Pathophysiology - Etiology - Symptoms - Diagnosis - Treatment - Special Situations - Clinical Trials
Congestive heart failure (CHF) occurs when the cardiac output is not adequate enough to meet the demands of the body. This can occur for several reasons as congestive heart failure is the predominant clinical presentation in multiple disease states. Heart failure can be due to:
Systolic dysfunction (reduced ejection fraction)
Diastolic dysfunction (relaxation or filling abnormality)
Valvular heart disease
Right heart failure
High output CHF (i.e. severe anemia, arteriovenous malformations)
Review of systolic congestive heart failure will be presented here. Review of diastolic congestive heart failure, valvular heart disease, right heart failure and high output heart failure are presented elsewhere.
Congestive heart failure affects approximately 6 million Americans every year and congestive heart failure remains one of the most common reasons for hospitalization.
The ACC/AHA classification of heart failure has four stages.
Stage A: Those at risk for heart failure, but who have not yet developed structural heart changes (diabetics, those with coronary disease without prior infarct).
Stage B: Individuals with structural heart disease (i.e. reduced ejection fraction, left ventricular hypertrophy, chamber enlargement), however no symptoms of heart failure have ever developed.
Stage C: Patients who have developed clinical heart failure.
Stage D: Patients with refractory heart failure requiring advanced intervention (biventricular pacemakers, left ventricular assist device, or transplantation).
Note that the ACC/AHA classification is much different from the New York Heart Association (NYHA) functional class (described below in symptoms section) in that there is no moving backwards between stages. Once symptoms develop, stage C heart failure is present and stage B will never again be achieved. The NYHA classification, in contrast, can move between class I and class IV relative quickly as these are all designated based on symptoms alone.
Congestive heart failure (CHF) results in the activation of multiple compensatory mechanisms in an attempt to increase cardiac output. These frequently work short term, however the long-term effects can be detrimental to the heart via negative remodeling. The two primary mechanisms (considered the “neurohormonal” response) includes activation of the sympathetic nervous system (SNS) and activation of the renin-angiotensin-aldosterone (RAAS) system. Medical therapy is aimed at reducing the activity of these two systems. A third compensatory response occurs via B-type natriuretic peptide and A-type natriuretic peptide. See the summary image below:
When the carotid baroreceptors sense a low blood pressure, one response is to activate the sympathetic nervous system (SNS). This increases epinephrine and norepinephrine levels which act to increase heart rate, contractility and afterload via peripheral vasoconstriction. In the short-term this will work to increase cardiac output and relieve heart failure symptoms, however chronically this has deleterious effects and causes further left ventricular systolic decline. Beta-blockers are the primary therapy to reduce this SNS activation.
When the renal perfusion is decreased, the kidney assumes hypovolemia although that is not always the case as low cardiac output can also decrease renal perfusion. The inherent compensatory mechanism is activation of the renin-angiotensin-aldosterone system (RAAS) in order to retain sodium and water. Angiotensin increases afterload via peripheral vasoconstriction raising blood pressure. The activation of the RAAS has been well shown to contribute to negative remodeling of the heart resulting in even worse overall cardiac function. The RAAS can be blocked by ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists and ADH antagonists (see Management section).
B-type natriuretic peptide and A-type natriuretic peptide has beneficial hemodynamic effects during heart failure and represent another natural mechanism to relieve symptoms. They are released primarily in the atrium as the elevated cardiac pressures stretch the atrial myocytes. They act to vasodilate and cause sodium excretion resulting in natriuresis. Nesiritide is a B-type natriuretic peptide analog that can be used to treat heart failure.
Endothelin has negative effects in regards to remodeling and vasoconstriction, however clinical trials of endothelin inhibitors have never shown a benefit and thus its role remains unclear.
There are a number of causes of systolic heart failure, however the most common is related to coronary artery disease and prior myocardial infarctions. This entity is termed an “ischemic cardiomyopathy” and accounts for nearly half of systolic heart failure cases in the United States.
Dilated cardiomyopathy is the second leading cause of systolic heart failure. This can be idiopathic (50% of cases), a viral cardiomyopathy, peripartum, hypertensive heart disease related or from less common causes. These include doxorubicin therapy, stress-induced (Takotsubo), alcohol related, selenium or thiamine deficiency, tachycardia-mediated, giant cell arteritis, hyperthyroidism, cocaine use, obstructive sleep apnea and familial cardiomyopathies.
