English Info.


Mesajgönderen Birsel tarih Sal Eyl 04, 2007 10:48 pm

In medicine, amyloid refers to a particular insoluble form that many different proteins can take, due to an alteration in their secondary structure. This characteristic alteration in the protein shape is called the beta-pleated sheet. Amyloidosis refers to a variety of conditions in which amyloid proteins are abnormally deposited in organs and/or tissues, causing disease.

Approximately 25 different proteins are known that can form amyloid in humans, most of them are constituents of the plasma.

Different amyloidoses can be systemic (affecting many different organ systems) or organ specific. Some are inherited, due to mutations in the precursor protein. Other, secondary forms are due to different diseases causing overabundant or abnormal protein production-such as with over production of immunoglobulin light chains in multiple myeloma (termed AL amyloid), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloid).

1 Diagnosis
2 Systemic amyloidosis
2.1 Primary/Hereditary amyloidosis
2.2 Secondary amyloidosis
2.3 Organ-specific amyloidosis
3 References
4 External links

[edit] Diagnosis
Amyloid can be diagnosed on histological examination of affected tissue. Amyloid deposits can be identified histologically by Congo red staining and viewing under polarized light where amyloid deposits produce a distinctive 'apple green birefringence'. Further, specific, tests are available to more precisely identify the amyloid protein. Biopsies are taken from affected organs (for example, the kidney), or often in the case of systemic amyloid, from the rectum or anterior abdominal adipose tissue. In addition, all amyloid deposits contain serum amyloid P component (SAP), a circulating protein of the pentraxin family. Radionuclide SAP scans have been developed which can anatomically localize amyloid deposits in patients.

[edit] Systemic amyloidosis

[edit] Primary/Hereditary amyloidosis
These rare hereditary disorders are usually due to point mutations in precursor proteins, and are also usually autosomal dominantly transmitted.The precursor proteins are;

transthyretin-the commonest implicated protein.
apolipoprotein B
apolipoprotein A1

[edit] Secondary amyloidosis
These are far more common than the primary amyloidoses.

AL amyloidosis (immunoglobulin light chains are the precursor protein, overproduced in multiple myeloma). This is sometimes, confusingly and erroneously, called 'primary amyloidosis'.
AA amyloidosis (the precursor protein is serum amyloid A protein (SAA), an acute-phase protein due to chronic inflammation). In contrast to AL amyloid, this has previously been termed 'secondary amyloidosis'.These occur with a wide variety of diseases associated with chronic inflammation, such as Rheumatoid arthritis, Familial Mediterranean fever or chronic infection.
Dialysis related amyloidosis (the precursor protein is beta-2-microglobulin which is not removed with dialysis, and thus accumulates in patients with end stage renal failure on dialysis).

[edit] Organ-specific amyloidosis
In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common idiopathic agent. The associated proteins are indicated in parentheses.

Neurological amyloid

Alzheimer's disease (Aβ 39-43)
Parkinson's disease (alpha-synuclein)
Huntington's disease (huntingtin)
Transmissible spongiform encephalopathies caused by prion protein (PrP) were sometimes classed as amyloidoses, as one of the four pathological features in diseased tissue is the presence of amyloid plaques. These diseases include;
Creutzfeldt-Jakob disease (PrP in cerebrum)
Kuru (diffuse PrP deposits in brain)
Fatal Familial Insomnia (PrP in thalamus)
Bovine spongiform encephalopathy (PrP in cerebrum of cows)
Cardiovascular amyloid

Cardiac amyloidosis
Senile cardiac amyloidosis-may cause heart failure
Congophilic angiopathy

Amylin deposition can occur in the pancreas in some cases of type 2 diabetes mellitus
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Cardiac amyloidosis

Mesajgönderen Birsel tarih Sal Eyl 04, 2007 10:50 pm

Cardiac amyloidosis

Cardiac amyloidosis is a disorder caused by deposits of an abnormal protein in the heart tissue, resulting in decreased heart function.

