Heart Failure: Difference between revisions

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'''Ineke Nederend''' MSc,  

 

 

==Introduction==

===History===

In 1628, William Harvey first described the circulation. Little understanding of the nature of heart failure (HF) could have existed before that time. There are accounts of a disease that now would be called heart failure, and herbal medicines like the ancient boiled bulb of squill, later on the broom plant (Cytisus scoparius) and the foxglove (Digitalis purpura) were used as diuretics to treat heart failure or dropsy (edema). The latter, foxglove, was described as a diuretic by William Withering in 1785 (1). The essential glycoside substance digitalis of the leaves of the plant improves contractility of the cardiac muscle and has important parasympathetic effects, particularly on the atrioventricular node. In the 1950’s, thiazide diuretics were introduced, in the 1960’s furosemide. For a long time, diuretics and digitalis were the main treatment options for HF. After vasodilator therapy for HF was being introduced around 1960, the first randomized trial showing mortality benefit with nitrates and alphablockers for HF was published in 1986.  In 1975, the first ACE inhibitor captopril was developed and approved for human use in 1981, with a first randomized trial published in 1987. Spironolacton, introduced in 1959, was used (in low dose) for HF only after the introduction of ACE inhibitors.  Betablockers were scarcely used in heart failure when they started to be shown beneficial in the 70’s,  , but it was only in 1994 that the first randomized trial showed mortality benefit with betablockers. 

===Framingham heart study===  

In 1948, the Framingham heart study was launched. At its start, 5209 residents of the town Framingham in the US aged between 30 and 62 were included for assessing risk factors for cardiac disease at follow up in the study which is still continued today. This study is considered the most important longitudinal source of data on the epidemiology of heart failure (2).  

==Definition and diagnosis==

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!colspan="2"|Table 1 Definition of heart failure

|colspan="2"|'''''Heart failure is a clinical syndrome in which patients have the following features:'''''

*'''Symptoms typical of heart failure'''

**Breathlessness

**Reduced exercise tolerance

|'''''And'''''

*'''Signs typical of heart failure'''

**Elevated jugular venous pressure **Hepatomegaly

**Third heart sound

**Pleuraeffusion

**Peripheral oedema, **Hepatojugular reflux

**Cardiomegaly on X-ray of the thorax

|'''''And'''''

*'''Objective evidence of a structural or functional abnormality of the heart at rest'''

**Abnormal echocardiogram

**Abnormal pump function on nuclear imaging or on MRI)

===Prevalence===

The prevalence of HF in the Western world is estimated as 1 to 2%, and the incidence is around 5 to 10 per 1000 persons per year (7,9). Because at young age coronary heart disease is more prevalent in men, prevalence of HF is also higher in this group compared to age matched women. At older age, prevalence of HF is equal between sexes.  

===Acute and chronic heart failure===

Heart failure may become a chronic condition, in which HF is persistent, either with recurrences or with slow progression. A patient may be described as decompensated when chronic stable HF deteriorates.  Acute HF has traditionally been used to describe the nature of the clinical presentation, as severe or of recent onset. Different clinical presentations fall under this definition.  

===Systolic versus diastolic heart failure===

Heart failure patients may be broadly classified into one of two groups, or a combination of both, depending on the left ventricular ejection fraction (LVEF). The LVEF is most often assessed with echocardiography (see table 3).  When the LVEF is less than 45%, systolic pump function is abnormal and it is named systolic HF (3). If LVEF is preserved (>50%), symptoms are attributed to impaired relaxation of the heart during diastole and therefore is labeled as diastolic HF or HF with a preserved LVEF (3, 4). As a result of impaired relaxation, end diastolic pressure and subsequently left atrial- and pulmonary pressure will rise with subsequent alveolar pulmonary edema as a consequence. LF diastolic dysfunction may be present in asymptomatic patients, and it is considered an important precursor of heart failure (5). Frequently, patients have both systolic and diastolic heart failure at the same time, but the term for this ailment is still systolic heart failure.

The term heart failure is not limited to a failing left ventricle; the right ventricle may also be involved in the process and there may also be isolated right ventricular heart failure.  

===Pathophysiology of heart failure===

HF is caused by a loss of cardiac pump function which can be due to a structural abnormality of the heart muscle (e.g. myocardial infarction) or a change in the heart function (and often structure) in response to an abnormal load (e.g. aortic valve stenosis). The relationship between loading the ventricle (by filling it) and its output was described by Frank and Starling in 1918 and has become the cornerstone in understanding heart failure and how to treat it. The relationship determines that by loading the heart (increasing its filling or its pressure) the output increases (Figure 1). A heart that has a lower output can be improved by increasing its volume and its loading pressure. This is what naturally happens (LV dilatation and increased filling pressure) when the heart doesn’t pump out enough volume, and in the first phase of disease compensates for the loss of contractility. It takes more energy from the heart to work at increased loading, but the heart has a reasonable energy reserve.  In a chronic situation, remodeling of the heart progresses (by hypertrophy of myocytes and dilatation by increasing myocyte length and matrix changes), which in the long term leads to a further loss in function. The result is further increased loading pressures in the heart and by communicating the diastolic loading pressures to the left atrium and pulmonary veins, the pulmonary capillaries may become overloaded, to leak water to the lungs. That is the actual restriction towards further filling the heart as a tool to improve its function; even poor left ventricles may be filled more to increase their output (6) but the patients’ pulmonary capillaries cannot tolerate these hydrostatic pressures and start to leak water.   

