear regression of stroke work with the end-diastolic volume. The slope of the PRSW relationship is a highly linear index of myocardial contractility that is insensitive to preload and afterload.


During heart failure, myocardial contractility is reduced, which decreases the slope of the PRSW relationship. Recent studies also indicate that the volume axis intercept of the PRSW relationship (not the slope) may be a better indicator of the severity of contractile dysfunction.


“The heart will pump what it receives”- Starling’s law of the heart


The  Frank–Starling mechanism  describes the ability of the heart to change its force of contraction (and, hence, stroke volume) in response to changes in venous return. In other words, if the end-diastolic volume increases, there is a corresponding increase in stroke volume.


The Frank–Starling mechanism can be explained on the basis of preload. As the heart fills with more blood than usual, there is an increase in the load experienced by each  myocyte . This stretches the muscle fibers, increasing the affinity of  troponin C  to Ca 2+  ions, causing a greater number of  cross-bridges  to form within the muscle fibers. This increases the contractile force of the cardiac muscle, resulting in increased stroke volume.


Frank–Starling curves can be used as an indicator of muscle contractility (inotropy). However, there is no single Frank–Starling curve on which the ventricle operates but rather a family of curves, each of which defined by the afterload and inotropic state of the heart. Increased afterload or decreased inotropy shifts the curve down and to the right. Decreased afterload and increased inotropy shifts the curve up and to the left.


Arterial elastance (Ea) is a measure of arterial load and is calculated as the simple ratio of ventricular end-systolic pressure to stroke volume.


In mathematical terms,

 E

 a

 =

 ESP
 SV

 =

 Heart Rate

 ×

 Resistance

 {\displaystyle {\text{E}}_{\text{a}}={\frac {\text{ESP}}{\text{SV}}}={\text{Heart Rate}}\times {\text{Resistance}}}


By characterizing both the ventricular and arterial systems in terms of pressure and stroke volume, it is possible to study the ventriculo-arterial coupling (the interaction between the heart and the arterial system).


In  dilated cardiomyopathy , the ventricle becomes dilated without compensatory thickening of the wall. The LV is unable to pump enough blood to meet the metabolic demands of the organism.


The end-systolic and diastolic volumes increase and the pressures remain relatively unchanged. The ESPVR and EDPVR curves are shifted to the right.


Left ventricular hypertrophy  (LVH) is an increase in the thickness and mass of the myocardium. This could be a normal reversible response to cardiovascular conditioning (athletic heart) or an abnormal irreversible response to chronically increased volume load (preload) or increased pressure load (afterload). Shown is a diagram of pathological hypertrophy reducing EDV and SV.


The thickening of the ventricular muscle results in decreased chamber compliance. As a result, LV pressures are elevated, the ESV is increased, and the EDV is decreased, causing an overall reduction in cardiac output.


Restrictive cardiomyopathy  includes a group of heart disorders in which the walls of the ventricles become stiff (but not necessarily thickened) and resist normal filling with blood between heartbeats.


This condition occurs when heart muscle is gradually infiltrated or replaced by scar tissue or when abnormal substances accumulate in the heart muscle. The ventricular systolic pressure remains normal, diastolic pressure is elevated and the cardiac output is reduced.


Aortic valve stenosis  is abnormal narrowing of the aortic valve. This results in much greater LV pressures than the aortic pressures during LV ejection. The magnitude of the pressure gradient is determined by the severity of the stenosis and the flow rate across the valve.


Severe aortic stenosis results in


This is a narrowing of the  mitral valve  orifice when the valve is open.  Mitral stenosis  impairs LV filling so that there is a decrease in end-diastolic volume (preload). This leads to a decrease in stroke volume by the Frank–Starling mechanism and a fall in cardiac output and aortic pressure. This reduction in afterload (in particular, aortic diastolic pressure) enables the end-systolic volume to decrease slightly but not enough to overcome the decline in end-diastolic volume. Therefore, because end-diastolic volume decreases more than end-systolic volume decreases, the stroke volume decreases.


Aortic insufficiency  (AI) is a condition in which the aortic valve fails to close completely at the end of systolic ejection, causing leakage of blood back through the valve during LV diastole.


The constant backflow of blood through the leaky aortic valve implies that there is no true phase of isovolumic relaxation. The LV volume is greatly increased due to the enhanced ventricular filling.


