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Heart failure

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. The severity of the heart failure is mainly decided based on ejection fraction and also measured by the severity of symptoms. Other conditions that have symptoms similar to heart failure include obesity, kidney failure, liver disease, anemia, and thyroid disease.

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. These cause heart failure by altering the structure or the function of the heart or in some cases both. 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. Left-sided heart failure may be present with a reduced ejection fraction or with a preserved ejection fraction. Heart failure is not the same as cardiac arrest, in which blood flow stops completely due to the failure of the heart to pump.

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

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

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. The risk of death is comparable to that of some cancers. In the United Kingdom, the disease is the reason for 5% of emergency hospital admissions. Heart failure has been known since ancient times; it is mentioned in the Ebers Papyrus around 1550 BCE.

Definition
Heart failure is not a disease but a syndrome – a combination of signs and symptoms – caused by the failure of the heart to pump blood to support the circulatory system at rest or during activity. 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. The filling failure and high intracardiac pressure can lead to fluid accumulation in the veins and tissue. 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.

Signs and symptoms
Congestive heart failure is a pathophysiological condition in which the heart's output is insufficient to meet the needs of the body and lungs. 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.

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). 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.

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.

Left-sided failure
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 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.

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.

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. 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.

Right-sided failure

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.

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).

Biventricular failure
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.

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 increase stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side.

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

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. 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.

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. Recent reports from clinical trials have also linked variation in blood pressure to heart failure and cardiac changes that may give rise to heart failure.

High-output heart failure
High-output heart failure happens when the amount of blood pumped out is more than typical and the heart is unable to keep up. This can occur in overload situations such as blood or serum infusions, kidney diseases, chronic severe anemia, beriberi (vitamin B1/thiamine deficiency), hyperthyroidism, cirrhosis, Paget's disease, multiple myeloma, arteriovenous fistulae, or arteriovenous malformations.

Acute decompensation
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.

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

Medications
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 ), salbutamol, and tamsulosin.

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. Similarly, the ACC/AHA recommends against the use of COX-2 inhibitor medications in people with heart failure. 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. 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.

Breast cancer patients are at high risk of heart failure due to several factors. After analysing 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). 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.

Supplements
Certain alternative medicines carry a risk of exacerbating existing heart failure, and are not recommended. This includes aconite, ginseng, gossypol, gynura, licorice, lily of the valley, tetrandrine, and yohimbine. Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. 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. Lily of the valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lead to low blood pressure through inhibition of L-type calcium channels. Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism.

Pathophysiology
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.

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 reduced ability to cross-link actin and myosin myofilaments in over-stretched heart muscle.

Diagnosis
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. 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. This is recommended in those with symptoms consistent with heart failure such as shortness of breath.

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". This definition is consistent with an international 2021 report termed "Universal Definition of Heart Failure". Score-based algorithms have been developed to help in the diagnosis of HFpEF, which can be challenging for physicians to diagnose. 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".

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

"Left", "right" and mixed heart failure
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.

By ejection fraction
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. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are:
 * 1) Heart failure with reduced ejection fraction (HFrEF): Synonyms no longer recommended are "heart failure due to left ventricular systolic dysfunction" and "systolic heart failure". HFrEF is associated with an ejection fraction less than 40%.
 * 2) Heart failure with mildly reduced ejection fraction (HFmrEF), previously called "heart failure with mid-range ejection fraction", is defined by an ejection fraction of 41–49%.
 * 3) Heart failure with preserved ejection fraction (HFpEF): Synonyms no longer recommended include "diastolic heart failure" and "heart failure with normal ejection fraction."  HFpEF occurs when the left ventricle contracts normally during systole, but the ventricle is stiff and does not relax normally during diastole, which impairs filling.

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. 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).

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. 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. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle.

Ultrasound
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.

Chest X-ray
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 be able to detect Kerley lines.

Electrophysiology
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.

Blood tests
N-terminal pro-BNP (NT-proBNP) is the favoured biomarker for the diagnosis of heart failure, according to guidelines published 2018 by NICE in the UK. Brain natriuretic peptide 32 (BNP) is another biomarker commonly tested for heart failure. 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 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.

Angiography
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. 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.

Staging
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. 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 the walking distance or exercise tolerance on formal testing.

