Coronary steal  (with its  symptoms  termed  coronary steal syndrome  or  cardiac steal syndrome ) is a phenomenon where an alteration of  circulation  patterns leads to a reduction in the blood flow directed to the  coronary circulation . [ 1 ]  It is caused when there is narrowing of the  coronary arteries  and a coronary vasodilator [ 2 ]  is used – "stealing" blood away from those parts of the heart.


This happens as a result of the narrowed coronary arteries being always maximally dilated to compensate for the decreased upstream blood supply. Thus, dilating the  resistance vessels  in the coronary circulation causes blood to be shunted away from the coronary vessels supplying the  ischemic zones , creating more  ischemia .


Mild coronary steal may occur without any symptoms, but as the syndrome progresses, chest pain is usually the first obvious symptom. In worse cases, symptoms can include dizziness, flushing, headaches, nausea, and shortness of breath. [ 3 ]


It is associated with  dipyridamole . Dipyridamole is thus a pharmacological success diagnostically, but a therapeutic failure because of the coronary steal phenomenon. [ 4 ]


Coronary steal is also the mechanism in most drug-based  cardiac stress tests ; When a patient is incapable of doing physical activity they are given a vasodilator that produces a "cardiac steal syndrome" as a diagnostic procedure. The test result is positive if the patient's symptoms reappear or if ECG alterations are seen. [ citation needed ]


Hydralazine can potentially cause this condition as well, as it is a direct arteriolar vasodilator. [ citation needed ]


It has been associated with  nitroprusside . [ 5 ]


Coronary arteriovenous fistula between coronary artery and another cardiac chamber, like, the coronary sinus, right atrium, or right ventricle may cause steal syndrome under conditions like myocardial infarction and possible angina or ventricular arrhythmias, if the shunt is large in magnitude. [ 6 ]


It can also be associated with new patterns of blood vessel growth. [ 7 ]


Coronary steal syndrome can be diagnosed by:


Coronary steal is sometimes treated by surgery. [ 8 ]


Coronary thrombosis  is defined as the formation of a blood clot inside a blood vessel of the heart. This blood clot may then restrict  blood flow within the heart , leading to heart tissue damage, or a  myocardial infarction , also known as a heart attack. [ 1 ]


Coronary thrombosis is most commonly caused as a downstream effect of  atherosclerosis , a buildup of  cholesterol  and fats in the artery walls. The smaller vessel diameter allows less blood to flow and facilitates progression to a  myocardial infarction . Leading risk factors for coronary thrombosis are high  low-density lipoprotein cholesterol , smoking,  sedentary lifestyle , and  hypertension . [ 2 ]


Symptoms of coronary thrombosis are not always evident at the start. Symptoms include chest pain, shortness of breath, and discomfort in the upper body.


A coronary thrombosis is a medical emergency (life threatening) and requires urgent care at a hospital.


A coronary thrombus is  asymptomatic  until it causes significant obstruction, leading to various forms of  angina  or eventually a  myocardial infarction . Common warning symptoms are crushing chest pain, shortness of breath, and upper body discomfort. [ 2 ]


Coronary thrombosis and  myocardial infarction  are sometimes used as synonyms, although this is technically inaccurate as the thrombosis refers to the  blocking of blood vessels  with a thrombus, while myocardial infarction refers to heart  tissue death  due to the consequent loss of  blood flow  to the heart. Due to extensive  collateral circulation , a coronary thrombus does not necessarily cause tissue death and may be asymptomatic. [ citation needed ]


The formation of coronary thrombosis generally follows the same mechanism as other blood clots in the body, the  coagulation cascade . Also applicable is the  Virchow's triad  of blood stasis,  endothelial  injury, and  hypercoagulable state .  Atherosclerosis  contributes to coronary thrombosis formation by facilitating blood stasis as well as causing local endothelial injury. [ citation needed ]


Due to the large number of cases of myocardial infarction leading to death and disease in the world, there has been extensive study towards the generation of clots specifically in the  coronary arteries . [ citation needed ]  Some areas of focus:


Clinical signs of myocardial infarction (heart attack) or  angina  if coronary thrombus is symptomatic:


Imaging modalities used to evaluate the presence of coronary thrombi: [ 9 ]


Postmortem examiners may look for  Lines of Zahn , to determine whether blood clotted in the heart vessels before or after death. [ 11 ]


Management of symptomatic coronary thrombosis follows established treatment algorithms for myocardial infarction. Treatment options include: [ 12 ]


To address the possibility of identifying and treating asymptomatic coronary artery disease to prevent development of coronary thrombosis, a study published 2018 determined that preemptive treatment with  percutaneous coronary intervention  did not lead to a difference in death or myocardial infarction over a 15-year period. [ 13 ]


There are numerous treatments currently being studied for management and prevention of coronary thrombosis.  Statin  drugs, in addition to their primary  cholesterol -lowering mechanisms of action, have been studied to target a number of pathways that may decrease coronary  inflammation  and subsequent thrombosis. [ 14 ]


Another realm of potential treatments in early stages of adoption is in therapeutic use of contrast  ultrasound  on thrombus dissolution. [ 15 ]


Thrombosis  is defined as the formation of a  thrombus (blood clot)  inside a  blood vessel , leading to obstruction of blood flow within the  circulatory system . Coronary thrombosis refers to the formation and presence of thrombi in the coronary arteries of the heart. The heart does not contain veins, but rather  coronary sinuses  that serve the purpose of returning  de-oxygenated blood  from the heart muscle. [ citation needed ]


A thrombus is a type of  embolism , a more general term for any material that partially or fully blocks a blood vessel. An  atheroembolism , or cholesterol embolism, is when an  atherosclerotic  plaque ruptures and becomes an embolism.  Atherosclerosis  is the progressive thickening of blood vessels and plaque formation that eventually can lead to  coronary artery disease . [ citation needed ]


Coronary vasospasm  refers to when a  coronary artery  suddenly undergoes either complete or sub-total temporary occlusion. [ 1 ]


In 1959, Prinzmetal et al. described a type of chest pain resulting from coronary vasospasm, referring to it as a variant form of classical  angina pectoris . [ 2 ]  Consequently, this angina has come to be reported and referred to in the literature as  Prinzmetal angina . [ 3 ]  A subsequent study distinguished this type of angina from classical angina pectoris further by showing normal coronary arteries on  cardiac catheterization . This finding is unlike the typical findings in classical angina pectoris, which usually shows  atherosclerotic  plaques on cardiac catheterization. [ 3 ]


When coronary vasospasm occurs, the occlusion temporarily produces  ischemia . A wide array of symptoms or presentations can follow: ranging from asymptomatic myocardial ischemia, sometimes referred to as silent ischemia, to  myocardial infarction  and even sudden  cardiac death . [ 4 ] [ 1 ]


Coronary vasospasm classically produces chest pain at rest, also known as  variant angina  (vasospastic angina or Prinzmetal's angina). [ 5 ]  Chest pain is more common at certain times of the day, usually from late night to early morning. [ 6 ]  These episodes can be accompanied by nausea, vomiting, cold sweating, and even syncope. [ 7 ] [ 8 ]  Coronary vasospasm is also associated with symptoms of fatigue and tiredness, dyspnea, and palpitations. [ 5 ]  These can sometimes be the primary presenting symptoms, but they can also occur in conjunction with chest pain. [ 5 ]


There are cases of coronary vasospasm that occur without any symptoms at all, leading to episodes of silent or asymptomatic myocardial ischemia. [ 7 ] [ 8 ]


Depending on how long the occlusion lasts, a spectrum of different myocardial ischemic syndromes can occur. Shorter episodes of occlusion can lead to what is referred to as silent myocardial ischemia due to its asymptomatic nature. [ 1 ]  These episodes can also be accompanied by arrhythmias. [ 1 ]  Longer episodes of occlusion can lead to stable or unstable angina, myocardial infarction, and sudden cardiac death. [ 1 ]


Unlike classical  angina pectoris , traditional cardiovascular risk factors are not thought to be significantly associated with coronary vasospasm. [ 9 ]  The exception to this is with smoking, which is known to be a modifiable risk factor for vasospastic angina. [ 9 ] [ 10 ]


There are several risk factors that are thought to precipitate, or trigger, episodes of coronary vasospasm. Many of these factors work by exerting effects on the autonomic nervous system. One of the mechanisms through which this occurs is via increasing sympathetic nervous system activity. The resulting increased sympathetic outflow leads to vasoconstrictive effects on blood vessels. [ 9 ]  For example, cocaine use can trigger vasospasm in coronary arteries through its actions on adrenergic receptors causing vasoconstriction. [ 11 ]  Exercise, cold weather, physical activity or exertion, mental stress, hyperventilation are additional precipitating factors. [ 9 ] [ 7 ]


The exact pathophysiology behind coronary vasospasm has not been elucidated. Instead, a combination of different factors has been proposed to contribute to coronary vasospasm. [ 12 ]  In general, it is thought that an abnormality within a coronary artery causes it to become hyperreactive to vasoconstrictor stimuli. This abnormality can be located in one segment of the coronary artery, or it may be diffuse and present throughout the entire artery. If and when vasoconstrictor stimuli act upon the hyperreactive segment of the artery, then vasospasm can result. [ 9 ]  Ultimately, when large coronary arteries undergo vasospasm, this can lead to either complete or transient occlusion of blood flow within the artery. As a result, ischemia to the tissues served by the artery can occur. Symptoms due to ischemia can follow. [ 13 ]


Some of the factors that have been proposed to contribute to coronary vasospasm include the following: [ 1 ] [ 12 ]


There are no set criteria to diagnose coronary vasospasm. Thorough history taking by a clinician can assist in the diagnosis of coronary vasospasm. In cases where symptoms of chest pain are present, identifying features that distinguish episodes of vasospastic angina from traditional angina can aid in the diagnosis. [ 6 ]  Features such as chest pain at rest, a diurnal variation in tolerance for exercise with a reduction in tolerance for exercise in the morning, and responsiveness of chest pain to  calcium channel blockers  as opposed to  beta blockers  can be important clues. [ 6 ]


EKG can occasionally be used to diagnose episodes of coronary vasospasm. However, relying on EKG is not always possible due to the transient nature of coronary vasospasm episodes. [ 6 ] [ 19 ]  Due to the challenge of capturing episodes of coronary vasospasm spontaneously, provocative testing to induce coronary vasospasm during coronary catheterization can be used to make the diagnosis. [ 19 ]  Provocative testing relies upon the use of pharmacological agents that promote or trigger episodes of vasospasm. Agents commonly administered include ergonovine and  acetylcholine . Both pharmacological agents have vasoconstrictive effects on coronary arteries. [ 19 ]  However, in the clinical setting, provocative testing is not routinely performed. [ 20 ]  The reason for this is due to the adverse effects of these pharmacological agents. [ 20 ]