[edit] Causes
Amyloidosis refers to buildup of a fibril called amyloid in tissues anywhere in the body. Fibrils are proteins produced in excess that are deposited in different organs and slowly replace normal tissue.

Different types of amyloidosis are caused by different types of proteins, such as "AL" and "AA." In cardiac amyloidosis there may be associated conduction disturbances (changes in the way the cardiac electrical impulse is transmitted through the heart).

Cardiac amyloidosis usually occurs during primary amyloidosis (called AL type amyloidosis). Primary amyloidosis usually accompanies multiple myeloma, a blood disorder in which too much of a certain type of protein is produced. This excess protein is deposited in the heart and in other organs such as the kidney. Deteriorating kidney function also occurs.

The heart is less frequently compromised by secondary amyloidosis (called AA type amyloidosis). Senile amyloidosis, however, is a type of secondary amyloidosis which does involve the heart. It is caused by overproduction of a protein different from both the AA and AL types. This particular protein is deposited mainly in the heart, but it can also infiltrate blood vessels. Senile cardiac amyloidosis is becoming more common as the average age of the population increases.

Cardiac amyloidosis is the most typical restrictive cardiomyopathy, and it is also known as “stiff heart syndrome.” Much less frequently, cardiac amyloidosis leads to dilated cardiomyopathy.

Cardiac amyloidosis is more common in men than in women.

[edit] Symptoms
Palpitations (sensation of feeling heart beat)
Swelling of legs, ankles, or other portion of the body (such as abdominal swelling or enlargement)
Excessive urination at night
Fatigue, reduced activity tolerance
Shortness of breath with activity
Breathing difficulty while lying down

[edit] Signs and Tests
The diagnosis of cardiac amyloidosis is difficult to make. The findings from an examination are not specific and may indicate enlargement of the heart and fluid in the lungs.

Listening with a stethoscope may reveal lung crackles, heart murmurs, or other abnormal sounds. The liver may be enlarged and neck veins may be distended. The blood pressure may be low or may drop when rising to a standing position (orthostatic hypotension).

Heart enlargement, congestion of the lungs or the veins in the lungs, decreased movement and/or functioning of the heart, heart failure, or signs of amyloidosis in the heart and other organs may show on the following tests:

Chest x-ray
Chest or abdomen CT scan
Coronary angiography
Nuclear heart scans (MUGA, RNV)
Magnetic resonance imaging (MRI)
An ECG may reveal conduction disturbances, arrhythmias such as atrial fibrillation, ventricular tachycardia, or premature and ectopic beats.

An echocardiogram may be used to assess the thickness of the heart wall, the size of the chambers in the heart, and the ability of the heart to fill and pump blood. Sometimes an unusual texture of the heart muscle or the endocardium (the lining of the heart) can be seen as well.

A cardiac biopsy that reveals amyloid confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis. Amyloidosis is frequently confirmed by biopsy of abdominal fat, kidney, or bone marrow.

[edit] Treatment
Physical activity may continue as long as the patient can tolerate it. Diet restrictions vary with the extent of cardiomyopathy and heart failure. These may include salt and/or fluid restrictions.

Diuretics (water pills) may be given to remove excess fluid. Digoxin may be used cautiously to improve heart control in patients with atrial fibrillation. Daily weight measurement may be recommended. A weight gain of 3 or 4 pounds or more over 1 or 2 days can indicate excessive fluid accumulation.

Some people benefit from chemotherapy or prednisone.

A pacemaker may be needed if the conduction system is involved. When heart function is very poor, a heart transplant may be considered for some patients (not in those with AL type amyloidosis, however, since their disease compromises many organs). In one type of secondary amyloidosis, liver transplantation is also required.

[edit] Prognosis
Cardiac amyloidosis is a chronic and progressive condition. A cardiologist may estimate the prognosis according to the thickness of your left ventricle and to the degree of restriction in the heart (cardiac stiffness). For primary amyloidosis, the median survival after diagnosis is about 2.1 years.