In its 2001 guidelines, the American College of Cardiology/American Heart Association working group introduced four stages of heart failure:
 * Stage A: People at high risk for developing HF in the future, but no functional or structural heart disorder
 * Stage B: A structural heart disorder, but no symptoms at any stage
 * Stage C: Previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment
 * Stage D: Advanced disease requiring hospital-based support, a heart transplant, or palliative care

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.
 * The degree of coexisting illness: i.e. heart failure/systemic hypertension, heart failure/pulmonary hypertension, heart failure/diabetes, heart failure/kidney failure, etc.
 * Whether the problem is primarily increased venous back pressure (preload), or failure to supply adequate arterial perfusion (afterload)
 * Whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure)

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

Prevention
A person's risk of developing heart failure is inversely related to 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. 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.

According to Johns Hopkins and the American Heart Association there are a few ways to help to prevent a cardiac event. Johns Hopkins states that stopping tobacco use, reducing high blood pressure, physical activity and your diet can drastically effect 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.

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. 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.

Management
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.

Acute decompensation
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 normal atmosphere.

Chronic management
The goals of the treatment for people with chronic heart failure are the prolongation of life, prevention of acute decompensation, and reduction of 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 the majority of 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 psychological and educational needs of people and needs of caregivers. Iron supplementation appears to reduce hospitalization but not all-cause mortality in patients with iron deficiency and heart failure.

Advance care planning
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. This involves discussing an individual's future care plan in consideration of the individual's preferences and values. The findings are however, based on low-quality evidence.

Monitoring
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). Remote monitoring can be effective to reduce complications for people with heart failure.

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

Exercise and physical activity
Exercise should be encouraged and tailored to suit individual's capabilities. A meta-analysis found that centre-based group interventions delivered by a physiotherapist are helpful in promoting physical activity in HF. There is a need for additional training for physiotherapists in delivering behaviour change intervention alongside an exercise programme. 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 extremely 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 everyday environment of the patient (Adding object to the environment; e.g., exercise step or treadmill). Encouragement to walk or exercise in various settings beyond CR (e.g., home, neighbourhood, parks) is also promising (Generalisation of target behaviour). 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. 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.

Medication
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).

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

Inhibitors of the renin–angiotensin system (RAS) are recommended in heart failure. The angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan is recommended as first choice of RAS inhibitors in American guidelines published by AHA/ACC in 2022. Use of angiotensin-converting enzyme (ACE) inhibitors (ACE-I), or angiotensin receptor blockers (ARB) if the person develops a long-term cough as a side effect of the ACE-I, is associated with improved survival, fewer hospitalizations for heart failure exacerbations, and improved quality of life in people with heart failure. 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.

Beta-adrenergic blocking agents (beta blockers) add to the improvement in symptoms and mortality provided by ACE-I/ARB. 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. 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.

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. It is especially beneficial in the black population.

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).

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.

Other medications
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.

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, with the exception of mineralocorticoid antagonists such as spironolactone.

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

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.

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

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. Ivabradine has been found to reduce the risk of hospitalization for heart failure exacerbations in this subgroup of people with heart failure.

Implanted devices
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.

Cardiac contractility modulation (CCM) is a treatment for people with moderate to severe left ventricular systolic heart failure (NYHA class 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. CCM is approved for use in Europe, and was approved by the Food and Drug Administration for use in the United States in 2019.

About one-third of people with 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. However, in the two-thirds of people without prolonged QRS duration, CRT may actually be harmful.

Surgical therapies
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.

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. A major limitation of this treatment option is the scarcity of hearts available for transplantation.

Palliative care
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. 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. 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.

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.

Prognosis
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. Easy methods for identifying people that are low-risk are:
 * ADHERE Tree rule indicates that people with blood urea nitrogen < 43 mg/dL and systolic blood pressure at least 115 mm Hg have less than 10% chance of inpatient death or complications.
 * BWH rule indicates that people with systolic blood pressure over 90 mm Hg, respiratory rate of 30 or fewer breaths per minute, serum sodium over 135 mmol/L, and no new ST–T wave changes have less than 10% chance of inpatient death or complications.