Valvular heart disease is the third leading cause of systolic heart failure. This includes aortic valve stenosis, aortic valve regurgitation, mitral valve stenosis and mitral regurgitation. In many developing nations, the most common cause of systolic heart failure is Chagas disease related to Trypanosoma cruzi transmitted by triatomine bugs.
Recall that right heart failure and diastolic heart failure are different entities from the left-sided systolic heart failure reviewed here. The most common cause of right heart failure is pressure overload related to left heart failure. Diastolic heart failure is most commonly caused by hypertension as a part of "hypertensive heart disease". Aging of the heart contributes to diastolic heart failure as well.
The general symptoms of congestive heart failure are the same regardless of the etiology and are attributed to either fluid retention (related to the activated RAAS) or low cardiac output. They can also be categorized as from left heart failure versus right heart failure.
Left heart failure will result in low cardiac output symptoms and transmission of the increased left-sided cardiac pressures into the lungs causing pulmonary edema and a sense of dyspnea. With physical exertion the heart demands increased cardiac output which is not able to be satisfied in states of heart failure and thus left heart pressures increase significantly causing this transient pulmonary edema.
As those increased pressures from the left heart affect the right ventricle, right heart failure can ensue. The most common cause of right heart failure is left heart failure.
Right heart failure symptoms include lower extremity dependant edema. When the legs are elevated at night, the fluid redistributes centrally causing pulmonary edema resulting in orthopnea (dyspnea while laying flat) or paroxysmal nocturnal dyspnea (PND). Hepatic congestion can occur causing right upper quadrant abdominal pain.
Symptoms related to low cardiac output include fatigue, weakness and in extreme cases, cardiac cachexia can occur.
The New york Heart Association (NYHA) functional class helps to classify patients based on their symptoms of heart failure.
Class I: No symptoms of heart failure
Class II: Symptoms of heart failure with moderate exertion such as ambulating 2 blocks or 2 flights of stairs
Class III: Symptoms of heart failure with minimal exertion such as ambulating 1 block or 1 flight of stairs, but no symptoms at rest
Class IV: Symptoms of heart failure at rest
Note that the NYHA functional class differs from the ACC/AHA heart failure classification system in that the former allows movement from one class to the other while the ACC/AHA classification does not (see below).
The diagnosis of congestive heart failure is predominantly by history and physical, although echocardiography and cardiac catheterization can be beneficial.
Physical examination during systolic congestive heart failure will reveal an S3 heart sound if significant left ventricular dilation is present. An S4 heart sound can be present in diastolic heart failure. The point of maximal intensity (PMI) will be laterally displaced and at times the S3 can even be palpable. Cardiac murmurs will be present if valvular heart disease is present contributing to the heart failure such as aortic stenosis or mitral regurgitation.
Physical examination in states of right heart failure may reveal elevated jugular venous pressure including hepatojugular reflux, lower extremity pitting edema, and ascites. Pleural effusions may be present and are more prominent on the right compared to the left.
Echocardiography is indicated in all patients with a new diagnosis of congestive heart failure to help determine the etiology. The left ventricular systolic function can be measured including the ejection fraction. Diastolic function assessment can help determine the left heart pressures. The cardiac valves can be interrogated for significant regurgitant or stenotic lesions.
Cardiac catheterization including coronary angiography is indicated whenever anginal symptoms accompany a new onset of congestive heart failure (class I). If no angina is present, stress testing to evaluated for ischemia as a contributor is recommended. Alternatively, coronary CT angiography can be done when no angina is present to exclude occlusive coronary artery disease.
Lifestyle modifications to help decrease the risk of volume overload leading to hospitalization is important. Fluid restriction to about 2 liters of all liquids daily should be maintained as well as sodium restriction of 2g daily. Monitoring daily weights at home in order to dose diuretics on a prn or individualized basis is recommended. Educating patients in regards to the importance of medication compliance is crucial to prevent decompensated episodes of heart failure.
There are many available pharmacotherapies which have an abundance of clinical evidence to support mortality reduction and symptom improvement in patients with congestive heart failure. It is important to understand which therapies are the most important and reduce mortality versus those that are for symptom relief only.
ACE inhibitors/Angiotensin Receptor Blockers
Angiotensin converting enzyme inhibitors (ACE inhibitors) are a class of oral medications that act primarily through blockade of the angiotensin converting enzyme (ACE). This enzyme converts angiotensin I to angiotensin II. Angiotensin II causes vasoconstriction increasing afterload thus increasing systemic blood pressure. Angiotensin contributes to the production of aldosterone which normally acts to retain sodium and water.