[edit] Complications
Congestive heart failure
Atrial fibrillation or ventricular arrhythmias
Sick sinus syndrome (occasionally)
Symptomatic cardiac conduction system disease (arrhythmias related to abnormal conduction of impulses through the heart muscle)
Low blood pressure and dizziness from excessive urination (from medication)
Increased sensitivity to digoxin with the potential for digoxin toxicity and related arrhythmias
Ascites (fluid accumulation in the abdomen)
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Heart failure

Mesajgönderen Birsel tarih Sal Eyl 04, 2007 10:53 pm

Heart failure

Congestive heart failure (CHF), also called congestive cardiac failure (CCF) or just heart failure, is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood through the body. It is not to be confused with "cessation of heartbeat", which is known as asystole, or with cardiac arrest, which is the cessation of normal cardiac function with subsequent hemodynamic collapse leading to death. Because not all patients have volume overload at the time of initial or subsequent evaluation, the term "heart failure" is preferred over the older term "congestive heart failure".

Congestive heart failure is often undiagnosed due to a lack of a universally agreed definition and difficulties in diagnosis, particularly when the condition is considered "mild". Even with the best therapy, heart failure is associated with an annual mortality of 10%.[1] It is the leading cause of hospitalization in people older than 65.[2]

[edit] Classification
There are many different ways to categorize heart failure, including:

the side of the heart involved, (left heart failure versus right heart failure)
whether the abnormality is due to contraction or relaxation of the heart (systolic dysfunction vs. Diastolic dysfunction)
whether the abnormality is due to low cardiac output or high systemic vascular resistance (low-output heart failure vs. high-output heart failure)
the degree of functional impairment conferred by the abnormality (as in the New York Heart Association Functional Classification classes I-IV)

[edit] Signs and symptoms

[edit] Symptoms
The symptoms depend largely on the side of the heart which is failing predominantly. If both sides are functioning inadequately, symptoms and signs from both categories may be present.

Given that the left side of the heart pumps blood from the lungs to the organs, failure to do so leads to congestion of the lung veins and symptoms that reflect this, as well as reduced supply of blood to the tissues. The predominant respiratory symptom is shortness of breath on exertion (dyspnea, dyspnée d'effort) - or in severe cases at rest - and easy fatigueability. Orthopnea is increasing breathlessness on reclining, measured in the number of pillows required to lie comfortably. Paroxysmal nocturnal dyspnea is a nighttime attack of severe breathlessness, usually several hours after going to sleep. Poor circulation to the body leads to dizziness, confusion and diaphoresis and cool extremities at rest.

The right side of the heart pumps blood returned from the tissues to the lungs to exchange CO2 for O2. Hence, failure of the right side leads to congestion of peripheral tissues. This may lead to peripheral edema or anasarca and nocturia (frequent nighttime urination when the fluid from the legs is returned to the bloodstream). In more severe cases, ascites (fluid accumulation in the abdominal cavity) and hepatomegaly (painful enlargement of the liver) may develop.

Heart failure may decompensate easily; this may occur as the result of any intercurrent illness (such as pneumonia), but specifically myocardial infarction (a heart attack), anaemia, hyperthyroidism or arrhythmias. These place additional strain on the heart muscle, which may cause symptoms to rapidly worsen. Excessive fluid or salt intake (including intravenous fluids for unrelated indications), and medication that causes fluid retention (such as NSAIDs and thiazolidinediones), may also precipitate decompensation.

[edit] Signs
In examining a patient with possible heart failure, a health professional would look for particular signs. General signs indicating heart failure are a laterally displaced apex beat (as the heart is enlarged) and a gallop rhythm (additional heart sounds) in case of decompensation. Heart murmurs may indicate the presence of valvular heart disease, either as a cause (e.g. aortic stenosis) or as a result (e.g. mitral regurgitation) of the heart failure.