A very important method for assessing prognosis in people with advanced heart failure is cardiopulmonary exercise testing (CPX testing). CPX testing is usually required prior to heart transplantation as an indicator of prognosis. CPX testing involves measurement of exhaled oxygen and carbon dioxide during exercise. The peak oxygen consumption (VO2 max) is used as an indicator of prognosis. As a general rule, a VO2 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 VO2 max <10 cc/kg/min have a clearly poorer prognosis. The most recent International Society for Heart and Lung Transplantation guidelines 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/VCO2 slope > 35 from the CPX test. The heart failure survival score is calculated using a combination of clinical predictors and the VO2 max from the CPX test.

Heart failure is associated with significantly reduced physical and mental health, resulting in a markedly decreased quality of life. 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%.

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.

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

Rates are predicted to increase. 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). Heart failure is the leading cause of hospitalization in people older than 65.

United States
In the United States, heart failure affects 5.8 million people, and each year 550,000 new cases are diagnosed. 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. 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. 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 high incidence of diabetes and hypertension.

Nearly one of every four people (24.7%) hospitalized in the U.S. with congestive heart failure are readmitted within 30 days. 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, people 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.

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

Developing world
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.

Sex
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. 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.

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

History
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 papurus (around 1500 BCE); Greeks described cases of dyspnea, fluid retention and fatigue compatible with heart failure;

Romans used the flowering plant Drimia maritima (sea squill), which contains cardiac glycosides, for the treatment of dropsy; descriptions pertaining to heart failure are also known in the civilizations of ancient India and China. 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. Although shortage of breath had been connected to heart disease by Avicenna round 1000 CE, 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.

The role of the heart in fluid retention began to be better appreciated, as dropsy of the chest (fluid accumulation in and round the lungs causing shortage 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. Dropsy attributable to other causes, e.g. kidney failure, was differentiated in the 19th century. 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.

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.

One of the earliest treatments of heart failure, relief of swelling by bloodletting with various methods, including leeches, continued through the centuries. Along with bloodletting, Jean-Baptiste de Sénac in 1749 recommended opiates for acute shortage of breath due to heart failure. 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. The diuretic effects of inorganic mercury salts, which were used to treat syphilis, had already been noted in the 16th century by Paracelsus; in the 19th century they were used by noted physicians like John Blackall and William Stokes. 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.

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. Oral mercurial diuretics were introduced in the 1950s; so were thiazide diuretics, which caused less toxicity, and are still used. 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. 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. 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.

Economics
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.

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.

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

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. Currently, an increasing body of research is directed at understanding the role of perturbations of epigenetic processes in cardiac hypertrophy and fibrotic scarring.

title: Heart failure


text:
Closed platform

A closed platform, walled garden, or closed ecosystem is a software system wherein the carrier or service provider has control over applications, content, and/or media, and restricts convenient access to non-approved applicants or content. This is in contrast to an open platform, wherein consumers generally have unrestricted access to applications and content.

Overview
For example, in telecommunications, the services and applications accessible on a cell phone on any given wireless device were formerly tightly controlled by the mobile operators. The operators limited the applications and developers that were available on users' home portals and home pages. Thus, a service provider might restrict user access to users whose account exhausted the pre-paid money on their account. This has long been a central issue constraining the telecommunications sector, as developers face huge hurdles in making their applications available to end-users.

In a more extreme example, the regulated 1970s American telephone system, Bell, owned all the hardware (including all phones) and had indirect control over the information sent through their infrastructure. It was an open government-sanctioned natural monopoly regulated by the Communications Act of 1934. However, in the landmark case Hush-A-Phone v. United States, Bell unsuccessfully sued a company producing plastic telephone attachments.

More generally, a walled garden can refer to a closed or exclusive set of information services provided for users. Similar to a real walled garden, a user is unable to escape this closed environment except through the designated entry/exit points or if the walls are removed.