When the LV begins to contract and develop pressure, blood is still entering the LV from the aorta (since aortic pressure is higher than LV pressure), implying that there is no true isovolumic contraction. Once the LV pressure exceeds the aortic diastolic pressure, the LV begins to eject blood into the aorta.


The increased end-diastolic volume (increased preload) activates the Frank–Starling mechanism to increase the force of contraction, LV systolic pressure, and stroke volume.


Mitral regurgitation  (MR) occurs when the mitral valve fails to close completely, causing blood to flow back into the left atrium during ventricular systole.


The constant backflow of blood through the leaky mitral valve implies that there is no true phase of isovolumic contraction. Since the afterload imposed on the ventricle is reduced, end-systolic volume can be smaller than normal.


There is also no true period of isovolumic relaxation because some LV blood flows back into the left atrium through the leaky mitral valve. During ventricular diastolic filling, the elevated atrial pressure is transmitted to the LV during filling so that LV end-diastolic volume (and pressure) increases. This would cause the afterload to increase if it were not for the reduced outflow resistance (due to mitral regurgitation) that tends to decrease afterload during ejection. The net effect of these changes is that the width of the PV loop is increased (i.e., ventricular stroke volume is increased). However, ejection into the aorta (forward flow) is reduced. The increased ventricular stroke volume in this case includes the volume of blood ejected into the aorta as well as the volume ejected back into the left atrium.


Pressure–volume loops  are widely used in  basic and preclinical research . Left ventricular PV loops are considered to be the gold standard for  hemodynamic  assessment and are widely used in research to evaluate cardiac performance. While it has long been possible to measure pressure in real time from the left  ventricle , measuring the volume was technically more difficult.


The use of ultrasonic  sonomicrometry  and the development of the conductance catheter triggered renewed interest in PV loops studies. In sonomicrometry, small ultrasonic transducers (usually referred to as "crystals") transmit signals to each other, and the distance between them is accurately determined based on the transit-time of the signals. By knowing the long and short axis lengths of the ventricle, ventricular volume is easily and accurately determined. Conductance catheters measure instantaneous conductance in the left ventricle, which is then converted to blood volume using complex formulas and usually after determining and applying various correction factors. Typically only one method is used to perform PV studies in research settings.


The miniaturization of sonomicrometer crystals and pressure catheters have made mice PV loop studies feasible and more common.


A  sonomicrometer  system is composed of an electronic signal-processing unit that is connected to small ultrasonic transducers (crystals). A computer acting as a data acquisition and display device obtains data in real time from the signal processor unit, while the crystals are implanted in or on the left ventrical. As few as 2 or as many as 6 crystals can be used to perform 1-axis, 2-axis, or 3-axis length measurements of the axial planes of the heart, usually at a rate of 200 to 2000 times per second. A typical sonomicrometer system has a resolution of 12 micrometres, enabling high-resolution measurements of the axial lengths.


Ventricular volume is computed directly (either in micro-liters or milli-liters) by combining the axial length measurements in standard spherical or ellipsoidal volume equations:


V
 o
 l
 u
 m
 e
 =

 4
 3

 ×
 π
 ×

 r

 3

 {\displaystyle Volume={\frac {4}{3}}\times \pi \times r^{3}}

  (for a single-axis measurement)


V
 o
 l
 u
 m
 e
 =

 π
 6

 ×

 L

 1

 ×

 L

 2

 2

 {\displaystyle Volume={\frac {\pi }{6}}\times L_{1}\times L_{2}^{2}}

  (for a two-axis measurement, where L1 is the length of the long axis)


V
 o
 l
 u
 m
 e
 =

 π
 6

 ×

 L

 1

 ×

 L

 2

 ×

 L

 3

 {\displaystyle Volume={\frac {\pi }{6}}\times L_{1}\times L_{2}\times L_{3}}

  (for a three-axis measurement)


When the axial measurements are acquired in terms of millimeters, then the volume units in these equations will be in terms of milliliters.


A conductance catheter contains two or more ring-shaped electrodes along its length. When a high-frequency low-amplitude constant current is passed through the outer electrodes to generate an electric field, the potential difference between any pair of inner electrodes is inversely proportional to the amount of conductive material at that site.


Conductance  is defined as the applied current divided by the voltage measured between two adjacent electrodes.


The conductance catheter technique has no major drawbacks but requires careful  calibration  of conductance signals. Other techniques exist but this article focuses on the well-established conductance catheter technique.