Predominant left-sided clinical signs are pulmonary edema (abnormal lung sounds due to fluid accumulation), evidence for pleural effusions (fluid collection in the pleural cavity), and cyanosis (due to poor absorption of oxygen by fluid-filled lungs).

Right-sided signs are peripheral edema, ascites and hepatomegaly, an increased jugular venous pressure and hepatojugular reflux and parasternal heave.

[edit] Diagnosis

[edit] Imaging
Echocardiography is commonly used to support a clinical diagnosis of heart failure. This modality uses ultrasound to determine the proportion of blood entering the heart that is pumped by each heartbeat, the ejection fraction. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (connective tissue sac surrounding the heart). Echocardiography may also aid in deciding what treatments will help the patient, such as medication, insertion of an implantable cardioverter-defibrillator or cardiac resynchronization therapy.

Chest X-rays are frequently used to aid in the diagnosis of CHF. In the compensated patient, 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, there may be evidence of vascular redistribution ("upper lobe blood diversion"), Kerley lines, cuffing of the areas around the bronchi, and interstitial edema.

[edit] Electrophysiology
An electrocardiogram (ECG/EKG) is 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).

[edit] Blood tests
Blood tests routinely performed include electrolytes (sodium, potassium), measures of renal function, liver function tests, thyroid function tests, a complete blood count, and often C-reactive protein if infection is suspected. A specific test for heart failure is B-type natriuretic peptide (BNP), which is found to be elevated in heart failure. 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.

[edit] Angiography
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.

[edit] Monitoring
Various measures are often used to assess the progress of patients being treated for heart failure. These include fluid balance (calculation of fluid intake and excretion), monitoring body weight (which in the shorter term reflects fluid shifts).

[edit] Causes
Causes and contributing factors to congestive heart failure include the following (with specific reference to left (L) or right (R) sides):

Ischemic heart disease/Myocardial infarction (coronary artery disease)
Hypertension (L)
Chronic arrhythmias
Valvular heart disease (site depending on the affected valve, e.g. aortic stenosis affects L) and aortic coarctation (L)
Pulmonary hypertension (R)
Thyroid disease (hyperthyroidism and hypothyroidism)
Chronic severe anemia
Cardiac fibrosis

[edit] Treatment
The treatment of CHF focuses on treating the symptoms and signs of CHF and preventing the progression of disease. If there is a reversible cause of the heart failure (e.g. infection, alcohol ingestion, anemia, thyrotoxicosis, arrhythmia, or hypertension), that should be addressed as well. Reversible cause treatments can include exercise, eating healthy foods, reduction in salty foods, and abstinence of smoking and drinking alcohol.

[edit] Non-pharmacological measures
Patients with CHF are educated to undertake various non-pharmacological measures to improve symptoms and prognosis. Such measures include:[3]

Moderate physical activity, when symptoms are mild or moderate; or bed rest when symptoms are severe.
Weight reduction – through physical activity and dietary modification, as obesity is a risk factor for heart failure and ventricular hypertrophy.
Sodium restriction – excessive sodium intake may precipitate or exacerbate heart failure, thus a "no added salt" diet (60–100 mmol total daily intake) is recommended for patients with CHF. More severe restrictions may be required in severe CHF.
Fluid restriction – patients with CHF have a diminished ability to excrete free water load. They are also at an increased risk of hyponatremia due to the combination of decreased sodium intake and diuretic therapy. Generally water intake should be limited to 1.5 L daily or less in patients with hyponatremia, though fluid restriction may be beneficial regardless in symptomatic reduction.

[edit] Pharmacological management
There is a significant evidence–practice gap in the treatment of CHF; particularly the underuse of ACE inhibitors and β-blockers and aldosterone antagonists which have been shown to provide mortality benefit.[4] Treatment of CHF aims to relieve symptoms, maintain a euvolemic state (normal fluid level in the circulatory system), and to improve prognosis by delaying progression of heart failure and reducing cardiovascular risk. Drugs used include: diuretic agents, vasodilator agents, positive inotropes, ACE inhibitors, beta blockers, and aldosterone antagonists (e.g. spironolactone). It should be noted that while intuitive, increasing heart function with some drugs, such as the positive inotrope Milrinone, leads to increased mortality[5][6].