Aspects
A 2008 Harvard Business School working paper, entitled "Opening Platforms: How, When and Why?", differentiated a platform's openness/closedness by four aspects and gave example platforms:

Examples
Some examples of walled gardens include:
 * In the 1990s, AOL developed what later was called its "walled garden" model of service. The idea was to preferentially offer sponsored content to users when possible. During this period, CBS paid to provide sports content, ABC paid to provide news, and 1-800-Flowers paid to be the default florist for anyone seeking one. This strategy became AOL's first good method for selling advertisements. In its time, this method was highly profitable to AOL.
 * Amazon's Kindle line of eReaders. As an October 2011 Business Insider article, entitled "How Amazon Makes Money From The Kindle" observes: "Amazon's Kindle is no longer just a product: It's a whole ecosystem." Moreover, as Business Insider noted "The Kindle ecosystem is also Amazon's fastest-growing product and could account for more than 10% of the company's revenue next year."
 * Apple iOS and other mobile devices, which are restricted to running pre-approved applications from a digital distribution service.
 * Barnes & Noble's Nook devices. In late December 2011, B&N began pushing the automatic, over-the-air firmware update 1.4.1 to Nook Tablets that removed users' ability to gain root access to the device and the ability to sideload applications from sources other than the official Barnes and Noble NOOK Store (without modding). Nook HD devices were similarly "closed", until May 2013, when BN opened its ecosystem somewhat by permitting users to install the Google Play Store and the various Android apps offered there, including those of rivals, such as Audible.com, ComiXology, Kindle, Kobo, and Google itself.
 * The Encrypted Media Extensions specification provides APIs to control playback of encrypted content. This is part of the World Wide Web Consortium's web standards and was authored by members working from Google, Microsoft and Netflix.
 * Kwangmyong, the national intranet service that operates in North Korea. It operates as a "walled garden" network, as no information from overseas is permitted to enter the network without government approval.
 * Verizon Wireless' CDMA network and policies effectively prohibiting activation of non-Verizon sanctioned devices on their network. Verizon Wireless is frequently noted (and often criticized) for this practice.
 * Permissioned blockchains have been called the “walled gardens” of 2017.
 * Video game consoles have a long history of walled gardens, with developers needing to purchase licences to develop for the platform, and, in some cases, needing editorial approval from the console manufacturer prior to publishing games.
 * Super-apps such as WeChat have been called walled gardens by critics.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Closed platform


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User talk:BT (usurped)

We don't require people to read the rules before contributing but most people naturally log-in before they get as far along as you (and moving content from one page to another is a fairly advanced editing function! :). No biggie and welcome! --mav 05:03 20 Jun 2003 (UTC)

Request for usurpation
Hello, BT. A request has been made at Changing username/Usurpations to usurp, or "take over", your username because another user would like to use it to edit. The changing username guideline allows a username that is not being actively used to be usurped if the user is given an opportunity to object and does not do so.

If you have an email set in your preferences, you should be getting an email from a bureaucrat or changing username clerk explaining how to consent or object to this process.

If you do not object to being renamed to a new username in order for another user to use the name you currently have, please log in and post a reply here saying so (you may also tell us what username you would like to be renamed to, or we will provide you with a generic one).

If you do nothing : the request may be filled shortly, and your account will be moved to a generic username. You may request that it be moved to a new username of your choice at any time.

If you object to being renamed : please log in and make an edit to this page clearly stating that you object to usurpation. Any objection on your part will prevent usurpation.

Please note that even if your current username is usurped, you can still edit and your data will not be lost; your preferences, watchlist, and other user settings will be transferred to a new username.

Thank you for your time. 78.98.82.54 (talk) 18:27, 28 November 2013 (UTC)

title: User talk:BT (usurped)


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Coxsackie B4 virus

Coxsackie B4 virus are enteroviruses that belong to the Picornaviridae family. These viruses can be found worldwide. They are positive-sense, single-stranded, non-enveloped RNA viruses with icosahedral geometry. Coxsackieviruses have two groups, A and B, each associated with different diseases. Coxsackievirus group A is known for causing hand-foot-and-mouth diseases while Group B, which contains six serotypes, can cause a varying range of symptoms like gastrointestinal distress myocarditis. Coxsackievirus B4 has a cell tropism for natural killer cells and pancreatic islet cells. Infection can lead to beta cell apoptosis which increases the risk of insulitis.