Reducing the activity of the renin-angiotensin-aldosterone system (RAAS) is crucial in heart failure during which it is overactive and contributes to negative remodeling. ACE inhibitors can reduce the symptoms of heart failure and have been shown in multiple clinical trials to have a mortality benefit in systolic heart failure patients. Doses are usually started low and titrated up to a predetermined goal dose if the patient is able to tolerate it. Examples of commonly used ACE inhibitors include lisinopril, captopril, ramipril and enalapril.
Angiotensin receptor blockers (ARBs) are a class of oral medications that act primarily through blockade of the angiotensin receptor. Very similar effects on the RAAS are achieved when using ARBs compared to ACE inhibitors. ARBs are primarily used when a systolic heart failure patient is not able to tolerate an ACE inhibitor, frequently due to a cough.
These drugs have been shown in multiple clinical trials to give a significant mortality benifit.
Beta-blockers antagonize beta-1 and beta-2 receptors which are the usual targets of the sympathetic nervous system (SNS) including epinephrine and norepinephrine. The overactive SNS has deleterious effects on long-term cardiac function as described earlier. Three beta-blockers are FDA approved in the United States for the treatment of systolic congestive heart failure and include: metoprolol succinate, carvedilol, and bisoprolol.
Beta-blockers are contraindicated specifically in systolic heart failure when pulmonary edema is present, when there are signs of cardiogenic shock, severe bradycardia, hypotension or wheezing related to asthma.
Beta-blockers should be initiated in patients hospitalized for acute systolic congestive heart failure prior to hospital discharge. It is reasonable to withhold beta-blockers in patients who were previously taking them in the outpatient setting for chronic systolic heart failure when they are admitted with a heart failure exacerbation.
These drugs have been shown in multiple clinical trials to give a significant mortality benifit.
Aldosterone antagonists (spironolactone, eplerenone) also known as “potassium sparing diuretics” block the action of aldosterone inhibiting the reuptake of sodium and water. Normally, when sodium reabsorbed it is exchanged with potassium which is then excreted. Since aldosterone inhibition decreases sodium reabsorption, it also decreases potassium excretion resulting in higher serum potassium levels.
Spironolactone is indicated (class IIa, level of evidence B) in systolic heart failure with recent or current New York Heart Association functional class IV symptoms, preserved renal function and a normal potassium concentration.
Spironolactone was investigated in the RALES trial and a mortality benefit was shown in New York Heart Association functional class III and IV patients. Significant hyperkalemia did contribute to sudden cardiac death.
The aldosterone antagonist eplerenone was evaluated in the EPHESUS trial leading to the recommendation for its use with an ACE inhibitor prior to hospital discharge after an acute coronary syndrome if there is left ventricular systolic dysfunction (EF < 40%) and either diabetes or symptomatic heart failure present and no contraindication. A class effect is likely present and thus spironolactone is frequently used instead of eplerenone due to cost concerns, although there is no direct data to support this practice. In this population, aldosterone antagonists to give a mortality benefit.
Digoxin blocks the sodium/potassium ATPase pump. The mechanism by which this decreases AV conduction is not clear however is perhaps due to increased vagal tone. Intracellular calcium within the cardiac myocytes is increased by digoxin resulting in increased inotropy (contractility) and thus digoxin is frequently used when atrial fibrillation and left ventricular systolic dysfunction coexist.
Digoxin therapy gets a class I indication for the treatment of symptomatic systolic congestive heart failure. The DIG (Digitalis Intervention Group) trial showed no mortality benefit, however there was improvement in symptoms and fewer hospitalizations for heart failure.
Commonly, if systolic heart failure is present in combination with atrial fibrillation and an uncontrolled ventricular rate, digoxin therapy is utilized. Digoxin toxicity is a concern and the dose must be adjusted in the setting of renal failure.
The loop diuretics furosemide, bumetanide and torsemide and utilized to help maintain euvolemia in heart failure patients. These drugs are for symptom relief only and have never been shown to have a mortality benefit. The dose frequently needs adjusting based on the patients lifestyle including fluid and salt intake.
Tolvaptan is a vasopressin receptor antagonist. Vasopressin (a.k.a. ADH or antidiuretic hormone) helps to regulate water retention by absorbing water in the collecting ducts of the nephron. Blocking this receptor will allow water to be excreted more readily. Many heart failure patients present with some degree hyponatremia from water retention. Tolvaptan has been shown in more than one clinical trial to raise sodium levels, however mortality and rehospitalization was not improved and thus the role for this therapy is not well defined. Specifically, tolvaptan is FDA approved for the treatment of euvolemic hyponatremia and hypervolemic hyponatremia.