[edit] Angiotensin-modulating agents
ACE inhibitor (ACE) therapy is recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressure.[7][8][9] ACE inhibitors improve symptoms, decrease mortality and reduce ventricular hypertrophy. Angiotensin II receptor antagonist therapy (also referred to as AT1-antagonists or angiotensin receptor blockers), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy.[10][11]

[edit] Diuretics
Diuretic therapy is indicated for relief of congestive symptoms. Several classes are used, with combinations reserved for severe heart failure:[3]

Loop diuretics (e.g. furosemide) – most commonly used class in CHF, usually for moderate CHF.
Thiazide diuretics (e.g. hydrochlorothiazide) – useful for mild CHF.
Potassium-sparing diuretics (e.g. amiloride) – used first-line use to correct hypokalaemia.
Spironolactone is used as add-on therapy to ACEI plus loop diuretic in severe CHF.
Eplerenone is specifically indicated for post-MI reduction of cardiovascular risk.

[edit] Beta blockers
Until recently, β-blockers were contraindicated in CHF, owing to their negative inotropic effect and ability to produce bradycardia – effects which worsen heart failure. However, current guidelines recommend β-blocker therapy for patients with systolic heart failure due to left ventricular systolic dysfunction after stabilization with diuretic and ACEI therapy, irrespective of symptomatic severity or blood pressure.[9] As with ACEI therapy, the addition of a β-blocker can decrease mortality and improve left ventricular function. Several β-blockers are specifically indicated for CHF including: bisoprolol, carvedilol, and extended-release metoprolol.

[edit] Positive inotropes
Digoxin, once used as first-line therapy, is now reserved for control of ventricular rhythm in patients with atrial fibrillation; or where adequate control is not achieved with ACEI plus loop diuretic. There is no evidence that positive inotropes reduce mortality in CHF, although some studies suggest a decreased rate in hospital admissions. It is contraindicated in cardiac tamponade and restrictive cardiomyopathy

[edit] Alternative vasodilators
The combination of isosorbide dinitrate/hydralazine is the only vasodilator regimen, other than ACE inhibitors or angiotensin II receptor antagonists, with proven survival benefits. This combination appears to be particularly beneficial in CHF patients with an African American background, who respond less effectively to ACEI therapy.[12][13]

[edit] Devices and surgery
Patients with NYHA class III or IV, left ventricular ejection fraction (LVEF) of 35% or less and a QRS interval of 120 ms or more may benefit from cardiac resynchronization therapy (CRT; pacing both the left and right ventricles), through implantation of an bi-ventricular pacemaker, or surgical remodelling of the heart. These treatment modalities may make the patient symptomatically better, improving quality of life and in some trials have been proven to reduce mortality.

The COMPANION trial demonstrated that CRT improved survival in individuals with NYHA class III or IV heart failure with a widened QRS complex on EKG.[14] The CARE-HF trial showed that patients receiving CRT and optimal medical therapy benefited from a 36% reduction in all cause mortality, and a reduction in cardiovascular-related hospitalization.[15]

Patients with NYHA class II, III or IV, and LVEF of 35% (without a QRS requirement) may also benefit from an implantable cardioverter-defibrillator (ICD), a device that is proven to reduce all cause mortality by 23% compared to placebo. This mortality benefit was observed in patients who were already optimally-managed on drug therapy.[16]

Another current treatment involves the use of left ventricular assist devices (LVADs). LVADs are battery-operated mechanical pump-type devices that are surgically implanted on the upper part of the abdomen. They take blood from the left ventricle and pump it through the aorta. LVADs are becoming more common and are often used by patients who have to wait for heart transplants.