Viral structure and genome
Coxsackievirus B4 is one of the six serotypes found in Group B and is a positive sense, single-stranded, non-enveloped RNA virus. Its genome is linear and is 7,293 nucleotides in length with both a 5’ and 3’ untranslated region and encodes its own 3’ poly-A tail. The 5’ untranslated region contains an internal ribosomal entry site (Type I IRES). Covalently bonded to the 5’ UTR is the viral protein VPg which aids in viral entry and replication. 2A and 3C are viral proteinases which aid in the cleavage of the polyprotein encoded for by the genome. 3D is the RNA-dependent RNA polymerase (RdRP). 2B, 2C, and 3A are core viral proteins. The genome also codes for 4 capsid proteins, VP4, VP1, VP2, and VP3 that form an icosahedral capsid for the viral particles that is about 30 nm. VP1-VP3 are responsible for the outer surface of the virion, while VP4 is imbedded within the capsid. Altogether, the polyprotein encoded for by the coxsackievirus genome is almost 2,200 amino acids in length, and is eventually cleaved by the 2A and 3C proteinases as well as by host cell proteinases.

As Coxsackievirus B4, and all other members of the picornavirus family, are non-enveloped, they are notably resilient to disinfectants, solvents, low pH levels (i.e. stomach acid), low temperatures, and 70% alcohol.

Attachment, entry and uncoating
The capsid of Coxsackie viruses have a distinguishable depression around the fivefold axis, termed the “canyon.” The canyon is thought to help with viral attachment through the interaction with cell surface molecules. (Riabi, 2014) When VP1 binds to the Coxsackie-Adenovirus receptor (CAR), which can be found on heart muscle cells as well as epithelial and endothelial cells, a conformational change causes the host cell receptors to form a pore in the plasma membrane through which the VPg-linked viral genome could enter the cell. Uncoating is unnecessary as it leaves the capsid at the plasma membrane and the genome is simply injected into the cytoplasm.

Replication
For positive sense, single-stranded RNA viruses, translation occurs before transcription. Upon entry of the genome into the cytoplasm of the host cell, the IRES in the 5’ UTR recruits ribosomal subunits (cap-independent mechanism) which starts the translation process. Once the polypeptide is completely translated, viral proteinases 2A and 3C, as well as cellular proteinases, cleave the polyprotein into individual proteins that will help continue the viral replication process. As soon as viral proteins have been translated and cleaved, negative sense transcripts of the viral genome are made to serve as a template for more positive-sense viral genome transcripts (which also serves as mRNA which can also be translated into more viral proteins). The viral genome encodes for a poly-A tail, which can be recognized by cellular initiation factors and ribosomal subunits which kick starts the transcription process to make the negative-sense strand, forming a double-stranded RNA intermediate

Upon transcription of the negative sense RNA, it needs to get primed in order to start making more positive sense RNA genome. The VPg protein that is covalently linked to the 5’ end of the RNA genome has 2 U’s attached to it. The purpose of these U’s is to modify the VPg protein which serves as a protein primer which the viral RdRP can recognize and start forming more genome from the negative-sense.

The viral protein 2C brings positive sense RNA genomes to the endoplasmic reticulum where assembly and maturation will occur.

While all of this is occurring, viral proteinases are working to turn off host cell protein synthesis by cleaving the eIF-4 initiation factor. This process accomplishes the inhibition of ribosomes binding to host cell mRNAs. This effectively shuts down cap-dependent translation in the host cell.

Assembly, maturation and egress
Once viral genome and viral proteins reach high enough concentrations within the host cell, structural proteins must assemble. The final step in maturation of the virus is when VP0, a precursor protein, is cleaved into VP2 and VP4. Viral capsid proteins come together to form pentamers, 12 of which come together to form an empty capsid, or procapsid (Expasy, Hunt, 2010). As mentioned before, the viral protein 2C brings CB4 viral genome to the endoplasmic reticulum where vesicle formation begins. The ER membrane moves to surround the genome and proteins, at which point the procapsid attaches to the exterior of the vesicle and encapsidates the genome and proteins. It is at this point that VP0 gets cleaved by a cellular proteinase and the virus finally becomes fully mature and infectious. Since CB4 is a non-enveloped virus, it accomplishes egress through cytolysis, breaking through the plasma membrane in order to move on to infect other cells in the host (Hunt, 2010)

Symptoms
Coxsackie B 1–4 viruses are typically the most severe and fatal neonatal diseases. Common symptoms can include myocarditis, meningoencephalitis, and hepatitis. Other less severe symptoms can include pneumonia, Gastrointestinal symptoms, pancreatitis, and seizures. Patients with Coxsackie B4 virus have seemed to have herpangina, tonsillitis, and pharyngitis.