(NOTE: For typical catheter configurations the linear relationship of the inverse potential difference to the amount of material is only an approximation. It is only valid for volumes where the diameter of that volume is less than the distance between the measuring electrodes.)


The formula by Baan et al. (1984) for obtaining ventricular volume is as follows:

 V
 =

 1
 α

 ×
 ρ
 ×

 L

 2

 ×
 (
 G
 −

 G

 P

 )

 {\displaystyle V={\frac {1}{\alpha }}\times \rho \times L^{2}\times (G-G^{P})}


The conductance measured by the catheter is actually the conductance of the blood and of the surrounding myocardial tissue. This latter conductance is called the parallel conductance (G P ).


From the above equation, it can be seen that the volume measurement requires the knowledge of  α ,  ρ ,  L , and  G P .


The equation may be considered to be a straight line of the form y = mx + b, where  m  (the gain) is a combination of the three terms 1/ α ,  ρ , and  L 2  and  b  (the offset) is  G P .


L  is available from catheter data sheets, while  ρ  can be measured directly using appropriate equipment.


Ideally, gain should be determined in every experiment. While  L  is known and  ρ  can be measured, the  α  factor poses more difficulties. Indeed, the only way to obtain a reliable gain (encompassing  α ) involves directly measuring cardiac output. Therefore, for most purposes, an educated estimate is used based on values found in the literature.


To take into account the parallel conductance,  G P , the most common method involves injection of hypertonic saline into the subject—enough to temporarily reduce blood resistance, and therefore increase preload, but not so much as to alter haemodynamics. The minimum and maximum volumes (V max  and V min ) from each loop in the series of loops are plotted on a graph. V max  and V min  lines are extrapolated and at their point of intersection, where V max  is equal to V min , must be zero—conductance is parallel conductance only. The volume at this point is the correction volume.


Admittance  techniques offer an alternative to the saline bolus as a means of determining  G P .


Several parameters can be calculated for each loop (e.g. end-diastolic pressure, end-systolic pressure, ejection and filling intervals, contractility index, stroke volume, and ejection fraction).


More importantly, other interesting  parameters are derived from series of loops  obtained under changing conditions. For example, the end-diastolic pressure-volume relationship (EDPVR) and end-systolic pressure-volume relationship (ESPVR) are derived from series of loops obtained by slowly inflating a balloon to occlude the inferior vena cava, a procedure that reduces  cardiac preload .


EDPVR and ESPVR are valuable because they are load-independent indices of left ventricular function.
They also measure left ventricle Compliance/Stiffness (EDPVR) and Contractility (ESPVR) respectively.


Other parameters derived from series of loops are:


The  Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22  trial, also known as  PROVE-IT   TIMI   22 , was a   randomized, double-blind ,  clinical trial  that recruited 4,162 people admitted within 10 days of an  acute coronary event  and randomised them to the  lipid-lowering drugs   pravastatin  (40 mg) or  atorvastatin  (80 mg) and a 10-day course of the antibiotic  gatifloxacin  or  placebo . [ 1 ]  The participants enrolled at 349 sites across Australia, Europe, and North America between November 2000 and December 2001, and the study concluded that statin treatment for  secondary prevention  reduced  coronary heart disease  (CHD) events and that atorvastatin had a more marked effect than pravastatin. The study was published in  The New England Journal of Medicine  and reported at the  American College of Cardiology  Annual Scientific Session in 2004. [ 2 ] [ 3 ] [ 4 ]


Pulmonary angiography  (or  pulmonary arteriography , conventional pulmonary angiography ,  selective pulmonary angiography ) is a medical  fluoroscopic  procedure used to visualize the pulmonary arteries and much less frequently, the pulmonary veins. It is a minimally invasive procedure performed most frequently by an  interventional radiologist  or  interventional cardiologist  to visualise the arteries of the lungs.


Pulmonary angiography is useful as the confirmation test where the non-invasive imaging such as  CT pulmonary angiography  is inconclusive on determining the presence of  pulmonary embolism . [ 1 ]  The accuracy of pulmonary angiography may be higher than clinical examination,  arterial blood gas  results, and  ventilation/perfusion scan . [ 2 ]  Pulmonary angiography is also used to confirm  chronic thromboembolic pulmonary hypertension  (CTEPH) and provides a platform for  balloon pulmonary angioplasty  to treat the disease. [ 3 ]


CT pulmonary angiography  has nearly entirely replaced conventional pulmonary angiography in common practice as it is less invasive, faster, safer, and provides most of the same diagnostic information with the added benefit of visualizing the lung tissue as well as other structures. Nevertheless, it is still used in cases where CT angiography is nondiagnostic.