When coronary vasospasm causes an artery to undergo complete occlusion, an EKG might show evidence of ST-segment elevation in the leads indicative of that artery's territory. Transient ST-segment depression can also occur, usually in the setting of sub-total occlusion of an artery. [ 7 ]


Additional EKG findings in coronary vasospasm include evidence of arrhythmias that might be induced by ischemia: ventricular premature contractions, ventricular tachycardia, ventricular fibrillation, and more. [ 7 ]


Chest pain due to coronary vasospasm was described in the medical literature by Prinzmetal et al. in 1959. [ 2 ]  This discovery led to this type of angina being referred to in the literature as Prinzmetal angina. [ 3 ] [ 20 ]  A following study further distinguished this angina from classical angina pectoris due to the fact that the results showed that the patients with chest pain due to coronary vasospasm lacked evidence of atherosclerosis on cardiac catheterization. [ 3 ] [ 20 ]  Angina due to coronary vasospasm is also known as variant angina. [ 20 ]


During the 70’s and 80’s, intense research [ 21 ]  headed by Dr. Robert A. Chahine resulted in the delineation of Spasm's role in Prinzmetal's angina, allowing for easy identification and effective treatment. [ 22 ]


Cœur en sabot  (French for "clog-shaped heart" or "boot-shaped heart" [ 1 ] ) is a  radiological sign  seen most commonly in patients with  tetralogy of Fallot , [ 2 ]  a cyanotic congenital heart disease. It is a radiological term to describe the following findings in the x-ray: [ citation needed ]


Echocardiography  has been used for confirmation and differentiation of congenital heart diseases. [ citation needed ]


Coxsackieviruses -induced cardiomyopathy  are  positive-stranded  RNA viruses in  picornavirus  family and the genus  enterovirus , acute  enterovirus infections  such as Coxsackievirus B3 have been identified as the cause of  virally induced   acute myocarditis , resulting in  dilated cardiomyopathy . [ 1 ]   Dilated cardiomyopathy in humans can be caused by multiple factors including hereditary defects in the cytoskeletal protein  dystrophin  in  Duchenne muscular dystrophy (DMD)  patients). A heart that undergoes dilated cardiomyopathy shows unique enlargement of ventricles, and thinning of the ventricular wall that may lead to heart failure.  In addition to the genetic defects in dystrophin or other cytoskeletal proteins, a subset of dilated cardiomyopathy is linked to enteroviral infection in the heart, especially coxsackievirus B. Enterovirus infections are responsible for about 30% of the cases of acquired dilated cardiomyopathy in humans. [ 2 ]


Coxsackievirus shows a cardiac tropism partly due to the high expression of coxsackievirus and adenovirus receptors (CAR) in cardiomyocytes. [ 3 ]  Coxsackievirus B genome is approximately 7.4 Kb and translated as a  polycistronic  polyprotein. Upon translation, the  polyprotein  is cleaved by two essential viral proteases, 2A and 3C. The viral protease 2A cleaves the proteins in a sequence specific manner. These viral proteases can also act on host proteins exerting negative effects on the residing cell. Enteroviral protease 2A can cleave the cytoskeletal dystrophin protein in cardiomyocytes disrupting the dystrophin glycoprotein (DCG) complex. The cleavage site of dystrophin by protease 2A occurs in the hinge 3 region of the protein resulting a disruption of DCG complex and loss of  sarcolemma  integrity and increasing myocyte permeability. This eventually results in similar cardiac deformities observed in dilated cardiomyopathy caused by hereditary defects in dystrophin in DMD patients. Additionally, dystrophin deficiency has been shown to increase the severity in dilated cardiomyopathy in a mouse model for DMD. The increased susceptibility of dystrophin deficient heart to coxsackievirus-induced dilated cardiomyopathy is attributed to more efficient release of the virus from infected cells resulting an increase in viral-mediated cytopathic effects. [ 4 ]


Viral-induced dilated cardiomyopathy can be characterized using different methods. A 2011 study showed in coxsackievirus infected heart  proteome , increased levels of fibrotic  extracellular matrix  proteins and reduced amounts of energy-producing enzymes can be observed suggesting they could be characteristic in enteroviral cardiomyopathy. [ 5 ]


There are notable differences between the hereditary dilated cardiomyopathy in DMD and acute coxsackieviral-mediated cardiomyopathy. [ 6 ]


A wide variety of treatment modalities are currently recommended including  Immunosuppressive agents ,  intravenous immunoglobulins (IVIG) , and  antiviral agents  although the effectiveness of these treatments are not well established and no specific treatment is available. [ 7 ]


Duroziez's disease  is a  congenital  variant of  mitral stenosis . It was described in 1877 by  Paul Louis Duroziez . [ 1 ]


Eisenmenger syndrome  or  Eisenmenger's syndrome  is defined as the process in which a long-standing left-to-right  cardiac shunt  caused by a  congenital heart defect  (typically by a  ventricular septal defect ,  atrial septal defect , or less commonly,  patent ductus arteriosus ) causes  pulmonary hypertension [ 1 ] [ 2 ]  and  eventual reversal of the shunt into a  cyanotic   right-to-left shunt . Because of the advent of fetal screening with  echocardiography  early in life, the incidence of heart defects progressing to Eisenmenger syndrome has decreased.


Eisenmenger syndrome in a  pregnant  mother can cause serious complications, [ 3 ]  though successful delivery has been reported. [ 4 ]  Maternal mortality ranges from 30% to 60%, and may be attributed to  fainting spells ,  blood clots forming in the veins and traveling to distant sites , hypovolemia,  coughing up blood  or  preeclampsia . Most deaths occur either during or within the first weeks after delivery. [ 5 ]  Pregnant women with Eisenmenger syndrome should be hospitalized after the 20th week of pregnancy, or earlier if clinical deterioration occurs.


Signs and symptoms of Eisenmenger syndrome include the following: [ 6 ]


One of the most severe and common complications of Eisenmenger syndrome is cardiac arrhythmia, especially  supraventricular arrhythmias . Approximately 40% of patients diagnosed with Eisenmenger syndrome were also found to have these arrhythmias during routine  ECG  screenings. These arrhythmias have worse  prognosis  in patients with Eisenmenger syndrome, compared to the general population, and can be a source of  sudden cardiac death . [ 9 ]


A number of congenital heart defects can cause Eisenmenger syndrome, including  atrial septal defects ,  ventricular septal defects ,  patent ductus arteriosus , and more complex types of acyanotic  heart disease . [ 1 ]


Diagnosis of Eisenmenger syndrome is typically conducted via  transthoracic echocardiography , which facilitates the identification and evaluation of shunts, anatomical defects, and ventricular function. Following diagnosis, or in some cases of inconclusive diagnosis, a  cardiac catheter  may be used to both confirm the diagnosis and to assess the patient's pulmonary arterial pressure, an important predictive value for prognosis and treatment. [ 9 ]


If the inciting defect in the heart is identified  before  it causes significant pulmonary hypertension, it can normally be repaired through surgery, preventing the disease. [ 10 ]  After  pulmonary hypertension  is sufficient to reverse the blood flow through the defect, however, the maladaptation is considered irreversible, and a  heart–lung transplant  or a  lung transplant  with repair of the heart is the only curative option.
Transplantation is the final therapeutic option and only for patients with poor prognosis and quality of life. Timing and appropriateness of transplantation remain difficult decisions. [ 5 ]  5-year and 10-year survival ranges between 70% and 80%, 50% and 70%, 30% and 50%, respectively. [ 11 ] [ 12 ] [ 13 ]  Since the average life expectancy of patients after lung transplantation is as low as 30% at 5 years, patients with  reasonable functional status  related to Eisenmenger syndrome have  improved survival with conservative medical care  compared with transplantation. [ 14 ]


Various medicines and therapies for pulmonary hypertension are under investigation for treatment of the symptoms. [ 15 ]


Antiarrhythmic drugs  are important for many patients with Eisenmenger syndrome, as evidence suggests that arrhythmia-induced sudden cardiac death may be the leading cause of death among patients with the disease. These therapies generally aim to restore and maintain sinus rhythm, but the specific interventions chosen will depend on the nature of the patient's arrhythmia. [ 9 ]


Eisenmenger syndrome was  named [ 16 ]  by Paul Wood after  Victor Eisenmenger , who first described [ 17 ]  the condition in 1897. [ 18 ]


Embryocardia  is a condition in which  S 1  and  S 2  ( the two  heart sounds  that produce the typical " lubb-dubb " sound of the heart) become indistinguishable and equally spaced. [ 1 ]  Thus the normal "lubb-dubb" rhythm of the heart becomes a "tic-toc" rhythm resembling the heart sounds of a  fetus . This indicates a serious loss of natural fluctuation and often precedes a fatal collapse. [ 2 ] [ 3 ]  This condition is observed in  myocarditis . [ 4 ]


Endocardial fibroelastosis  ( EFE ) is a rare  heart  disorder usually occurring in children two years old and younger. [ 1 ]  It may also be considered a reaction to stress, not necessarily a specific disease. [ 2 ]


It should not be confused with  endomyocardial fibrosis . [ citation needed ]


EFE is characterized by a thickening of the innermost lining of the heart chambers (the  endocardium ) due to an increase in the amount of supporting connective tissue and elastic fibres. It is an uncommon cause of unexplained  heart failure  in infants and children, and is one component of  HEC syndrome . Fibroelastosis is strongly seen as a primary cause of  restrictive cardiomyopathy  in children, along with  cardiac amyloidosis , which is more commonly seen in progressive multiple myeloma patients and the elderly. [ citation needed ]


A review cites references to 31 different diseases and other stresses associated with the EFE reaction. [ 2 ]  These include infections, cardiomyopathies, immunologic diseases, congenital malformations, even electrocution by lightning strike. EFE has two distinct  genetic  forms, each having a different mode of  inheritance . An  X-linked recessive  form, [ 3 ]  and an  autosomal   recessive  form [ 4 ]  have both been observed.