CB4 virus has caused transplacental infections in mice. Infection in the first couple weeks of gestation has been shown to be harmful for dams as well as the fetus, causing reduced litter sizes, abortion, or stillbirth. Pups that were born from dams infected on days 4 and 17 of gestation had significantly (p < 0.05) greater pancreatic abnormalities leading to symptoms similar to diabetes.

Coxsackie B4 virus and type 1 diabetes
One theory proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas, but to date there is no stringent evidence to support this hypothesis in humans.

A 2004 systematic review analyzing a possible association between coxsackievirus B infection and type 1 diabetes was inconclusive. A 2011 systematic review and meta-analysis showed an association between enterovirus infections and type 1 diabetes, but in contrast, other studies have shown that rather than triggering an autoimmune process, enterovirus infections, as coxsackievirus B, could protect against onset and development of type 1 diabetes.

Transmission to neonates
Enteroviruses commonly infect neonates and infants younger than 12 months. Coxsackie b viruses are usually spread to infants through perinatal transmission. However, more severe cases of coxsackie B viruses are spread through transplacental transmission. Common symptoms of neonatal coxsackie B virus infection in children include meningitis and/or encephalitis. Coxsackie B4 virus is able to infect the brain and spinal cord and cause inflammation.

Diagnosis
Infection due to Coxsackie B viruses can be determined by measuring the amount of neutralizing antibodies in the blood, PCR, and through microscopic detection. It is difficult to diagnose CBV based on the symptoms.

title: Coxsackie B4 virus


text:
Cyclamate

Cyclamate is an artificial sweetener. It is 30–50 times sweeter than sucrose (table sugar), making it the least potent of the commercially used artificial sweeteners. It is often used with other artificial sweeteners, especially saccharin; the mixture of 10 parts cyclamate to 1 part saccharin is common and masks the off-tastes of both sweeteners. It is less expensive than most sweeteners, including sucralose, and is stable under heating. Safety concerns led to it being banned in a few countries, though the European Union considers it safe.

Chemistry
Cyclamate is the sodium or calcium salt of cyclamic acid (cyclohexanesulfamic acid), which itself is prepared by reacting freebase cyclohexylamine with either sulfamic acid or sulfur trioxide.

Prior to 1973, Abbott Laboratories produced sodium cyclamate (Sucaryl) by a mixture of ingredients including the addition of pure sodium (flakes or rods suspended in solvent) with cyclohexylamine, chilled and filtered through a high speed centrifugal separator, dried, granulated and micro-pulverised for powder or tablet usage.

History
Cyclamate was discovered in 1937 at the University of Illinois by graduate student Michael Sveda. Sveda was working in the lab on the synthesis of an antipyretic drug. He put his cigarette down on the lab bench, and when he put it back in his mouth, he discovered the sweet taste of cyclamate.

The patent for cyclamate was purchased by DuPont and later sold to Abbott Laboratories, which undertook the necessary studies and submitted a New Drug Application in 1950. Abbott intended to use cyclamate to mask the bitterness of certain drugs such as antibiotics and pentobarbital. In 1958, it was designated GRAS (Generally Recognized as Safe) by the United States Food and Drug Administration. Cyclamate was marketed in tablet form for use by diabetics as an alternative tabletop sweetener, as well as in a liquid form. As cyclamate is stable to heat, it was and is marketed as suitable for use in cooking and baking.

In 1966, a study reported that some intestinal bacteria could desulfonate cyclamate to produce cyclohexylamine, a compound suspected to have some chronic toxicity in animals. Further research resulted in a 1969 study that found the common 10:1 cyclamate–saccharin mixture increased the incidence of bladder cancer in rats. The released study was showing that eight out of 240 rats fed a mixture of saccharin and cyclamates, at levels equivalent to humans ingesting 550 cans of diet soda per day, developed bladder tumors.