Types of catheters that can be used are pigtail catheters and balloon occlusion catheters. Tip of the catheter is advanced through the  inferior vena cava ,   right atrium ,  right ventricle , right ventricular outflow tract, pulmonary trunk, and the tip is parked in the left pulmonary artery. [ 4 ]


Conventional pulmonary angiography was first performed in 1931 by Portuguese angiography pioneers  Lopo de Carvalho ,  Egas Moniz  and colleagues. [ 5 ]  Robb and Steinberg described pulmonary angiography by infusion of peripheral radiocontrast. [ 6 ] [ 7 ]


A  pulse duplicator  is a device used to duplicate the pulsing flow of the human heart and the associated  hemodynamics .  It is used to research the conditions of heart disease. [ 1 ] [ 2 ] [ 3 ]  Pulse duplicators can be used to conduct  in vitro  or  ex vivo  testing.  Common uses include testing new  artificial heart valves [ 4 ]  and simulating procedures like  transcatheter aortic valve replacement . [ 5 ]


A pulse duplicator replicates parts of the circulatory system.  Many pulse duplicators model only half the heart, commonly the left atrium and ventricle, in order to test the  mitral  and  aortic valves .


A common design to model the heart uses a  piston  to simulate the contraction and expansion of the heart.  An alternate design uses a flexible plastic heart model, or an ex vivo heart, and applies  hydraulic  pressure to induce contraction and expansion. [ 1 ] [ 6 ]


The circulatory system blood vessels are typically modeled using tubing. Compliance chambers and narrow tubing can be used to model the  Windkessel effect . [ 7 ]


A pulse duplicator is categorized as a lump parameter model, also known as a Windkessel model, if it uses a limited set of compliance chambers and resistance tubing to model the sum of circulatory compliance and resistance.  A pulse duplicator is a wave propagation model if it physically replicates the circulatory system in a more anatomically correct manner.  [ 2 ]


A pulse duplicator is filled with a fluid with a similar  viscosity  and  specific gravity  compared to blood. One such blood analog is a mixture of water,  glycerol , and a small amount of  sodium chloride . [ 5 ] [ 2 ]


Pulse oximetry  is a  noninvasive  method for monitoring blood  oxygen saturation .  Peripheral oxygen saturation  (Sp O 2 ) readings are typically within 2% accuracy (within 4% accuracy in 95% of cases) of the more accurate (and invasive) reading of arterial oxygen saturation (Sa O 2 ) from  arterial blood gas  analysis. [ 1 ]


A standard pulse oximeter passes two wavelengths of  light  through tissue to a  photodetector . Taking advantage of the  pulsate  flow of  arterial blood , it measures the change in  absorbance  over the course of a  cardiac cycle , allowing it to determine the absorbance due to arterial blood alone, excluding unchanging absorbance due to  venous blood , skin, bone, muscle, fat, and, in many cases,  nail polish . [ 2 ]  The two wavelengths measure the quantities of bound (oxygenated) and unbound (non-oxygenated) hemoglobin, and from their ratio, the percentage of bound hemoglobin is computed.
The most common approach is  transmissive pulse oximetry . In this approach, one side of a thin part of the patient's body, usually a  fingertip  or  earlobe , is illuminated, and the photodetector is on the other side. Fingertips and earlobes have disproportionately high blood flow relative to their size, in order to keep warm, but this will be lacking in  hypothermic  patients. [ 1 ]  Other convenient sites include an  infant's  foot or an unconscious patient's  cheek  or  tongue .