A Cardiac MRI can show eccentric patchy thickening of  endocardium which is a non-specific finding. Myocardial biopsy is a definitive test. [ citation needed ]


The cause should be identified and, where possible, the treatment should be directed to that cause. A last resort form of treatment is  heart transplant . [ 5 ]


An infant with dilated, failing heart was no rarity on the pediatric wards of hospitals in the mid-twentieth century. On autopsy, most of these patients' hearts showed the thickened endocardial layer noted above. This was thought to be a disease affecting both the heart muscle and the endocardium and it was given various names such as: idiopathic hypertrophy of the heart, endocardial sclerosis, cardiac enlargement of unknown cause, etc. Some of these hearts also had overt congenital anomalies, especially aortic stenosis and coarctation of the aorta. [ citation needed ]


The term "endocardial fibroelastosis" was introduced by Weinberg and Himmelfarb in 1943. [ 6 ]  In their pathology laboratory they noted that usually the  endocardium  was pearly white or opaque instead of normally thin and transparent and microscopically showed a systematic layering of collagenous and  elastic fibers . They felt their new term was more adequately descriptive, and, indeed it was quickly and widely adopted. Clinicians began applying it to any infant with a dilated, failing heart, in spite of the fact that the only way to definitively establish the presence of EFE was to see it at autopsy. EFE had quickly become the name of a disease, and it continues to be used by many physicians in this way, though many patients with identical symptoms do not have the endocardial reaction of EFE. [ citation needed ]


In the latter decades of the twentieth century, new discoveries and new thinking about heart muscle disease gave rise to the term "cardiomyopathy". Many of the cases of infantile cardiac failure were accordingly called "primary cardiomyopathy" as well as "primary EFE", while those with identifiable congenital anomalies stressing the heart were called "secondary EFE". In 1957 Black-Schaffer proposed a unitary explanation that stress on the ventricle, of any kind, may trigger the endocardial reaction, so that all EFE could be thought of as secondary. [ 7 ]


Evidence gradually accumulated as to the role of infection as one such type of stress. The studies of Fruhling and colleagues in 1962 were critical. [ 8 ]  They followed a series of epidemics of  Coxsackie virus  infection in their part of France. After each epidemic there were increased numbers of cases with EFE coming to autopsy. On closer study there were cases of pure acute myocarditis, cases of mixed myocarditis and EFE, and cases where myocarditis had healed, leaving just EFE. They were able to culture Coxsackie virus from the tissues of many of the cases at all stages  of this apparent progression. A similar progression from myocarditis to EFE was later observed at Johns Hopkins but no virology was done. [ 9 ]


Noren and colleagues at the  University of Minnesota , acting on an idea floated at a pediatric meeting, were able to show a relation between exposure to maternal  mumps  in fetal life, EFE, and a positive skin test for mumps in infants. [ 10 ]  This brought on a large ongoing controversy and finally prompted a virologist colleague of theirs to inject embryonated eggs with  mumps virus . [ 11 ]  The chicks at first showed the changes of myocarditis, about a year later, typical EFE, and transitional changes in between. Despite this, the controversy about the role of mumps continued as the actual incidence of EFE plummeted. The proponents of mumps as a cause pointed to this as the effect of the recent implementation of widespread mumps immunization. [ citation needed ]


Evidence that  viral  infection may play a role as a cause or trigger of EFE was greatly reinforced by the study directed by Towbin in the virus laboratory of  Texas Children's Hospital . [ 12 ]  They applied the methods of today's genetics to old preserved specimens from autopsies of patients with EFE done well before mumps immunization began and found mumps genome in the tissues of over 80% of these patients. It seems undeniable that transplacental mumps infection had been in the past the major cause of EFE, and that immunization was indeed the cause of EFE having become rare. [ citation needed ]


Non-infectious causes of EFE have also been studied, spurred by the opening of new avenues of genetics research. Now there are specific named genes associated with certain cardiomyopathies, some of which show the characteristic reaction of EFE. A typical example is Barth syndrome and the responsible gene, tafazzin. [ 13 ]


Developments in echocardiography, both the technology of the machines and the skill of the operators, have made it no longer necessary to see the endocardium at autopsy. EFE can now be found non-invasively by the recording of increased endocardial echos.  Fetal echocardiography has shown that EFE can begin to accumulate as early as 14 weeks of gestation, and increase with incredible rapidity [ 14 ]  and even that it can be reversed if the stress can be removed early in fetal life. [ 15 ]


The North American Pediatric Cardiomyopathy Registry was founded in 2000 and has been supported since by the National Heart, Lung and Blood Institute. Because of the logic of the diagnostic tree, where EFE applies to many branches of the tree and thus cannot occupy a branch, it is not listed by the Registry as a cause but rather, "with EFE" is a modifier that can be applied to any cause. [ 16 ]


Thus, the past half-century has seen EFE evolve from a mysterious but frequently observed disease to a rare but much better understood reaction to many diseases and other stresses. [ citation needed ]


Eosinophilic myocarditis  is  inflammation  in the  heart muscle  that is caused by the infiltration and destructive activity of a type of  white blood cell , the  eosinophil . Typically, the disorder is associated with  hypereosinophilia , i.e. an eosinophil blood cell count greater than 1,500 per microliter (normal 100 to 400 per microliter). It is distinguished from non-eosinophilic  myocarditis , which is heart inflammation caused by other types of white blood cells, i.e.  lymphocytes  and  monocytes , as well as the respective descendants of these cells,  NK cells  and  macrophages . This distinction is important because the eosinophil-based disorder is due to a particular set of underlying diseases and its preferred treatments differ from those for non-eosinophilic myocarditis. [ 1 ] [ 2 ]


Eosinophilic myocarditis is often viewed as a disorder that has three progressive stages. The first stage of eosinophilic myocarditis involves acute inflammation and cardiac cell  necrosis  (i.e. areas of dead cells); it is dominated by symptoms characterized as the  acute coronary syndrome  such as  angina ,  heart attack  and/or  congestive heart failure . The second stage is a thrombotic stage wherein the  endocardium  (i.e. interior wall) of the diseased heart forms  blood clots  which  break off, travel in, and block blood  through  systemic  or  pulmonary  arteries; this stage may dominate the initial presentation in some individuals. The third stage is a fibrotic stage wherein  scarring  replaces damaged heart muscle tissue to cause a clinical presentation dominated by a poorly contracting heart and  cardiac valve disease . [ 3 ] [ 4 ] [ 5 ]  Perhaps less commonly, eosinophilic myocarditis, eosinophilic thrombotic myocarditis, and eosinophilic fibrotic myocarditis are viewed as three separate but sequentially linked disorders in a spectrum of disorders termed eosinophilic cardiac diseases. [ 1 ]  The focus here is on eosinophilic myocarditis as a distinct disorder separate from its thrombotic and fibrotic sequelae.


Eosinophilic myocarditis is a rare disorder. It is usually associated with, and considered secondary to, an underlying cause for the pathological behavior of the eosinophils such a  toxic reaction to a drug  (one of its more common causes in developed nations), the consequence of certain types of  parasite  and  protozoan   infections  (a more common cause of the disorder in areas with these infestations), or the result of  excessively high levels of activated blood eosinophils  due to a wide range of other causes. [ 6 ]  The specific treatment (i.e. treatment other than measures to support the cardiovascular system) of eosinophilic myocarditis differs from the specific treatment of other forms of myocarditis in that it is focused on relieving the underlying reason for the excessively high numbers and hyperactivity of eosinophils as well as on inhibiting the pathological actions of these cells. [ 6 ] [ 7 ] [ 8 ]


Symptoms in eosinophilic myocarditis are highly variable. They tend to reflect the many underlying disorders causing eosinophil dysfunction as well as the widely differing progression rates of cardiac damage. Before cardiac symptoms are detected, some 66% of cases have symptoms of a common cold and 33% have symptoms of  asthma ,  rhinitis ,  urticarial , or other allergic disorder. Cardiac manifestations of eosinophilic myocarditis range from none to life-threatening conditions such as  cardiogenic shock  or sudden death due to abnormal  heart rhythms . More commonly the presenting cardiac symptoms of the disorder are the same as those seen in other forms of heart disease:  chest pain , shortness of breath, fatigue, chest  palpitations , light headedness, and  syncope . [ 7 ]  In its most extreme form, however, eosinophilic myocarditis can present as acute necrotizing eosinophilic myocarditis, i.e. with symptoms of chaotic and potentially lethal  heart failure  and  heart arrhythmias . This rarest form of the disorder reflects a rapidly progressive and extensive eosinophilic infiltration of the heart that is accompanied by massive  myocardial  cell  necrosis . [ 1 ] [ 9 ]


Hypereosinophilia  (i.e. blood eosinophil counts at or above 1,500 per microliter) or, less commonly,  eosinophilia  (counts above 500 but below 1,500 per microliter) are found in the vast majority of cases of eosinophilic myocarditis and are valuable clues that point to this rather than other types of myocarditis or myocardial injuries. However, elevated blood eosinophil counts may not occur during the early phase of the disorder. Other, less specific laboratory findings implicate a cardiac disorder but not necessarily eosinophilic myocarditis. These include elevations in blood markers for systemic inflammation (e.g.  C reactive protein ,  erythrocyte sedimentation rate ), elevations in blood markers for cardiac injury (e.g.  creatine kinase ,  troponins ); and abnormal  electrocardiograms  ( mostly  ST segment - T wave  abnormalities). [ 7 ]


There are many  causes of eosinophilia  that may underlie eosinophilic myocarditis. These causes are classified as primary (i.e. a defect intrinsic to the eosinophil cell line), secondary (induced by an underlying disorder that stimulates the proliferation and activation of eosinophils), or  idiopathic  (i.e. unknown cause). Non-idiopathic causes of the disorder are sub-classified into various forms of  allergic ,  autoimmune ,  infectious , or  malignant  diseases and  hypersensitivity reactions  to drugs, vaccines, or transplanted hearts. While virtually any cause for the elevation and activation of blood eosinophils must be considered as a potential cause for eosinophilic myocarditis,  the following list gives the principal types of eosinophilia known or thought to underlie the disorder. [ citation needed ]


Primary conditions that may lead to eosinophilic myocarditis are:


Secondary conditions that may lead to eosinophilic myocarditis are:


The DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe immunological  drug reaction . It differs from other drug reactions in that it:  a)  is caused by a particular set of drugs;  b)  typically occurs after a delay of 2 to 8 weeks following intake of an offending drug;  c)  presents with a specific set of signs and symptoms (i.e.  modest  or  extreme  elevations in blood  eosinophil  and  atypical lymphocyte  counts; acute onset of a skin rash;  lymphadenopathy ; fever;  neuralgia ; and involvement of at least one internal organ such as the liver, lung, or heart;  d)  develops in individuals with particular genetic predispositions; and  e)  involves reactivation of  latent viruses , most commonly  human herpesvirus 6  or more rarely  human herpes virus 5  (i.e. human cytomegalovirus),  human herpesvirus 7 , and  human herpesvirus 4  (i.e. Epstein–Barr virus). These viruses usually become dormant after infecting humans but under special circumstances, such as drug intake, are reactivated and may contribute to serious diseases such as the DRESS syndrome. [ 20 ] [ 21 ]