Sales continued to expand, and in 1969, annual sales of cyclamate had reached $1 billion, which increased pressure from public safety watchdogs to restrict the usage of cyclamate. In October 1969, Department of Health, Education & Welfare Secretary Robert Finch, bypassing Food and Drug Administration Commissioner Herbert L. Ley, Jr., removed the GRAS designation from cyclamate and banned its use in general-purpose foods, though it remained available for restricted use in dietary products with additional labeling; in October 1970, the FDA, under a new commissioner, banned cyclamate completely from all food and drug products in the United States.

Abbott Laboratories claimed that its own studies were unable to reproduce the 1969 study's results, and, in 1973, Abbott petitioned the FDA to lift the ban on cyclamate. This petition was eventually denied in 1980 by FDA Commissioner Jere Goyan. Abbott Labs, together with the Calorie Control Council (a political lobby representing the diet foods industry), filed a second petition in 1982. Although the FDA has stated that a review of all available evidence does not implicate cyclamate as a carcinogen in mice or rats, cyclamate remains banned from food products in the United States. The petition is now held in abeyance, though not actively considered. It is unclear whether this is at the request of Abbott Labs or because the petition is considered to be insufficient by the FDA.

In 2000, a paper was published describing the results of a 24-year-long experiment in which 16 monkeys were fed a normal diet and 21 monkeys were fed either 100 or 500 mg/kg cyclamate per day; the higher dose corresponds to about 30 cans of a diet beverage. Two of the high-dosed monkeys and one of the lower-dosed monkeys were found to have malignant cancer, each with a different kind of cancer, and three benign tumors were found. The authors concluded that the study failed to demonstrate that cyclamate was carcinogenic because the cancers were all different and there was no way to link cyclamate to each of them. The substance did not show any DNA-damaging properties in DNA repair assays.

Legal status
Cyclamate is approved as a sweetener in at least 130 countries. In the late 1960s, cyclamate was banned in the United Kingdom; however, it was approved after being re-evaluated by the European Union in 1996.

In the Philippines, cyclamate was banned until the Philippine Food and Drug Administration lifted the ban in 2013, declaring it safe for consumption. Cyclamate remains banned in the United States and South Korea.

Brands
Sweeteners produced by Sweet'n Low and Sugar Twin for Canada contain cyclamate, though not those produced for the United States.
 * Assugrin (Switzerland, Brazil)
 * Cap Cangkir (Indonesia)
 * Chuker (Argentina) – Merisant Company 2, SARL
 * Cologran
 * Huxol (Germany) in liquid form
 * Hermesetas (Switzerland, incl. UK market) in mini tablet, granulated, and liquid form
 * Novasweet (Russia)
 * Rio (Produced under license and authority of SweetLife AG Switzerland by SweetLife Ltd, China)
 * Sucaryl
 * Sugar Twin (Canada)
 * Suitli (Bulgaria)
 * Sweet'n Low (Canada)
 * Sugromax (New Zealand)
 * El Dorra (Tunisia)

title: Cyclamate


text:
Desensitization

Desensitization can refer to:
 * Desensitization (telecommunications)
 * Desensitization (medicine)
 * Desensitization (psychology)
 * Desensitization of explosives, see Phlegmatized
 * Desensitization, Allergen immunotherapy
 * Desensitization, another name for Exposure therapy

title: Desensitization


text:
El Caney

El Caney (also Caney) is a small village six kilometers (four miles) to the northeast of Santiago, Cuba. "Caney" means longhouse in Taíno.

Overview
It was known in centuries past as the site where Hernán Cortés received a vision supposedly ordering him to Christianize Mexico. The settlement was host to the Battle of El Caney on 1 July 1898.

Notable people

 * Manuel Fernández (1871–1921), Spanish general
 * Lorenzo Hierrezuelo (1907– 1993), Cuban trova musician

title: El Caney


text:
San Juan Hill

San Juan Hill is a series of hills to the east of Santiago, Cuba, running north to south. The area is known as the San Juan Heights or in Spanish Alturas de San Juan before the Spanish–American War of 1898, and are now part of Lomas de San Juan.

Overview
This area was the site of the Battle of San Juan Hill during the Spanish–American War. The Americans named the lesser heights "Kettle Hill" and the higher southern hill "San Juan Hill" after the battle of July 2, 1898. The two high points or hills are connected by a draw or saddle on a north–south axis.