Reflectance pulse oximetry  is a less common alternative, placing the photodetector on the same surface as the illumination. This method does not require a thin section of the person's body and therefore may be used almost anywhere on the body, such as the forehead, chest, or feet, but it still has some limitations. Vasodilation and pooling of venous blood in the head due to compromised venous return to the heart can cause a combination of arterial and venous pulsations in the forehead region and lead to spurious Sp O 2  results. Such conditions occur while undergoing  anaesthesia  with  endotracheal intubation  and mechanical ventilation or in patients in the  Trendelenburg position . [ 3 ]


A pulse oximeter is a  medical device  that indirectly monitors the oxygen saturation of a patient's  blood  (as opposed to measuring oxygen saturation directly through a blood sample) and changes in blood volume in the skin, producing a  photoplethysmogram  that may be further processed into  other measurements . [ 4 ]  The pulse oximeter may be incorporated into a multiparameter patient monitor. Most monitors also display the pulse rate. Portable, battery-operated pulse oximeters are also available for transport or home blood-oxygen monitoring. [ 5 ]


Pulse oximetry is particularly convenient for  noninvasive  continuous measurement of blood oxygen saturation. In contrast, blood gas levels must otherwise be determined in a laboratory on a drawn blood sample. Pulse oximetry is useful in any setting where a patient's  oxygenation  is unstable, including  intensive care , operating, recovery, emergency and hospital ward settings,  pilots  in unpressurized aircraft, for assessment of any patient's oxygenation, and determining the effectiveness of or need for supplemental  oxygen . Although a pulse oximeter is used to monitor oxygenation, it cannot determine the metabolism of oxygen, or the amount of oxygen being used by a patient. For this purpose, it is necessary to also measure  carbon dioxide  (CO 2 ) levels. It is possible that it can also be used to detect abnormalities in ventilation. However, the use of a pulse oximeter to detect  hypoventilation  is impaired with the use of supplemental oxygen, as it is only when patients breathe room air that abnormalities in respiratory function can be detected reliably with its use. Therefore, the routine administration of supplemental oxygen may be unwarranted if the patient is able to maintain adequate oxygenation in room air, since it can result in hypoventilation going undetected. [ 6 ]


Because of their simplicity of use and the ability to provide continuous and immediate oxygen saturation values, pulse oximeters are of critical importance in  emergency medicine  and are also very useful for patients with respiratory or cardiac problems, [ 7 ]  especially  COPD , or for diagnosis of some  sleep disorders  such as  apnea  and  hypopnea . [ 8 ]  For patients with  obstructive sleep apnea , pulse oximetry readings will be in the 70–90% range for much of the time spent attempting to sleep. [ 9 ]


Portable battery-operated pulse oximeters are useful for pilots operating in non-pressurized aircraft above 10,000 feet (3,000 m) or 12,500 feet (3,800 m) in the U.S. [ 10 ]  where supplemental oxygen is required. Portable pulse oximeters are also useful for mountain climbers and athletes whose oxygen levels may decrease at high  altitudes  or with exercise. Some portable pulse oximeters employ software that charts a patient's blood oxygen and pulse, serving as a reminder to check blood oxygen levels. [ citation needed ]


Connectivity advancements have made it possible for patients to have their blood oxygen saturation continuously monitored without a cabled connection to a hospital monitor, without sacrificing the flow of patient data back to bedside monitors and centralized patient surveillance systems. [ 11 ]


For patients with  COVID-19 , pulse oximetry helps with early detection of  silent hypoxia , in which the patients still look and feel comfortable, but their Sp O 2  is dangerously low. [ 5 ]  This happens to patients either in the hospital or at home. Low Sp O 2  may indicate severe COVID-19-related pneumonia, requiring a ventilator. [ 12 ]


Continuous monitoring with pulse oximetry is generally considered safe for most patients for up to 8 hours. However, prolonged use in certain types of patients can cause burns due to the heat emitted by the infrared LED, which reaches up to 43°C. Additionally, pulse oximeters occasionally develop electrical faults which causes them to heat up above this temperature. Patients at greater risk include those with delicate or fragile skin, such as infants, particularly premature infants, and the elderly. Additional risks for injury include lack of pain response where the probe is placed, such as having an insensate limb, or being unconscious or under anesthesia, or having communication difficulties. Patients who are at high risk for injury should be have the site of their probe moved frequently, i.e. every hour, whereas patients who are at lower risk should have theirs moved every 2-4 hours. [ 13 ]


Pulse oximetry solely measures hemoglobin saturation, not  ventilation  and is not a complete measure of respiratory sufficiency. It is not a substitute for  blood gases  checked in a laboratory, because it gives no indication of base deficit, carbon dioxide levels, blood  pH , or  bicarbonate  (HCO 3 − ) concentration. The metabolism of oxygen can readily be measured by monitoring expired CO 2 , but saturation figures give no information about blood oxygen content. Most of the oxygen in the blood is carried by hemoglobin; in severe anemia, the blood contains less hemoglobin, which despite being saturated cannot carry as much oxygen. [ citation needed ]


Pulse oximetry also is not a complete measure of circulatory oxygen sufficiency. If there is insufficient  bloodflow  or insufficient hemoglobin in the blood ( anemia ), tissues can suffer  hypoxia  despite high arterial oxygen saturation.