Eosinophils normally function to neutralize invading microbes, primarily  parasites  but also certain types of fungi and viruses. In conducting these functions, eosinophils normally occupy the gastrointestinal tract, respiratory tract, and skin where they produce and release on demand a range of toxic reactive oxygen species (e.g.  hypobromite ,  hypobromous acid ,  superoxide , and  peroxide ) and also release on demand a preformed armamentarium of chemical signals including  cytokines ,  chemokines ,  growth factors , lipid mediators (e.g.  leukotrienes ,  prostaglandins ,  platelet activating factor ,  5-oxo-eicosatetraenoic acid ), and toxic proteins (e.g.  metalloproteinases ,  major basic protein ,  eosinophil cationic protein ,  eosinophil peroxidase , and  eosinophil-derived neurotoxin ). These agents serve to orchestrate robust  inflammatory responses  that destroy invading  microorganisms . Eosinophils also participate in  transplant rejection ,  Graft-versus-host disease , the destruction or walling off of foreign objects, and the killing of  cancer cells . In conducting these functions, eosinophils enter tissues that they do not normally occupy. [ citation needed ]


When overproduced and over-activated, such as in cases of eosinophilic myocarditis, eosinophils behave as though they were attacking a foreign or malignant tissue: they enter a seemingly normal organ such as the heart, misdirect their reactive oxygen species and armamentarium of preformed molecules toward seemingly normal tissue such as heart muscle, and thereby produce serious damage such as heart failure. [ 1 ] [ 22 ] [ 23 ] [ 24 ]  Animal model studies suggest reasons why eosinophils are directed to and injure the heart muscle. Mice made hypereosinophilic by the forced overexpression of an interleukin-5 transgene ( interleukin 5  stimulates eosinophil proliferation, activation, and migration) develop eosinophilic myocarditis. A similar eosinophilic endocarditis occurs in mice immunized with the cardiac muscle protein, mouse myosin. In the latter model, endocarditis is reduced by inhibiting the cytokine  interleukin-4  or eosinophils and is exacerbated by concurrently blocking two cytokines,  interferon gamma  and  interleukin-17A . Finally, certain eosinophil- attracting  agents, viz.,  eotaxins , are elevated in the cardiac tissue of myosin-immunized mice that are concurrently depleted of interferon-gamma and interleukin-17A. Eotaxins are also elevated in the cardiac muscle biopsy specimens of individuals with eosinophilic myocarditis compared to their levels in non-eosinophilic myocarditis. These findings suggest that eosinophilic myocarditis is caused by the abnormal proliferation and activation of eosinophils and that their directional migration into the heart is evoked by a set of cytokines and chemoattractants in mice and possibly humans. [ 3 ]


In eosinophilic myocarditis,  echocardiography  typically gives non-specific and only occasional findings of  endocardium  thickening,  left ventricular hypertrophy , left ventricle dilation, and involvement of the  mitral  and/or  tricuspid valves . However, in acute necrotizing eosinophilic myocarditis, echocardiography usually gives diagnostically helpful evidence of a non-enlarged heart with a thickened and poorly contracting  left ventricle .  Gadolinium -based  cardiac magnetic resonance  imaging is the most useful  non-invasive procedure  for diagnosing eosinophilic myocarditis. It supports this diagnosis if it shows at least two of the following abnormalities:  a)  an increased signal in  T2-weighted images ;  b)  an increased global myocardial early enhancement ratio between myocardial and  skeletal muscle  in enhanced  T1 images  and  c)  one or more focal enhancements distributed in a non-vascular pattern in late enhanced T1-weighted images. Additionally, and unlike in other forms of myocarditis, eosinophilic myocarditis may also show enhanced gadolinium uptake in the sub-endocardium. [ 1 ] [ 7 ]  However, the only definitive test for eosinophilic myocarditis is cardiac muscle biopsy showing the presence of eosinophilic infiltration. Since the disorder may be patchy, multiple tissue samples taken during the procedure improve the chances of uncovering the pathology but in any case, negative results do not exclude the diagnosis. [ 5 ] [ 7 ]


Eosinophilic coronary periarteritis is an extremely rare heart disorder caused by extensive eosinophilic infiltration of the  adventitia  and periadventitia, i.e. the soft tissues, surrounding the  coronary arteries . The  intima ,  tunica media , and  tunica intima  layers of these arteries remain intact and are generally unaffected. Thus, this disorder is characterized by episodes of  angina , particularly  Prinzmetal's angina , and chaotic heart  arrhythmias  which may lead to sudden death. The disorder is considered distinct from eosinophilic myocarditis as well as other forms of  inflammatory arterial disorders  in that it is limited to the coronary artery system. [ 1 ] [ 25 ]


Due to its rarity, no comprehensive treatment studies on eosinophilic myocarditis have been conducted. Small studies and  case reports  have directed efforts towards:  a)  supporting cardiac function by relieving heart failure and suppressing life-threatening  abnormal heart rhythms ;  b)  suppressing eosinophil-based cardiac inflammation; and  c)  treating the underlying disorder. In all cases of symptomatic eosinophilic myocarditis that lack specific treatment regimens for the underlying disorder, available studies recommend treating the inflammatory component of this disorder with non-specific  immunosuppressive drugs , principally high-dosage followed by slowly tapering to a low-dosage maintenance  corticosteroid  regimens. It is recommended that affected individuals who fail this regimen or present with  cardiogenic shock  be treated with other non-specific immunosuppressive drugs viz.,  azathioprine  or  cyclophosphamide , as adjuncts to, or replacements for, corticosteroids. However, individuals with an underlying therapeutically accessible disease should be treated for this disease; in seriously symptomatic cases, such individuals may be treated concurrently with a corticosteroid regimen. Examples of diseases underlying eosinophilic myocarditis that are recommended for treatments directed at the underlying disease include  [ 6 ] [ 7 ] [ 12 ] [ 26 ]


The prognosis of eosinophilic myocarditis is anywhere from rapidly fatal to extremely chronic or non-fatal. Progression at a moderate rate over many months to years is the most common prognosis. [ 1 ] [ 9 ]  In addition to the speed of inflammation-based heart muscle injury, the prognosis of eosinophilic myocarditis may be dominated by that of its underlying cause. For example, an underlying malignant cause for eosinophilia may be survival-limiting. [ 6 ] [ 9 ]


In 1936, the famed Swiss physician  Wilhem Löffler  first described heart damage that appeared due to massive cardiac eosinophil infiltrations and was associated with excessively high levels of blood eosinophils. Subsequent cases of this disorder, termed  Loeffler endocarditis , were found to occur in about 20% of individuals diagnosed with the  hypereosinophilic syndrome . Loeffler's and the latter cases had pathological features of eosinophil infiltrations not only into the heart's  myocardium  but also its  epicardium  (i.e. lining of the heart chambers). Although eosinophilic myocarditis due to other underlying causes may show little or no eosinophil infiltrations into the endocardium, Loeffler endocarditis is considered an important form of the disorder. [ 4 ]


Heart failure  ( HF ), also known as  congestive heart failure  ( CHF ), is a  syndrome  caused by an impairment in the  heart 's ability to  fill with and pump   blood .


Although symptoms vary based on which side of the heart is affected, HF typically presents with  shortness of breath ,  excessive fatigue , and bilateral  leg swelling . [ 3 ]  The severity of the heart failure is mainly decided based on  ejection fraction  and also measured by the severity of symptoms. [ 7 ]  Other conditions that have symptoms similar to heart failure include  obesity ,  kidney failure ,  liver disease ,  anemia , and  thyroid disease . [ 7 ]


Common causes of heart failure include  coronary artery disease ,  heart attack ,  high blood pressure ,  atrial fibrillation ,  valvular heart disease ,  excessive alcohol consumption ,  infection , and  cardiomyopathy . [ 4 ] [ 6 ]  These cause heart failure by altering the structure or the function of the heart or in some cases both. [ 6 ]  There are different types of heart failure:  right-sided heart failure , which affects the  right heart ,  left-sided heart failure , which affects the  left heart , and biventricular heart failure, which affects both sides of the heart. [ 11 ]  Left-sided heart failure may be present with a reduced  ejection fraction  or with a  preserved ejection fraction . [ 10 ]  Heart failure is not the same as  cardiac arrest , in which blood flow stops completely due to the failure of the heart to pump. [ 12 ] [ 13 ]


Diagnosis is based on symptoms, physical findings, and  echocardiography . [ 6 ]   Blood tests , and a  chest x-ray  may be useful to determine the underlying cause. [ 14 ]  Treatment depends on severity and case. [ 15 ]  For people with chronic, stable, or mild heart failure, treatment usually consists of lifestyle changes, such as  not smoking ,  physical exercise , and dietary changes, as well as medications. [ 16 ] [ 17 ] [ 18 ]  In heart failure due to left ventricular dysfunction,  angiotensin-converting-enzyme inhibitors ,  angiotensin II receptor blockers  (ARBs), or  angiotensin receptor-neprilysin inhibitors , along with  beta blockers ,  mineralocorticoid receptor antagonists  and  SGLT2 inhibitors  are recommended. [ 6 ]   Diuretics  may also be prescribed to prevent fluid retention and the resulting shortness of breath. [ 19 ]  Depending on the case, an implanted device such as a  pacemaker  or  implantable cardiac defibrillator   may sometimes be recommended. [ 15 ]  In some moderate or more severe cases,  cardiac resynchronization therapy  (CRT) [ 20 ]  or  cardiac contractility modulation  may be beneficial. [ 21 ]  In severe disease that persists despite all other measures, a cardiac assist device  ventricular assist device , or, occasionally,  heart transplantation  may be recommended. [ 19 ]


Heart failure is a common, costly, and potentially fatal condition, [ 22 ]  and is the leading cause of hospitalization and readmission in older adults. [ 23 ] [ 24 ]  Heart failure often leads to more drastic health impairments than the failure of other, similarly complex  organs  such as the kidneys or liver. [ 25 ]  In 2015, it affected about 40 million people worldwide. [ 8 ]  Overall, heart failure affects about 2% of adults, [ 22 ]  and more than 10% of those over the age of 70. [ 6 ]  Rates are predicted to increase. [ 22 ]


The risk of  death  in the first year after diagnosis is about 35%, while the risk of death in the second year is less than 10% in those still alive. [ 10 ]  The risk of death is comparable to that of some cancers. [ 10 ]  In the United Kingdom, the disease is the reason for 5% of emergency hospital admissions. [ 10 ]  Heart failure has been known since ancient times in  Egypt ; it is mentioned in the  Ebers Papyrus  around 1550 BCE. [ 26 ]