The fight for the San Juan Heights or Hills became known as the Battle of San Juan Hill due to a reporter's telegraphy error in which the plural "s" was dropped. American Army reports also referred to the heights as "hills".

On January 12, 1959, in this place, 72 prisoners accused of crimes during the dictatorship of Fulgencio Batista were shot by order of the commander of the Cuban Revolution Raúl Castro. The defendants did not have a trial with guarantees, and before this, they had been sentenced to death. They were buried in a 40-meter-long mass grave at the site. This event is known as the San Juan Hill Massacre.

title: San Juan Hill


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Glucagon

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver to engage in glycogenolysis: converting stored glycogen into glucose, which is released into the bloodstream. High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress. Glucagon belongs to the secretin family of hormones.

Structure
Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT).

The polypeptide has a molecular mass of 3485 daltons. Glucagon is a peptide (nonsteroid) hormone.

Production
The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Glucagon is produced from the preproglucagon gene Gcg. Preproglucagon first has its signal peptide removed by signal peptidase, forming the 160-amino acid protein proglucagon. Proglucagon is then cleaved by proprotein convertase 2 to glucagon (amino acids 33-61) in pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin (1–69), glicentin-related pancreatic polypeptide (1–30), oxyntomodulin (33–69), glucagon-like peptide 1 (72–107 or 108), and glucagon-like peptide 2 (126–158).

In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.

Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.

Regulation
Production, which is otherwise freerunning, is suppressed/regulated by amylin, a peptide hormone co-secreted with insulin from the pancreatic β cells. As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.

Secretion of glucagon is stimulated by:
 * Hypoglycemia
 * Epinephrine (via β2, α2, and α1 adrenergic receptors)
 * Arginine
 * Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
 * Acetylcholine
 * Cholecystokinin
 * Gastric inhibitory polypeptide
 * Gastrin

Secretion of glucagon is inhibited by:
 * Somatostatin
 * Amylin
 * Insulin (via GABA)
 * PPARγ/retinoid X receptor heterodimer.
 * Increased free fatty acids and keto acids into the blood.
 * Increased urea production
 * Glucagon-like peptide-1

Function
Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis. Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.

Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.

Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.

Mechanism of action

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates a G protein, a heterotrimeric protein with αs, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gαs separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates glycogen phosphorylase kinase. Phosphorylated glycogen phosphorylase kinase phosphorylates glycogen phosphorylase. Phosphorylated glycogen phosphorylase clips glucose units from glycogen as glucose 1-phosphate.

Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate. The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose 2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis) by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA inactivates the glycolytic enzyme pyruvate kinase, inactivates glycogen synthase, and activates hormone-sensitive lipase, which catabolizes glycerides into glycerol and free fatty acid(s), in hepatocytes.

Glucagon also inactivates acetyl-CoA carboxylase, which creates malonyl-CoA from acetyl-CoA, through cAMP-dependent and/or cAMP-independent kinases.

Malonyl-CoA is a byproduct of the Krebs cycle (downstream of glycolysis) and an allosteric inhibitor of Carnitine palmitoyltransferase I (CPT1), a mitochondrial enzyme important for bringing fatty acids into the intermembrane space of the mitochondria for β-oxidation. Glucagon decreases malonyl-CoA through inhibition of acetyl-CoA carboxylase and through reduced glycolysis through its aforementioned reduction in Fructose 2,6-bisphosphate. Thus, reduction in malonyl-CoA is a common regulator for the increased fatty acid metabolism effects of glucagon.

Pathology
Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema, reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1.

Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing a rapid breakdown of glycogen to glucose and fast ketogenesis. It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however, some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.

The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.

History
In the early 1920s, several groups noted that pancreatic extracts injected into diabetic animals would result in a brief increase in blood sugar prior to the insulin-driven decrease in blood sugar. In 1922, C. Kimball and John R. Murlin identified a component of pancreatic extracts responsible for this blood sugar increase, terming it "glucagon", a portmanteau of " gluc ose agon ist". In the 1950s, scientists at Eli Lilly isolated pure glucagon, crystallized it, and determined its amino acid sequence. This led to the development of the first radioimmunoassay for detecting glucagon, described by Roger Unger's group in 1959.

A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.

title: Glucagon