The final option, if other measures have failed, is cardiac transplant surgery (heart transplant) or implantation of an artificial heart. A radical new type of surgery, which is largely untested and is still in its first stages of development, was invented by Brazilian doctor Randas Batista in 1994. It involves removal of a swath of the left ventricle, to make contractions more efficient and prevent backflow of blood into the left atrium through the bicuspid valve. [1]

[edit] Palliative care and hospice
The growing number of patients with Stage D 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.

[edit] Prognosis
Among several clinical prediction rules for prognosing acute heart failure, the 'EFFECT rule' slightly outperformed other rules in stratifying patients and identifying those at low risk of death during hospitalization or within 30 days.[17] Easy methods for identifying low risk patients are:

ADHERE Tree rule indicates that patients 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 patients with systolic blood pressure over 90 mm Hg, respiratory rate of 30 or less breaths per minute, serum sodium over 135 mmol/L, no new ST-T wave changes have less than 10% chance of inpatient death or complications.

[edit] References
^ Stefan Neubauer (2007). "The failing heart — an engine out of fuel". N Engl J Med 356 (11): 1140-51. PMID 17360992.
^ Krumholz HM, Chen YT, Wang Y, Vaccarino V, Radford MJ, Horwitz RI (2000). "Predictors of readmission among elderly survivors of admission with heart failure". Am. Heart J. 139 (1 Pt 1): 72-7. PMID 10618565.
^ a b Smith A, Aylward P, Campbell T, et al. Therapeutic Guidelines: Cardiovascular, 4th edition. North Melbourne: Therapeutic Guidelines; 2003. ISSN 1327-9513
^ Jackson S, Bereznicki L, Peterson G. Under-use of ACE-inhibitor and β-blocker therapies in congestive cardiac failure. Australian Pharmacist 2005;24(12):936.
^ Packer M, Department of Medicine, Mount Sinai School of Medicine, City University of New York. (1989). "Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure.". Am J Cardiol 63 (2): 41A-45A. PMID 2642629.
^ Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al., Department of Medicine, Mount Sinai School of Medicine, City University of New York. (1991). "Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.". N Engl J Med 325 (21): 1468-75. PMID 1944425.
^ Krum H, National Heart Foundation of Australia and Cardiac Society of Australia & New Zealand Chronic Heart Failure Clinical Practice Guidelines Writing Panel. (2001). "Guidelines for management of patients with chronic heart failure in Australia.". Med J Aust 174 (9): 459-66. PMID 11386592.
^ Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. (2005). "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult". Circulation 112 (12): e154-235. PMID 16160202.
^ a b National Institute for Clinical Excellence. Chronic heart failure: management of chronic heart failure in adults in primary and secondary care. Clinical Guideline 5. London: National Institute for Clinical Excellence; 2003 Jul. Available from:
^ Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. (2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.". Lancet 362 (9386): 772-6. PMID 13678870.
^ Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. (2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.". Lancet 362 (9386): 759-66. PMID 13678868.
^ Exner DV, Dries DL, Domanski MJ, Cohn JN (2001). "Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.". N Engl J Med. 344 (18): 1351-7. PMID 11333991.
^ Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; African-American Heart Failure Trial Investigators. (2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.". N Engl J Med 351 (20): 2049-57. PMID 15533851.
^ Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. (2004). "Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure". N Engl J Med 350 (21): 2140-50. PMID 15152059.
^ Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. (2005). "The effect of cardiac resynchronization on morbidity and mortality in heart failure". N Engl J Med 352 (15): 1539-49. PMID 15753115.
^ Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. (2005). "Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.". N Engl J Med 352 (3): 225-37. PMID 15659722.
^ Auble TE, Hsieh M, McCausland JB, Yealy DM (2007). "Comparison of four clinical prediction rules for estimating risk in heart failure". Annals of emergency medicine 50 (2): 127-35, 135.e1-2. DOI:10.1016/j.annemergmed.2007.02.017. PMID 17449141.
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