Since pulse oximetry measures only the percentage of bound hemoglobin, a falsely high or falsely low reading will occur when hemoglobin binds to something other than oxygen:


A noninvasive method that allows continuous measurement of the  dyshemoglobins  is the pulse  CO-oximeter , which was built in 2005 by Masimo. [ 15 ]  By using additional wavelengths, [ 16 ]  it provides clinicians a way to measure the dyshemoglobins,  carboxyhemoglobin , and  methemoglobin  along with total hemoglobin. [ 17 ]


Because pulse oximeter devices are calibrated for healthy subjects, their accuracy is poor for critically ill patients and preterm newborns. [ 1 ]  Erroneously low readings may be caused by  hypoperfusion  of the extremity being used for monitoring (often due to a limb being cold or from  vasoconstriction  secondary to the use of  vasopressor  agents); incorrect sensor application; highly  calloused  skin; or movement (such as shivering), especially during hypoperfusion. To ensure accuracy, the sensor should return a steady pulse and/or pulse waveform. Pulse oximetry technologies differ in their abilities to provide accurate data during conditions of motion and low perfusion. [ 18 ] [ 19 ]   Obesity ,  hypotension  (low blood pressure), and some  hemoglobin variants  can reduce the accuracy of the results. [ 8 ]  Some home pulse oximeters have low  sampling  rates, which can significantly underestimate dips in blood oxygen levels. [ 8 ]


The accuracy of pulse oximetry deteriorates considerably for readings below 80%. [ 9 ]  Research has suggested that error rates in common pulse oximeter devices may be higher for adults with  dark skin color , leading to claims of encoding  systemic racism  in countries with multi-racial populations  such as the United States . [ 20 ] [ 21 ]  The issue was first identified decades ago; one of the earliest studies on this topic occurred in 1976, which reported reading errors in dark-skinned patients that reflected lower blood oxygen saturation values. [ 22 ]  Further studies indicate that while accuracy with dark skin is good at higher, healthy saturation levels, some devices overestimate the saturation at lower levels, which may lead to hypoxia not being detected. [ 23 ]  A study that reviewed thousands of cases of occult  hypoxemia , where patients were found to have oxygen saturation below 88% per arterial blood gas measurement despite pulse oximeter readings indicating 92% to 96% oxygen saturation, found that black patients were three times as likely as white patients to have their low oxygen saturation missed by pulse oximeters. [ 24 ]  Another research study investigated patients in the hospital with COVID-19 and found that occult hypoxemia occurred in 28.5% of black patients compared to only 17.2% of white patients. [ 25 ]  There has been research to indicate that black COVID-19 patients were 29% less likely to receive supplemental oxygen in a timely manner and three times more likely to have hypoxemia. [ 26 ]  A further study, which used a MIMIC-IV critical care dataset of both pulse oximeter readings and oxygen saturation levels detected in blood samples, demonstrated that black, Hispanic, and Asian patients had higher Sp O 2  readings than white patients for a given blood oxygen saturation level measured in blood samples. [ 27 ]  As a result, black, Hispanic, and Asian patients also received lower rates of supplemental oxygen than white patients. [ 27 ]  It is suggested that melanin can interfere with the absorption of light used to measure the level of oxygenated blood, often measured from a person's finger. [ 27 ]  Further studies and computer simulations show that the increased amounts of melanin found in people with darker skin scatter the photons of light used by the pulse oximeters, decreasing the accuracy of the measurements. As the studies used to calibrate the devices typically oversample people with lighter skin, the parameters for pulse oximeters are set based on information that is not equitably balanced to account for diverse skin colors. [ 28 ]  This inaccuracy can lead to potentially missing people who need treatment, as pulse oximetry is used for the screening of sleep apnea and other types of sleep-disordered breathing, [ 8 ]  which in the United States are conditions more prevalent among minorities. [ 29 ] [ 30 ] [ 31 ]  This bias is a significant concern, as a 2% decrease is important for respiratory rehabilitation, studies of sleep apnea, and athletes performing physical efforts; it can lead to severe complications for the patient, requiring an external oxygen supply or even hospitalization. [ 32 ]