Nesiritide is a recombinant form of B-type natriuretic peptide and is used for the treatment of acute decompensated heart failure. Nesiritide has potent vasodilatory properties and reduces pulmonary capillary wedge pressure effectively. This results in improvement of dyspnea.
Once large trial (ASCEND-HF) randomized 7141 patients to nesiritide versus placebo. While nesiritide did improve the symptom of dyspnea better than placebo, there was no reduction in 30 day rehospitalization and no mortality benefit. Hypotension was significant in the nesiritide group.
Nesiritide is not recommended for routine use during decompensated heart failure. If patients with normal blood pressures are not responding well to typical management with loop diuretics, then nesiritide can be considered.
Hydalazine and Nitrates
Hydralazine is a direct arterial vasodilator that decreases afterload. Isosorbide mononitrate is a long-acting oral nitrate that decreases preload. The combination of these two drugs has a similar effect as an ACE inhibitor or angiotensin receptor blocker without reducing renal function or causing hyperkalemia. The combination of hydralazine and nitrates, however, does not have the neurohormonal blockade benefit of ACE inhibitors or angiotensin receptor blockers which is thought to play an important role. Despite this a clear mortality benefit has been present with this combination when ACE inhibitors or ARBs are contraindicated, especially in the African American population.
The treatment of heart failure with therapies other then medications, such as the use of devices, is considered mechanical therapy. This includes biventricular pacing, implantable cardioverter defibrillators (ICDs) and left ventricular assist devices (LVADs).
Biventricular pacing is an excellent option for certain patients with advanced heart failure. Also known as “cardiac resynchronization therapy”, biventricular pacing has been shown to improve heart failure symptoms in a majority cases. The normal cardiac conduction system delivers the electrical impulse to both the right and left ventricles simultaneously, however in the presence of a left bundle branch block (LBBB) or right bundle branch block (RBBB), the electrical impulse will reach one ventricle first then slowly transmit to the other causing “cardiac dyssynchrony”. Remember that a LBBB and RBBB by definition prolong the QRS duration.
The indications for biventricular pacing are below:
Left ventricular ejection fraction < 35%, a QRS duration of > 120 ms and New York Heart Association (NYHA) functional class III or IV with optimal medical therapy.
Left ventricular ejection fraction < 35% and frequent reliance on right ventricular pacing (which significantly prolongs the QRS duration).
Left ventricular ejection fraction < 35% and NYHA functional class I or II who are undergoing pacemaker or implanted cardioverter defibrillator (ICD) insertion and may rely on frequent cardiac pacing.
A meta-analysis has shown a mortality benefit for those patients with a QRS duration of > 150 ms who receive biventricular pacing and not those with a QRS duration < 150 ms.
Many patients who are candidates for biventricular pacing also receive an implanted cardioverter defibrillator (ICD) at the same time.
When atrial fibrillation is present, the QRS complex occurs at random intervals and the biventricular pacing device does not know when to initiate atrial pacing and may not be able to initiate biventricular pacing (if the native QRS complex comes earlier than expected). This results in less beneficial effects on cardiac output and thus symptoms.
Therefore, it is recommended that any patient with permanent atrial fibrillation undergoing biventricular pacing also have AV nodal ablation performed, thus eliminating the unpredictability of the onset of the QRS complex allowing for near 100% biventricular pacing.
Implanted Cardioverter Defibrillator (ICD)
An implantable cardioverter defibrillator (ICD) is a permanent device in which a lead (wire) inserts into the right ventricle and monitors the heart rhythm. It is implanted similar to a pacemaker and the generator lays in the upper chest area. Therapies are delivered in the form of anti-tachycardia pacing (ATP) or shocks to convert to sinus rhythm from sustained ventricular tachycardia or ventricular fibrillation, both of which are life-threatening rhythms.
For primary prevention of sudden cardiac death, ICDs are indicated:
Patients with a prior myocardial infarction and a left ventricular ejection fraction of < 30% (MI must have been at least 40 days prior in order to allow time for recovery of LV systolic function).
Patients with systolic heart failure (New York Heart Association functional class II or III) and an ejection fraction < 35%. Optimal medical therapy must be present and at least 3 months must have elapsed in case the systolic function recovers to an ejection fraction > 35% in both non-ischemic cardiomyopathy patients and ischemic cardiomyopathy patients who underwent bypass surgery.