When the heart functions poorly as a pump and does not circulate blood adequately via the  circulatory system  to meet the demands of the body the term cardiovascular insufficiency is sometimes used. This generally leads to the syndrome of heart failure, a combination of  signs and symptoms [ 6 ] : 3612  [ 3 ]  It develops when the heart fails to properly fill with blood during  diastole , resulting in a decrease in  intracardiac pressures  or in ejection during  systole , reducing cardiac output to the rest of the body. [ 6 ] : 3612  [ 4 ] : e272   The filling failure and high intracardiac pressure can lead to fluid accumulation in ventricles of the heart. This manifests as water retention and swelling due to fluid accumulation ( edema ) called  congestion . Impaired ejection can lead to inadequate blood flow to the body tissues, resulting in  ischemia . [ 27 ] [ 28 ]


Congestive heart failure is a  pathophysiological  condition in which the  heart's output  is insufficient to meet the needs of the body and lungs. [ 10 ]  The term "congestive heart failure" is often used because one of the most common symptoms is  congestion  or fluid accumulation in the tissues and veins of the lungs or other parts of a person's body. [ 10 ]


Congestion manifests itself particularly in the form of  fluid accumulation and swelling (edema) , in the form of  peripheral edema  (causing swollen limbs and feet) and  pulmonary edema  (causing difficulty breathing) and  ascites  (swollen abdomen). [ 28 ]   Pulse pressure , which is the difference between the systolic ("top number") and diastolic ("bottom number") blood pressures, is often low/narrow (i.e. 25% or less of the level of the systolic) in people with heart failure, and this can be an early warning sign. [ 29 ]


Symptoms of heart failure are traditionally divided into left-sided and right-sided because the left and right ventricles supply different parts of the circulation. In biventricular heart failure, both sides of the heart are affected. Left-sided heart failure is the more common. [ 30 ]


The left side of the heart takes oxygen-rich blood from the lungs and pumps it to the rest of the  circulatory system  in the body (except for the  pulmonary circulation ). Failure of the left side of the heart causes blood to back up into the lungs, causing breathing difficulties and fatigue due to an insufficient supply of oxygenated blood. Common respiratory signs include  increased respiratory rate  and labored breathing (nonspecific signs of shortness of breath).  Rales  or crackles are heard initially in the lung bases and when severe in all  lung fields  indicate the development of  pulmonary edema  (fluid in the  alveoli ).  Cyanosis , indicates  deficiency of oxygen in the blood , is a late sign of extremely severe pulmonary edema. [ 31 ]


Other signs of left ventricular failure include a laterally displaced  apex beat  (which occurs when the heart is enlarged) and a  gallop rhythm  (additional heart sounds), which may be heard as a sign of increased blood flow or increased intracardiac pressure.  Heart murmurs  may indicate the presence of valvular heart disease, either as a cause (e.g.,  aortic stenosis ) or as a consequence (e.g.,  mitral regurgitation ) of heart failure. [ 32 ]


Reverse  insufficiency of the left ventricle causes congestion in the blood vessels of the lungs so that symptoms are predominantly respiratory. Reverse insufficiency can be divided into the failure of the left atrium, the left ventricle, or both within the left circuit. Patients will experience  shortness of breath (dyspnea)  on exertion and, in severe cases, dyspnea at rest. Increasing breathlessness while lying down, called  orthopnea , also occurs. It can be measured by the number of pillows required to lie comfortably, with extreme cases of orthopnea forcing the patient to sleep sitting up. Another symptom of heart failure is  paroxysmal nocturnal dyspnea : a sudden nocturnal attack of severe shortness of breath, usually occurring several hours after falling asleep. [ 33 ]  There may be " cardiac asthma " or  wheezing . Impaired left ventricular  forward  function can lead to symptoms of poor systemic perfusion such as  dizziness ,  confusion , and cool extremities at rest. Loss of consciousness may also occur due to loss of blood supply to the brain. [ 34 ]


Right-sided heart failure is often caused by  pulmonary heart disease  (cor pulmonale), which is typically caused by issues with  pulmonary circulation  such as  pulmonary hypertension  or  pulmonic stenosis . Physical examination may reveal pitting peripheral edema, ascites,  liver enlargement , and  spleen enlargement .  Jugular venous pressure  is frequently assessed as a marker of fluid status, which can be accentuated by testing  hepatojugular reflux . If the right ventricular pressure is increased, a  parasternal heave  which causes the compensatory increase in contraction strength may be present. [ 35 ]


Backward  failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin ( peripheral edema  or  anasarca ) and usually affects the dependent parts of the body first, causing foot and ankle swelling in people who are standing up and  sacral  edema in people who are predominantly lying down.  Nocturia  (frequent night-time urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and liver enlargement may develop. Significant liver congestion may result in impaired liver function ( congestive hepatopathy ), jaundice, and  coagulopathy  (problems of decreased or increased blood clotting). [ 36 ]


Dullness of the lung fields when  percussed  and reduced breath sounds at the base of the lungs may suggest the development of a  pleural effusion  (fluid collection  between the lung and the chest wall ). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain into both the systemic and pulmonary venous systems. When unilateral, effusions are often right-sided. [ 37 ]


If a person with a failure of one ventricle lives long enough, it will tend to progress to failure of both ventricles. For example, left ventricular failure allows pulmonary edema and pulmonary hypertension to occur, which increases stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side. [ 38 ]


Since heart failure is a  syndrome  and not a disease, establishing the underlying cause is vital to diagnosis and treatment. [ 39 ] [ 30 ]  In heart failure, the structure or the function of the heart or in some cases both are altered. [ 6 ] : 3612   Heart failure is the potential end stage of all heart diseases. [ 40 ]


Common causes of heart failure include  coronary artery disease , including a previous  myocardial infarction  (heart attack),  high blood pressure ,  atrial fibrillation ,  valvular heart disease ,  excess alcohol use ,  infection , and  cardiomyopathy  of an unknown cause. [ 9 ] [ 4 ] : e279  [ 6 ] : Table 5   In addition, viral infection and subsequent inflammation of the heart's myocardial tissue (termed  myocarditis ) can similarly contribute to the development of heart failure. Genetic predisposition plays an important role. If more than one cause is present, progression is more likely and prognosis is worse. [ 41 ]


Heart damage  can predispose a person to develop heart failure later in life and has many causes including systemic viral infections (e.g.,  HIV ),  chemotherapeutic agents  such as  daunorubicin ,  cyclophosphamide ,  trastuzumab  and  substance use disorders  of substances such as  alcohol ,  cocaine , and  methamphetamine . An uncommon cause is exposure to certain toxins such as  lead  and  cobalt . Additionally, infiltrative disorders such as  amyloidosis  and  connective tissue diseases  such as  systemic lupus erythematosus  have similar consequences.  Obstructive sleep apnea  (a condition of sleep wherein disordered breathing overlaps with obesity, hypertension, and/or diabetes) is regarded as an independent cause of heart failure. [ 42 ]  Recent reports from  clinical trials  have also linked variation in blood pressure to heart failure [ 43 ] [ 44 ]  and cardiac changes that may give rise to heart failure. [ 45 ]


High-output heart failure  happens when the amount of blood pumped out is more than typical and the heart cannot keep up. [ 46 ]  This can occur in  overload  situations such as blood or serum infusions, kidney diseases, chronic severe  anemia ,  beriberi  (vitamin B 1 / thiamine  deficiency),  hyperthyroidism ,  cirrhosis ,  Paget's disease ,  multiple myeloma ,  arteriovenous fistulae , or  arteriovenous malformations . [ 47 ] [ 48 ]


Chronic stable heart failure may easily  decompensate  (fail to meet the body's metabolic needs). This most commonly results from a concurrent illness (such as  myocardial infarction  (a heart attack) or  pneumonia ),  abnormal heart rhythms , uncontrolled  hypertension , or a person's failure to maintain a fluid restriction, diet, or medication. [ 49 ]


Other factors that may worsen CHF include: anemia, hyperthyroidism, excessive fluid or salt intake, and medication such as  NSAIDs  and  thiazolidinediones . [ 50 ]  NSAIDs increase the risk twofold. [ 51 ]


A number of medications may cause or worsen the disease. This includes  NSAIDs ,  COX-2 inhibitors , a number of  anesthetic  agents such as  ketamine , thiazolidinediones, some  cancer medications , several  antiarrhythmic medications ,  pregabalin ,  alpha-2 adrenergic receptor agonists ,  minoxidil ,  itraconazole ,  cilostazol ,  anagrelide ,  stimulants  (e.g.,  methylphenidate ),  tricyclic antidepressants ,  lithium ,  antipsychotics ,  dopamine agonists ,  TNF inhibitors ,  calcium channel blockers  (especially  verapamil  and  diltiazem [ 52 ] [ 53 ] ),  salbutamol , and  tamsulosin . [ 54 ]


By inhibiting the formation of  prostaglandins , NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing  blood pressure , and decreasing a person's response to diuretic medications. [ 54 ]  Similarly, the ACC/AHA recommends against using COX-2 inhibitor medications in people with heart failure. [ 54 ]  Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. [ 54 ]  Certain calcium channel blockers, such as  diltiazem  and  verapamil , are known to  decrease the force with which the heart ejects blood , thus are not recommended in people with heart failure with a reduced ejection fraction. [ 54 ]


Breast cancer patients are at high risk of heart failure due to several factors. [ 55 ]  After analyzing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). [ 56 ]  The pooled incidence of heart failure in breast cancer survivors was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up. [ 56 ]


Certain  alternative medicines  carry a risk of exacerbating existing heart failure, and are not recommended. [ 54 ]  This includes  aconite ,  ginseng ,  gossypol ,  gynura ,  licorice ,  lily of the valley ,  tetrandrine , and  yohimbine . [ 54 ]  Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. [ 54 ]  Ginseng can cause abnormally low or high blood pressure and may interfere with the effects of diuretic medications. Gossypol can increase the effects of diuretics, leading to toxicity.


Gynura can cause low blood pressure. Licorice can worsen heart failure by increasing blood pressure and promoting fluid retention. [ 54 ]  Lily of the Valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lower blood pressure by inhibiting  L-type calcium channels . Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism. [ 54 ]


Heart failure is caused by any condition that reduces the efficiency of the heart muscle, through damage or  overloading . Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the  renin–angiotensin system  and the sympathoadrenal system, lead to  fibrosis , dilation, and structural changes in the shape of the left ventricle from elliptical to spherical. [ 22 ]


The heart of a person with heart failure may have a reduced force of contraction due to overloading of the  ventricle . In a normal heart, increased filling of the ventricle results in increased contraction force by the  Frank–Starling law of the heart , and thus a rise in  cardiac output . In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to the reduced ability to cross-link  actin  and  myosin   myofilaments  in over-stretched heart muscle. [ 57 ]


No diagnostic criteria have been agreed on as the  gold standard  for heart failure, especially  heart failure with preserved ejection fraction  (HFpEF).