Another concern regarding pulse oximetry bias is that insurance companies and hospital systems increasingly use these numbers to inform their decisions. Pulse oximetry measurements are used to identify candidates for reimbursement. [ 33 ]  Similarly, pulse oximetry data is being incorporated into algorithms for clinicians. Early Warning Scores, which provide a record for analyzing a patient's clinical status and alerting clinicians if needed, incorporate algorithms with pulse oximetry information and can result in misinformed patient records. [ 33 ]


In addition to pulse oximeters for professional use, many inexpensive "consumer" models are available. Opinions vary about the reliability of consumer oximeters; a typical comment is "The research data on home monitors has been mixed, but they tend to be accurate within a few percentage points". [ 34 ]  Some smart watches with  activity tracking  incorporate an oximeter function. An article on such devices, in the context of diagnosing  COVID-19  infection, quoted João Paulo Cunha of the University of Porto, Portugal: "these sensors are not precise, that's the main limitation ... the ones that you wear are only for the consumer level, not for the clinical level". [ 35 ]  Pulse oximeters used for diagnosis of conditions such as COVID-19 should be Class IIB medical grade oximeters. Class IIB oximeters can be used on patients of all skin colors, low pigmentation and in the presence of motion. [ citation needed ]  When a pulse oximeter is shared between two patients, to prevent cross-infection it should be cleaned with alcohol wipes after each use or a disposable probe or finger cover should be used. [ 36 ]


According to a report by iData Research, the US pulse oximetry monitoring market for equipment and sensors was over $700 million in 2011. [ 37 ]


Mobile app  pulse oximeters use the flashlight and the camera of the phone, instead of infrared light used in conventional pulse oximeters. However, apps do not generate as accurate readings because the camera cannot measure the light reflection at two wavelengths, so the oxygen saturation readings that are obtained through an app on a smartphone are inconsistent for clinical use. At least one study has suggested these are not reliable relative to clinical pulse oximeters. [ 38 ]


A blood-oxygen monitor displays the percentage of blood that is loaded with oxygen. More specifically, it uses  light spectrometry  to measure what percentage of  hemoglobin , the protein in blood that carries oxygen, is loaded. Acceptable normal Sa O 2  ranges for patients without pulmonary pathology are from 95 to 99 percent. [ citation needed ]  For a person breathing room air at or near  sea level , an estimate of arterial pO 2  can be made from the blood-oxygen monitor  "saturation of peripheral oxygen"  (Sp O 2 ) reading. [ citation needed ]


A typical pulse oximeter uses an electronic processor and a pair of small  light-emitting diodes  (LEDs) facing a  photodiode  through a translucent part of the patient's body, usually a fingertip or an earlobe. One LED is red, with  wavelength  of 660 nm, and the other is  infrared  with a wavelength of 940 nm. Absorption of light at these wavelengths differs significantly between blood loaded with oxygen and blood lacking oxygen. Oxygenated hemoglobin absorbs more infrared light and allows more red light to pass through. Deoxygenated hemoglobin allows more infrared light to pass through and absorbs more red light. The LEDs sequence through their cycle of one on, then the other, then both off about thirty times per second which allows the photodiode to respond to the red and infrared light separately and also adjust for the ambient light baseline. [ 39 ]


The amount of light that is transmitted (in other words, that is not absorbed) is measured, and separate normalized signals are produced for each wavelength. These signals fluctuate in time because the amount of arterial blood that is present increases (literally pulses) with each heartbeat. By subtracting the minimum transmitted light from the transmitted light in each wavelength, the effects of other tissues are corrected for, generating a continuous signal for pulsatile arterial blood. [ 40 ]  The ratio of the red light measurement to the infrared light measurement is then calculated by the processor (which represents the ratio of oxygenated hemoglobin to deoxygenated hemoglobin), and this ratio is then converted to Sp O 2  by the processor via a  lookup table [ 40 ]  based on the  Beer–Lambert law . [ 39 ]  The signal separation also serves other purposes: a plethysmograph waveform ("pleth wave") representing the pulsatile signal is usually displayed for a visual indication of the pulses as well as signal quality, [ 4 ]  and a numeric ratio between the pulsatile and baseline absorbance (" perfusion index ") can be used to evaluate perfusion. [ 41 ]


SpO

 2

 =

 HbO

 2

 HbO

 2

 +
 Hb

 {\displaystyle {\ce {SpO2}}={\frac {{\ce {HbO2}}}{{\ce {{HbO2}+Hb}}}}}


where HbO 2  is oxygenated hemoglobin ( oxyhemoglobin ) and Hb is deoxygenated hemoglobin.