For secondary prevention of sudden cardiac death, ICDs are indicated:
Patients with documented cardiac arrest from sustained ventricular tachycardia or ventricular fibrillation or documented hemodynamically stable sustained ventricular tachycardia even if the left ventricular ejection fraction is > 35%, as long as no reversible cause is identified. The above must not be within 48 hours of an acute coronary syndrome.
Left Ventricular Assist Device
A left ventricular assist device is a surgically implanted cardiac assist mechanism which essentially acts like a heart. One cannula sits in the left ventricle which pulls blood out of the body into its chamber where it pumps blood to the second cannula inserted into the aorta.
Post-operative cardiogenic shock (not able to be weaned from cardiopulmonary bypass)
Back-up in patients undergoing high risk surgical procedures
Massive myocardial infarction without other therapeutic options
Severe cardiac decompensation (regardless of cause) such as progression of a non-ischemic cardiomyopathy
Bridge to transplantation
Chronic heart failure with a poor prognosis that are not a transplant candidate (LVAD implantation in this situation is termed “destination therapy” since their final destination is not transplant, but they will have the LVAD until death).
Heart Failure Exacerbations
When a patient becomes volume overloaded and presents with an acute episode of symptomatic heart failure, the term “heart failure exacerbation” is used.
The etiology of a heart failure exacerbation is crucial to determine in order to direct medical therapy in the right direction not only to improve the current heart failure symptoms, but to prevent recurrence. Every heart failure patient presenting to the emergency room or the hospital ward should be evaluated for the following:
Dietary non-compliance: Consuming large amounts of fluids and/or sodium can result in volume overload causing symptoms of heart failure and eventual pulmonary edema.
Medication non-compliance: Frequently, diuretics are not taken as prescribed due to the urinary side-effects. Also, uncontrolled hypertension from not taking other cardiovascular medications can contribute.
Ischemia: Acute coronary syndromes or progression of ischemic heart disease can cause heart failure exacerbations. All heart failure patients in the hospital should have at least one ECG performed as well as cardiac enzymes.
Arrhythmia: Multiple different arrhythmias can occur in heart failure patients resulting in volume overload from reduced cardiac output. These include atrial fibrillation and ventricular tachycardia.
Progression of the heart failure: Worsening of the cause of the patients heart failure, such as progression of valvular heart disease or further LV systolic decline in ischemic or non-ischemic cardiomyopathies cause trigger heart failure exacerbations.
Non-cardiac illness: Pneumonia, severe sepsis, and gastrointestinal bleeding are examples of conditions that require a higher cardiac output. In patients with already reduced heart function, these can trigger clinical heart failure.
Heart transplantation is considered a last resort therapy for end-stage heart failure when the above mentioned therapies fail. Refractory heart failure patients should be referred to a heart failure program capable of heart transplantation, especially if the VO2 max is < 10 mL/kg on cardiopulmonary stress testing.
Heart transplantation can improve survival in carefully selected individuals. The surgical process itself has an approximate 5% mortality rate. Afterwards, immunosuppressant drugs must be utilized including prednisone, cyclosporine and tacrolimus in order to prevent rejection.
Heart transplantation is contraindicated with severe fixed pulmonary hypertension, malignancy, any significant illness with limited survival, and any illness that would have a high likelihood of occurring in the transplanted heart. Age > 70 is only considered a relative contraindication.
With heart transplantation, survival is steadily improving. Most patients now live at least 10 years after transplantation with the highest mortality rate being within the first 6 months of transplantation.
The ranking system to determine eligibility for transplantation is below:
Status IA: The most critically ill patients. Must be hospitalized and requiring mechanical or pharmacological support to sustain life (intraaortic balloon counterpulsation, left ventricular assist device, high doses of intravenous inotropic therapy). New York Heart Association functional class IV.
Status 1B: Less critically ill, but still seriously impaired. These patients may have outpatient daily inotrope infusion. New York Heart Association functional class III or IV.
Status 2: The least urgent patients. These patients rarely receive transplantation since organs are in short supply and given to status 1A or status 1B patients first. New York Heart Association functional class II or III.
Related Congestive Heart Failure Links:
Clinical Trials in Heart Failure
1. Jessup et al. Medical Progress: Heart Failure. N Engl J Med 2003;348:2007-2018.
2. Heart Failure Society of America - Practice Guidelines
3. American College of Cardiology / American Heart Association Guidelines and Quality Standards
By Steven Lome