In the  UK , the  National Institute for Health and Care Excellence  recommends measuring  N-terminal pro-BNP (NT-proBNP)  followed by an  ultrasound of the heart  if positive. [ 14 ]  In  Europe , the  European Society of Cardiology , and in the United States, the  AHA / ACC / HFSA , recommend measuring NT-proBNP or BNP followed by an  ultrasound of the heart  if positive. [ 6 ] [ 4 ]  This is recommended in those with symptoms consistent with heart failure such as  shortness of breath . [ 4 ]


The  European Society of Cardiology  defines the diagnosis of heart failure as symptoms and signs consistent with heart failure in combination with "objective evidence of cardiac structural or functional abnormalities". [ 6 ]  This definition is consistent with an international 2021 report termed "Universal Definition of Heart Failure". [ 6 ] : 3613   Score-based algorithms have been developed to help in the diagnosis of  HFpEF , which can be challenging for physicians to diagnose. [ 6 ] : 3630   The  AHA / ACC / HFSA  defines heart failure as symptoms and signs consistent with heart failure in combination with shown "structural and functional alterations of the heart as the underlying cause for the clinical presentation", for HFmrEF and HFpEF specifically requiring "evidence of spontaneous or provokable increased left ventricle filling pressures". [ 4 ] : e276–e277


The  European Society of Cardiology  has developed a diagnostic algorithm for  HFpEF , named HFA-PEFF. [ 6 ] : 3630  [ 58 ]  HFA-PEFF considers symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes, elderly, atrial fibrillation), and diagnostic laboratory tests, ECG, and echocardiography. [ 4 ] : e277  [ 58 ]


One historical method of categorizing heart failure is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the  aorta  and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common, and left heart failure is a common cause of right heart failure. [ 59 ]


A more accurate classification of heart failure type is made by measuring  ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. [ 60 ]  Ejection fraction is given as a percentage with the normal range being between 50 and 75%. [ 60 ]  The types are:


Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms.  Acute decompensated heart failure  is a worsening of chronic heart failure symptoms, which can result in  acute respiratory distress . [ 66 ]   High-output heart failure  can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). [ 46 ]


Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it.  Cardiac arrest  and  asystole  refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked  coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. [ 67 ]  Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease.  Dilated cardiomyopathy  implies that the muscle damage has resulted in enlargement of the heart. [ 68 ]   Hypertrophic cardiomyopathy  involves enlargement and  thickening  of the heart muscle. [ 69 ]


An  echocardiogram  ( ultrasound  of the heart) is commonly used to support a clinical diagnosis of heart failure. This can determine the  stroke volume  (SV, the amount of blood in the heart that exits the ventricles with each beat), the  end-diastolic volume  (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the  ejection fraction  (EF). In pediatrics, the  shortening fraction  is the preferred measure of systolic function. Normally, the EF should be between 50 and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the  pericardium  (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding specific treatments, such as medication, insertion of an  implantable cardioverter-defibrillator , or  cardiac resynchronization therapy . Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and may manifest as regional wall motion abnormalities on echo. [ 70 ]


Chest X-rays  are frequently used to aid in the diagnosis of CHF. In a person who is compensated, this may show  cardiomegaly  (visible enlargement of the heart), quantified as the  cardiothoracic ratio  (proportion of the heart size to the chest). In left ventricular failure, evidence may exist of vascular redistribution (upper lobe blood diversion or cephalization),  Kerley lines ,  cuffing of the areas around  the  bronchi , and interstitial edema. Ultrasound of the lung may also detect Kerley lines. [ 72 ]


An  electrocardiogram  (ECG or EKG) may be used to identify  arrhythmias ,  ischemic heart disease ,  right  and  left ventricular hypertrophy , and presence of conduction delay or abnormalities (e.g.  left bundle branch block ). Although these findings are not specific to the diagnosis of heart failure, a normal ECG virtually excludes left ventricular systolic dysfunction. [ 73 ]


N-terminal pro-BNP (NT-proBNP)  is the favored biomarker for the diagnosis of heart failure, according to guidelines published 2018 by  NICE  in the  UK . [ 3 ]   Brain natriuretic peptide 32  (BNP) is another biomarker commonly tested for heart failure. [ 74 ] [ 6 ] [ 75 ]  An elevated NT-proBNP or BNP is a specific test indicative of heart failure. Additionally, NT-proBNP or BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If a myocardial infarction is suspected, various  cardiac markers  may be used.


Blood tests  routinely performed include  electrolytes  ( sodium ,  potassium ), measures of  kidney function ,  liver function tests ,  thyroid function tests , a  complete blood count , and often  C-reactive protein  if infection is suspected.


Hyponatremia  (low serum sodium concentration) is common in heart failure.  Vasopressin  levels are usually increased, along with renin, angiotensin II, and catecholamines to compensate for reduced circulating volume due to inadequate cardiac output. This leads to increased fluid and sodium retention in the body; the rate of fluid retention is higher than the rate of sodium retention in the body, this phenomenon causes hypervolemic hyponatremia (low sodium concentration due to high body fluid retention). This phenomenon is more common in older women with low body mass. Severe hyponatremia can result in accumulation of fluid in the brain, causing  cerebral edema  and  intracranial hemorrhage . [ 76 ]


Angiography  is the  X-ray  imaging of  blood vessels , which is done by injecting contrast agents into the  bloodstream  through a thin plastic tube ( catheter ), which is placed directly in the blood vessel. X-ray images are called angiograms. [ 77 ]  Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the  coronary arteries  to supply blood to the  myocardium  (heart muscle). As a result,  coronary catheterization  may be used to identify possibilities for revascularisation through  percutaneous coronary intervention  or  bypass surgery .


Heart failure is commonly stratified by the degree of functional impairment conferred by the severity of the heart failure, as reflected in the  New York Heart Association (NYHA) functional classification . [ 78 ]  The NYHA functional classes (I–IV) begin with class I, which is defined as a person who experiences no limitation in any activities and has no symptoms from ordinary activities. People with NYHA class II heart failure have slight, mild limitations with everyday activities; the person is comfortable at rest or with mild exertion. With NYHA class III heart failure, a marked limitation occurs with any activity; the person is comfortable only at rest. A person with NYHA class IV heart failure is symptomatic at rest and becomes quite uncomfortable with any physical activity. This score documents the severity of symptoms and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and does not reliably predict walking distance or exercise tolerance on formal testing. [ 79 ]


In its 2001 guidelines, the  American College of Cardiology / American Heart Association  working group introduced four stages of heart failure: [ 80 ]


The ACC staging system is useful since stage A encompasses "pre-heart failure" – a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC stage B would correspond to NYHA class I. ACC stage C corresponds to NYHA class II and III, while ACC stage D overlaps with NYHA class IV.


Histopathology  can diagnose heart failure in  autopsies . The presence of  siderophages  indicates chronic left-sided heart failure, but is not  specific  for it. [ 81 ]  It is also indicated by congestion of the pulmonary circulation.


A person's risk of developing heart failure is inversely related to the level of  physical activity . Those who achieved at least 500  MET-minutes/week  (the recommended minimum by U.S. guidelines) had lower heart failure risk than individuals who did not report exercising during their free time; the reduction in heart failure risk was even greater in those who engaged in higher levels of physical activity than the recommended minimum. [ 82 ]
Heart failure can also be prevented by lowering high blood pressure and high blood cholesterol, and by controlling diabetes. Maintaining a healthy weight, and decreasing sodium, alcohol, and sugar intake, may help. Additionally, avoiding tobacco use has been shown to lower the risk of heart failure. [ 83 ]


According to  Johns Hopkins  and the  American Heart Association  there are a few ways to help prevent a cardiac event. Johns Hopkins states that stopping tobacco use, reducing high blood pressure, physical activity, and nutrition can drastically affect the chances of developing heart disease. High blood pressure accounts for most cardiovascular deaths. High blood pressure can be lowered into the normal range by making dietary decisions such as consuming less salt. Exercise also helps to bring blood pressure back down. One of the best ways to help avoid heart failure is to promote healthier eating habits like eating more vegetables, fruits, grains, and lean protein. [ 84 ]


Diabetes is a major risk factor for heart failure. For women with Coronary Heart disease (CHD), diabetes was the strongest risk factor for heart failure. [ 85 ]  Diabetic women with depressed creatinine clearance or elevated BMI were at the highest risk of heart failure. While the annual incidence rate of heart failure for non-diabetic women with no risk factors is 0.4%, the annual incidence rate for diabetic women with elevated body mass index (BMI) and depressed creatinine clearance was 7% and 13%, respectively. [ 86 ]


Treatment focuses on improving the symptoms and preventing the progression of the disease. Reversible causes of heart failure also need to be addressed (e.g.  infection , alcohol ingestion, anemia,  thyrotoxicosis ,  arrhythmia , and hypertension). Treatments include lifestyle and pharmacological modalities, and occasionally various forms of device therapy. Rarely, cardiac transplantation is used as an effective treatment when heart failure has reached the end stage. [ 87 ]


In  acute decompensated heart failure , the immediate goal is to re-establish adequate perfusion and oxygen delivery to end organs. This entails ensuring that  airway, breathing, and circulation  are adequate. Immediate treatments usually involve some combination of vasodilators such as  nitroglycerin , diuretics such as  furosemide , and possibly  noninvasive positive pressure ventilation .  Supplemental oxygen  is indicated in those with oxygen saturation levels below 90%, but is not recommended in those with normal oxygen levels in the normal atmosphere. [ 88 ]


The goals of treatment for people with chronic heart failure are prolonging life, preventing acute decompensation, and reducing symptoms, allowing for greater activity.