Due to changes in blood volumes in the skin, a  plethysmographic  variation can be seen in the light signal received (transmittance) by the sensor on an oximeter. The variation can be described as a  periodic function , which in turn can be split into a DC component (the peak value) [ a ]  and an AC component (peak minus trough). [ 42 ]  The ratio of the AC component to the DC component, expressed as a percentage, is known as the  (peripheral)  perfusion  index  (Pi) for a pulse, and typically has a range of 0.02% to 20%. [ 43 ]  An earlier measurement called the  pulse oximetry plethysmographic  (POP) only measures the "AC" component, and is derived manually from monitor pixels. [ 41 ] [ 44 ]


Pleth variability index  (PVI) is a measure of the variability of the perfusion index, which occurs during breathing cycles. Mathematically it is calculated as  (Pi max  − Pi min )/Pi max  × 100% , where the maximum and minimum Pi values are from one or many breathing cycles. [ 42 ]  It has been shown to be a useful, noninvasive indicator of continuous fluid responsiveness for patients undergoing fluid management. [ 41 ]   Pulse oximetry plethysmographic waveform amplitude  (ΔPOP) is an analogous earlier technique for use on the manually-derived POP, calculated as  (POP max  − POP min )/(POP max  + POP min )×2 . [ 44 ]


In 1935, German physician  Karl Matthes  (1905–1962) developed the first two-wavelength ear O 2  saturation meter with red and green filters (later red and infrared filters). It was the first device to measure O 2  saturation. [ 45 ]


The original oximeter was made by  Glenn Allan Millikan  in the 1940s. [ 46 ]  In 1943 [ 47 ]  and as published in 1949, [ 48 ]   Earl Wood  added a pressure capsule to squeeze blood out of the ear so as to obtain an absolute O 2  saturation value when blood was readmitted. The concept is similar to today's conventional pulse oximetry, but was difficult to implement because of unstable  photocells  and light sources; today this method is not used clinically. In 1964 Shaw assembled the first absolute reading ear oximeter, which used eight wavelengths of light. [ citation needed ]


The first pulse oximetry was developed in 1972 by Japanese bioengineers  Takuo Aoyagi  and Michio Kishi at Japanese medical electronic equipment manufacturer  Nihon Kohden , using the ratio of red to infrared light absorption of pulsating components at the measuring site. Nihon Kohden manufactured the first pulse oximeter, Ear Oximeter OLV-5100. Surgeon Susumu Nakajima and his associates first tested the device in patients, reporting it in 1975. [ 49 ]  However, Nihon Kohden suspended the development of pulse oximetry and did not apply for a basic patent of pulse oximetry except in Japan, which facilitated further development and utilization of pulse oximetry later in U.S. In 1977,  Minolta  commercialized the first finger pulse oximeter OXIMET MET-1471. In the U.S., the first pulse oximetry was commercialized by  Biox  in 1980. [ 49 ] [ 50 ] [ 51 ]


By 1987, the standard of care for the administration of a general anesthetic in the U.S. included pulse oximetry. From the operating room, the use of pulse oximetry rapidly spread throughout the hospital, first to  recovery rooms , and then to  intensive care units . Pulse oximetry was of particular value in the neonatal unit where the patients do not thrive with inadequate oxygenation, but too much oxygen and fluctuations in oxygen concentration can lead to vision impairment or blindness from  retinopathy of prematurity  (ROP). Furthermore, obtaining an arterial blood gas from a neonatal patient is painful to the patient and a major cause of neonatal anemia. [ 52 ]  Motion artifact can be a significant limitation to pulse oximetry monitoring, resulting in frequent false alarms and loss of data. This is because during motion and low peripheral  perfusion , many pulse oximeters cannot distinguish between pulsating arterial blood and moving venous blood, leading to underestimation of oxygen saturation. Early studies of pulse oximetry performance during subject motion made clear the vulnerabilities of conventional pulse oximetry technologies to motion artifact. [ 18 ] [ 53 ]