Heart failure can result from a variety of conditions. In considering therapeutic options, excluding reversible causes is of primary importance, including  thyroid disease ,  anemia , chronic  tachycardia ,  alcohol use disorder ,  hypertension , and dysfunction of one or more  heart valves . Treatment of the underlying cause is usually the first approach to treating heart failure. In most cases, though, either no primary cause is found or treatment of the primary cause does not restore normal heart function. In these cases,  behavioral ,  medical  and  device  treatment strategies exist that can provide a significant improvement in outcomes, including the relief of symptoms, exercise tolerance, and a decrease in the likelihood of  hospitalization  or death. Breathlessness rehabilitation for  chronic obstructive pulmonary disease  and heart failure has been proposed with exercise training as a core component. Rehabilitation should also include other interventions to address shortness of breath including the psychological and educational needs of people and the needs of caregivers. [ 89 ]   Iron supplementation  appears to reduce hospitalization but not all-cause mortality in patients with iron deficiency and heart
failure. [ 90 ]


The latest evidence indicates that advance care planning (ACP) may help to increase documentation by medical staff regarding discussions with participants and improve an individual's depression. [ 91 ]  This involves discussing an individual's future care plan, preferences, and values. The findings are, however, based on low-quality evidence. [ 91 ]


The various measures often used to assess the progress of people being treated for heart failure include  fluid balance  (calculation of fluid intake and excretion) and monitoring  body weight  (which in the shorter term reflects fluid shifts). [ 92 ]  Remote monitoring can be effective to reduce complications for people with heart failure. [ 93 ] [ 94 ]


Behavior modification is a primary consideration in chronic heart failure management programs, with  dietary guidelines  regarding  fluid  and  salt  intake. [ 95 ]  Fluid restriction is important to reduce fluid retention in the body and to correct the hyponatremic status of the body. [ 76 ]  The evidence of the benefit of reducing salt, however, is poor as of 2018. [ 96 ]  Thirst is a common and burdensome symptom for patients to cope with.  Chewing gum  is an effective intervention to relieve thirst in patients experiencing heart failure, although patient acceptability remains an issue.


Exercise should be encouraged and tailored to suit an individual's capabilities. A meta-analysis found that center-based group interventions delivered by a physiotherapist help promote physical activity in HF. [ 97 ]  There is a need for additional training for physiotherapists in delivering behavior change intervention alongside an exercise program. An intervention is expected to be more efficacious in encouraging physical activity than the usual care if it includes  Prompts and cues  to walk or exercise, like a phone call or a text message. It is helpful if a trusted clinician provides explicit advice to engage in physical activity ( Credible source ). Another highly effective strategy is to place objects that will serve as a cue to engage in physical activity in the person's everyday environment ( Adding object to the environment ; e.g., exercise step or treadmill). Encouragement to walk or exercise in various settings beyond CR (e.g., home, neighborhood, parks) is also promising ( Generalisation of target behavior ). Additional promising strategies are  Graded tasks  (e.g., gradual increase in intensity and duration of exercise training),  Self-monitoring ,  Monitoring of physical activity by others without feedback ,  Action planning , and  Goal-setting . [ 98 ]  The inclusion of regular physical conditioning as part of a cardiac rehabilitation program can significantly improve  quality of life  and reduce the risk of hospital admission for worsening symptoms, but no evidence shows a reduction in mortality rates as a result of exercise.


Home visits and regular monitoring at heart-failure clinics reduce the need for hospitalization and improve  life expectancy . [ 99 ]


Quadruple medical therapy using a combination of  angiotensin receptor-neprilysin inhibitors (ARNI) ,  beta blockers ,  mineralocorticoid receptor antagonists (MRA) , and  sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors)  is the standard of care as of 2021 for heart failure with reduced ejection fraction (HFrEF). [ 100 ] [ 101 ]


There is no convincing evidence for pharmacological treatment of heart failure with preserved ejection fraction (HFpEF). [ 6 ]  Medication for HFpEF is symptomatic treatment with diuretics to treat congestion. [ 6 ]  Managing risk factors and comorbidities such as  hypertension  is recommended in HFpEF. [ 6 ]


Inhibitors of the  renin–angiotensin system  (RAS) are recommended for heart failure. The  angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan  is recommended as the first choice of RAS inhibitors in American guidelines published by AHA/ACC in 2022. [ 4 ]  Use of  ACE inhibitor , or  angiotensin receptor blockers  (ARBs) if the person develops a long-term cough as a side effect of the ACE-I, [ 102 ]  is associated with improved survival, fewer hospitalizations for heart failure exacerbations, and improved quality of life in people with heart failure. [ 103 ]  European guidelines published by ESC in 2021 recommends that  ARNI  should be used in those who still have symptoms while on an  ACE-I  or  ARB ,  beta blocker , and a  mineralocorticoid receptor antagonist . Use of the combination agent ARNI requires the cessation of ACE-I or ARB therapy at least 36 hours before its initiation. [ 4 ]


Beta-adrenergic blocking agents (beta blockers)  add to the improvement in symptoms and  mortality  provided by ACE-I/ARB. [ 103 ] [ 104 ]  The mortality benefits of beta blockers in people with systolic dysfunction who also have  atrial fibrillation  is more limited than in those who do not have it. [ 105 ]  If the ejection fraction is not diminished (HFpEF), the benefits of beta blockers are more modest; a decrease in mortality has been observed, but reduction in hospital admission for uncontrolled symptoms has not been observed. [ 106 ]


In people who are intolerant of ACE-I and ARB or who have significant kidney dysfunction, the use of combined  hydralazine  and a long-acting nitrate, such as  isosorbide dinitrate , is an effective alternate strategy. This regimen has been shown to reduce mortality in people with moderate heart failure. [ 107 ]  It is especially beneficial in the black population. [ a ] [ 107 ]


Use of a  mineralocorticoid antagonist , such as  spironolactone  or  eplerenone , in addition to beta blockers and ACE-I, can improve symptoms and reduce mortality in people with symptomatic heart failure with reduced ejection fraction (HFrEF). [ 16 ]


SGLT2 inhibitors  are used for heart failure with reduced ejection fraction as they have demonstrated benefits in reducing hospitalizations and mortality, regardless of whether an individual has comorbid Type 2 Diabetes or not. [ 4 ] [ 108 ]


Second-line medications for CHF do not confer a mortality benefit.  Digoxin  is one such medication. Its narrow therapeutic window, a high degree of toxicity, and the failure of multiple trials to show a mortality benefit have reduced its role in clinical practice. It is now used in only a small number of people with refractory symptoms, who are in atrial fibrillation, and/or who have chronic hypotension. [ 109 ] [ 110 ]


Diuretics have been a mainstay of treatment against symptoms of fluid accumulation, and include diuretics classes such as  loop diuretics  (such as  furosemide ),  thiazide-like diuretics , and  potassium-sparing diuretics . Although widely used, evidence on their efficacy and safety is limited, except for  mineralocorticoid antagonists  such as  spironolactone . [ 16 ] [ 111 ]


Anemia is an independent factor in mortality in people with chronic heart failure. Treatment of anemia significantly improves the quality of life for those with heart failure, often with a reduction in severity of the NYHA classification, and also improves mortality rates. [ 112 ] [ 113 ]  The  European Society of Cardiology  recommends screening for iron deficiency and treating with  intravenous iron  if deficiency is found. [ 6 ] : 3668–3669


The decision to anticoagulate people with HF, typically with left ventricular ejection fractions <35% is debated, but generally, people with coexisting atrial fibrillation, a prior embolic event, or conditions that increase the risk of an embolic event such as amyloidosis, left ventricular noncompaction, familial dilated cardiomyopathy, or a thromboembolic event in a first-degree relative. [ 80 ]


Vasopressin receptor antagonists  can also treat heart failure.  Conivaptan  is the first medication approved by the US  Food and Drug Administration  for the treatment of euvolemic hyponatremia in those with heart failure. [ 76 ]  In rare cases hypertonic 3% saline together with diuretics may be used to correct hyponatremia. [ 76 ]


Ivabradine  is recommended for people with symptomatic heart failure with reduced left ventricular ejection fraction who are receiving optimized guideline-directed therapy (as above) including the maximum tolerated dose of beta-blocker, have a normal heart rhythm and continue to have a resting heart rate above 70 beats per minute. [ 114 ]  Ivabradine has been found to reduce the risk of hospitalization for heart failure exacerbations in this subgroup of people with heart failure. [ 114 ]


In people with severe cardiomyopathy (left ventricular ejection fraction below 35%), or in those with recurrent VT or malignant arrhythmias, treatment with an automatic implantable cardioverter-defibrillator (AICD) is indicated to reduce the risk of severe life-threatening arrhythmias. The AICD does not improve symptoms or reduce the incidence of malignant arrhythmias but does reduce mortality from those arrhythmias, often in conjunction with antiarrhythmic medications. In people with left ventricular ejection (LVEF) below 35%, the incidence of  ventricular tachycardia  or  sudden cardiac death  is high enough to warrant AICD placement. Its use is therefore recommended in  AHA / ACC  guidelines. [ 20 ]


Cardiac contractility modulation  (CCM) is a  treatment  for people with moderate to severe  left ventricular  systolic heart failure (NYHA classes II–IV), which enhances both the strength of ventricular  contraction  and the heart's pumping capacity. The CCM mechanism is based on stimulation of the cardiac muscle by  nonexcitatory electrical signals , which are delivered by a  pacemaker -like device. CCM is particularly suitable for the treatment of heart failure with normal  QRS complex  duration (120 ms or less) and has been demonstrated to improve the symptoms, quality of life, and exercise tolerance. [ 21 ] [ 115 ] [ 116 ] [ 117 ] [ 118 ]  CCM is approved for use in Europe, and was approved by the Food and Drug Administration for use in the United States in 2019. [ 119 ] [ 120 ] [ 121 ]


About one-third of people with an  LVEF  below 35% have markedly altered conduction to the ventricles, resulting in dyssynchronous depolarization of the right and left ventricles. This is especially problematic in people with left bundle branch block (blockage of one of the two primary conducting fiber bundles that originate at the base of the heart and carry depolarizing impulses to the left ventricle). Using a special pacing algorithm, biventricular  cardiac resynchronization therapy  (CRT) can initiate a normal sequence of ventricular depolarization. In people with LVEF below 35% and prolonged QRS duration on ECG (LBBB or QRS of 150 ms or more), an improvement in symptoms and mortality occurs when CRT is added to standard medical therapy. [ 122 ]  However, in the two-thirds of people without prolonged QRS duration, CRT may be harmful. [ 20 ] [ 21 ] [ 123 ]


People with the most severe heart failure may be candidates for  ventricular assist devices , which have commonly been used as a bridge to heart transplantation but have been used more recently as a destination treatment for advanced heart failure. [ 124 ]


In select cases, heart transplantation can be considered. While this may resolve the problems associated with heart failure, the person must generally remain on an immunosuppressive regimen to prevent rejection, which has its own significant downsides. [ 125 ]  A major limitation of this treatment option is the scarcity of hearts available for transplantation.


People with heart failure often have significant symptoms, such as shortness of breath and chest pain. Palliative care should be initiated early in the HF trajectory, and should not be an option of last resort. [ 126 ]  Palliative care can not only provide symptom management, but also assist with advanced care planning, goals of care in the case of a significant decline, and making sure the person has a medical  power of attorney  and discussed his or her wishes with this individual. [ 127 ]  A 2016 and 2017 review found that palliative care is associated with improved outcomes, such as quality of life, symptom burden, and satisfaction with care. [ 126 ] [ 128 ]


Without transplantation, heart failure may not be reversible and heart function typically deteriorates with time. The growing number of people with stage IV heart failure (intractable symptoms of fatigue, shortness of breath, or chest pain at rest despite optimal medical therapy) should be considered for palliative care or  hospice , according to American College of Cardiology/American Heart Association guidelines. [ 127 ]


Prognosis in heart failure can be assessed in multiple ways, including clinical prediction rules and cardiopulmonary exercise testing. Clinical prediction rules use a composite of clinical factors such as laboratory tests and blood pressure to estimate prognosis. Among several  clinical prediction rules  for prognosticating acute heart failure, the 'EFFECT rule' slightly outperformed other rules in stratifying people and identifying those at low risk of death during hospitalization or within 30 days. [ 129 ]  Easy methods for identifying people that are low-risk are:


A crucial method for assessing prognosis in people with advanced heart failure is cardiopulmonary exercise testing (CPX testing). CPX testing is usually required before heart transplantation as an indicator of prognosis. CPX testing involves the measurement of exhaled oxygen and carbon dioxide during exercise. The peak oxygen consumption ( VO 2  max ) is used as an indicator of prognosis. As a general rule, a VO 2  max less than 12–14 cc/kg/min indicates poor survival and suggests that the person may be a candidate for a heart transplant. People with a VO 2  max <10 cc/kg/min have a poorer prognosis. The most recent International Society for Heart and Lung Transplantation guidelines [ 130 ]  also suggest two other parameters that can be used for evaluation of prognosis in advanced heart failure, the heart failure survival score and the use of a criterion of VE/VCO 2  slope > 35 from the CPX test. The heart failure survival score is calculated using a combination of clinical predictors and the VO 2  max from the CPX test.


Heart failure is associated with significantly reduced physical and mental health, resulting in a markedly decreased quality of life. [ 131 ] [ 132 ]  With the exception of heart failure caused by reversible conditions, the condition usually worsens with time. Although some people survive many years, progressive disease is associated with an overall annual mortality rate of 10%. [ 133 ]


Around 18 of every 1000 persons will experience an ischemic stroke during the first year after diagnosis of HF. As the duration of follow-up increases, the stroke rate rises to nearly 50 strokes per 1000 cases of HF by 5 years. [ 134 ]


In 2022, heart failure affected about 64 million people globally. [ 135 ]  Overall, around 2% of adults have heart failure. [ 22 ]  In those over the age of 75, rates are greater than 10%. [ 22 ]


Rates are predicted to increase. [ 22 ]  Increasing rates are mostly because of increasing lifespan, but also because of increased risk factors (hypertension, diabetes, dyslipidemia, and obesity) and improved survival rates from other types of cardiovascular disease (myocardial infarction, valvular disease, and arrhythmias). [ 136 ] [ 137 ] [ 138 ]  Heart failure is the leading cause of hospitalization in people older than 65. [ 139 ]


In the United States, heart failure affects 5.8 million people, and each year 550,000 new cases are diagnosed. [ 140 ]  In 2011, heart failure was the most common reason for hospitalization for adults aged 85 years and older, and the second-most common for adults aged 65–84 years. [ 141 ]  An estimated one in five adults at age 40 will develop heart failure during their remaining lifetimes and about half of people who develop heart failure die within 5 years of diagnosis. [ 142 ]  Heart failure – much higher in African Americans, Hispanics, Native Americans, and recent immigrants from Eastern Europe countries – has been linked in these ethnic minority populations to the high incidence of diabetes and hypertension. [ 143 ]


Nearly one of every four people (24.7%) hospitalized in the U.S. with congestive heart failure is readmitted within 30 days. [ 144 ]  Additionally, more than 50% of people seek readmission within 6 months after treatment and the average duration of hospital stay is 6 days. Heart failure is a leading cause of hospital readmissions in the U.S. People aged 65 and older were readmitted at a rate of 24.5 per 100 admissions in 2011. In the same year, heart failure patients under Medicaid were readmitted at a rate of 30.4 per 100 admissions, and uninsured people were readmitted at a rate of 16.8 per 100 admissions. These are the highest readmission rates for both categories. Notably, heart failure was not among the top-10 conditions with the most 30-day readmissions among the privately insured. [ 145 ]


In the UK, despite moderate improvements in prevention, heart failure rates have increased due to population growth and aging. [ 146 ]  Overall heart failure rates are similar to the four most common causes of cancer (breast, lung, prostate, and colon) combined. [ 146 ]  People from deprived backgrounds are more likely to be diagnosed with heart failure at a younger age. [ 146 ]


In tropical countries, the most common cause of heart failure is valvular heart disease or some type of cardiomyopathy. As underdeveloped countries have become more affluent, the incidences of  diabetes ,  hypertension , and  obesity  have increased, which have in turn raised the incidence of heart failure. [ citation needed ]


Men have a higher incidence of heart failure, but the overall prevalence rate is similar in both sexes since women survive longer after the onset of heart failure. [ 147 ]  Women tend to be older when diagnosed with heart failure (after  menopause ), they are more likely than men to have diastolic dysfunction, and seem to experience a lower overall quality of life than men after diagnosis. [ 147 ]


Some sources state that people of  Asian  descent are at a higher risk of heart failure than other ethnic groups. [ 148 ]  Other sources however have found that rates of heart failure are similar to rates found in other ethnic groups. [ 149 ]


For centuries, the disease entity which would include many cases of what today would be called heart failure was  dropsy ; the term denotes generalized edema, a major manifestation of a failing heart, though also caused by other diseases. Writings of ancient civilizations include evidence of their acquaintance with dropsy and heart failure: Egyptians were the first to use  bloodletting  to relieve fluid accumulation and shortage of breath, and provided what may have been the first documented observations on heart failure in the  Ebers papyrus  (around 1500 BCE). [ 150 ]  Greeks described cases of dyspnea, fluid retention and fatigue compatible with heart failure. [ 151 ]


Romans used the flowering plant  Drimia maritima  (sea squill), which contains  cardiac glycosides , for the treatment of dropsy; [ 152 ]  descriptions pertaining to heart failure are also known in the civilizations of ancient India and China. [ 153 ]  However, the manifestations of failing heart were understood in the context of these peoples' medical theories – including ancient Egyptian religion,  Hippocratic   theory of humours , or ancient  Indian  and  Chinese medicine , and the current concept of heart failure had not developed yet. [ 151 ] [ 153 ]  Although shortage of breath had been connected to heart disease by  Avicenna  round 1000 CE, [ 154 ]  decisive for modern understanding of the nature of the condition were the description of  pulmonary circulation  by  Ibn al-Nafis  in the 13th century, and of  systemic circulation  by  William Harvey  in 1628. [ 151 ]


The role of the heart in fluid retention began to be better appreciated, as  dropsy of the chest  (fluid accumulation in and around the lungs causing shortness of breath) became more familiar and the current concept of heart failure, which brings together swelling and shortage of breath due to fluid retention, began to be accepted, in the 17th and especially in the 18th century:  Richard Lower  linked dyspnea and foot swelling in 1679, and  Giovanni Maria Lancisi  connected jugular vein distention with right ventricular failure in 1728. [ 154 ]  Dropsy attributable to other causes, e.g. kidney failure, was differentiated in the 19th century. [ 155 ] [ 156 ] [ 157 ]  The stethoscope, invented by  René Laennec  in 1819,  x-rays , discovered by  Wilhelm Röntgen  in 1895, and  electrocardiography , described by  Willem Einthoven  in 1903, facilitated the investigation of heart failure. [ 40 ] [ 157 ]


The 19th century also saw experimental and conceptual advances in the physiology of heart contraction, which led to the formulation of the  Frank-Starling law  of the heart (named after physiologists  Otto Frank  and  Ernest Starling ), a remarkable advance in understanding mechanisms of heart failure. [ 158 ]


One of the earliest treatments of heart failure, relief of swelling by bloodletting with various methods, including  leeches , continued through the centuries. [ 159 ]  Along with bloodletting,  Jean-Baptiste de Sénac  in 1749 recommended  opiates  for acute shortage of breath due to heart failure. [ 157 ]  In 1785,  William Withering  described the therapeutic uses of the  foxglove  genus of plants in the treatment of edema; their extract contains  cardiac glycosides , including digoxin, still used today in the treatment of heart failure. [ 152 ]  The  diuretic effects of inorganic mercury salts , which were used to treat  syphilis , had already been noted in the 16th century by  Paracelsus ; [ 160 ]  in the 19th century they were used by noted physicians like  John Blackall  and  William Stokes . [ 161 ]  In the meantime,  cannulae  (tubes) invented by English physician  Reginald Southey  in 1877 was another method of removing excess fluid by directly inserting into swollen limbs. [ 159 ]


Use of organic mercury compounds as diuretics, beyond their role in syphilis treatment, started in 1920, though it was limited by their  parenteral  route of administration and their side-effects. [ 161 ] [ 162 ]  Oral mercurial diuretics were introduced in the 1950s; so were thiazide diuretics, which caused less toxicity, and are still used. [ 40 ] [ 161 ]  Around the same time, the invention of echocardiography by  Inge Edler  and  Hellmuth Hertz  in 1954 marked a new era in the evaluation of heart failure. [ 40 ]  In the 1960s,  loop diuretics  were added to available treatments of fluid retention, while a patient with heart failure received the first  heart transplant  by  Christiaan Barnard . [ 40 ] [ 161 ]  Over the following decades, new drug classes found their place in heart failure therapeutics, including  vasodilators  like  hydralazine ;  renin-angiotensin system  inhibitors; and  beta-blockers . [ 163 ] [ 164 ]


In 2011, nonhypertensive heart failure was one of the 10 most expensive conditions seen during inpatient hospitalizations in the U.S., with aggregate inpatient hospital costs more than $10.5 billion. [ 165 ]


Heart failure is associated with a high health expenditure, mostly because of the cost of hospitalizations; costs have been estimated to amount to 2% of the total budget of the  National Health Service  in the United Kingdom, and more than $35 billion in the United States. [ 166 ] [ 167 ]


Some research indicates that  stem cell therapy  may help. [ 168 ]  Although this research indicated benefits of stem cell therapy, other research does not indicate benefit. [ 169 ]  There is tentative evidence of longer life expectancy and improved left ventricular ejection fraction in persons treated with bone marrow-derived stem cells. [ 168 ]


The maintenance of heart function depends on appropriate  gene expression  that is regulated at multiple levels by  epignetic mechanisms  including  DNA methylation  and  histone post-translational modification . [ 170 ] [ 171 ]   Currently, an increasing body of research is directed at understanding the role of perturbations of epigenetic processes in  cardiac hypertrophy  and  fibrotic scarring . [ 170 ] [ 171 ]