Hemodynamic explanations (the heart as a pump) use the concept of preload (filling) and afterload (workload of the heart, which is wall tension and arterial pressure or vascular resistance). In this way, the progression of left sided heart failure towards right sided heart failure is explained as follows: prolonged left ventricular failure increases pressures in the left atrium (preload), which in time leads to a subsequent increased resistance in the pulmonary vascular system (which is the afterload of the right ventricle) and eventually may also lead to right ventricular failure.

Another relevant issue is afterload of the left ventricle influencing the output of the heart: as the afterload of the aortic pressure also influences the timing of closure of the aortic valve, a high aortic pressure will close the aortic valve early and will therefore diminish the output. Decreasing (theoretically diastolic, but more practically systolic) aortic pressure will increase the stroke volume by later closure of the aortic valves. (Figure 2)

[[Image:Image1.jpg|thumb|''Figure 2 Effects of decreased afterload. Red arrows indicate aortic valve opening, which occurs later and at higher LV systolic pressure when the diastolic aortic pressure is higher. Blue arrows indicate closing of the aortic valve. Bidirectional arrows represent stroke volume. When aortic pressure is decreased, stroke volume increases as a result of a lower aortic pressure during closure of the aortic valve.]]

Hormonal/ sympathetic system mechanisms (RAAS/ Sympathetic overstimulation) of heart failure are as important as the hemodynamic mechanisms of heart failure.  

A decreased cardiac output leads to diminished renal perfusion and release of hormones in the RAA-system: renin released in the circulation by the renal juxtoglomerular apparatus, which is stimulating the cleavage of angiotensinogen into angiotensins I and II during passage through the lungs. Angiotensin II stimulates vasoconstriction in the kidneys, and in other vascular systems, increasing blood pressure; the second effect of angiotensins is stimulating the release of aldosterone from the adrenals into the plasma, which retains sodium from the kidney tubules in the blood and thereby water. The RAA –system, which works as a compensatory mechanism for heart failure to increase blood pressure and blood volume, also stimulates hypertrophy of muscle cells and stimulates the formation of fibrosis, which in the long term are detrimental to heart failure.  

The other compensatory mechanism for heart failure, stimulation of the sympathetic nervous system, increases heart rate to increase cardiac output, which is a powerful compensatory mechanism. However, chronic stimulation of the sympathetic nerves to the heart, leading to higher heart rates, is toxic to the heart, by continuous release of norepinephrin to the myocyte. In addition, by their continued stimulation, the betareceptors for norepinephrin are downregulated in heart failure, which further diminishes the function and functional reserve of the heart.  

===Management===

[[Image:Image1.jpg|thumb|Figure 3 management in heart failure.]]

==Clinical aspects==

===History===

A careful history of the patient is important for the diagnosis and in order to identify the cause of HF. The history (and physical examination) can be used to differentiate between the abovementioned potential causes of HF (refer to Etiology of heart failure). Family history of HF, smoking status, hyperlipidaemia, hypertension and diabetes mellitus are factors that should be taken into account during the assessment of the patient history in order to draw a risk profile of the patient. Finally, the history should include previous events and the response to therapy.

===Symptoms and signs===

HF can manifest with a multitude of different symptoms and signs, but shortness of breath and tiredness are the most characteristic. The Framingham Heart Study defined major and minor diagnostic criteria for HF. 

*Dyspnea on ordinary exertion

*Hepatomegaly

*Pleural effusion

*Tachycardia (heart rate>120 beats/min.)

Minor criteria are acceptable only if they cannot be attributed to another medical condition (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome).

Diagnosis of HF requires the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria. The Framingham Heart Study criteria are 100% sensitive and 78% specific for identifying persons with definite congestive heart failure in an outpatient population (10).  

===Severity of HF===

In general, correlation between the severity of symptoms and the severity of HF in terms of loss of maximal oxygen consumption is weak (3). The New York Heart Association functional classification is used most frequently to classify the severity of HF (Table 2). Assessing severity is needed for the proper therapy/ medication to be chosen.  

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!colspan="2"|Table 2 NYHA functional classification

|colspan="2"|'''''Severity based on symptoms and physical activity'''''

|'''Class I'''

|'''Class II'''

|Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea.

|'''Class III'''

|Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in fatigue, palpitation, or dyspnoea.

|'''Class IV'''

|Unable to carry on any physical activity without discomfort. Symptoms at rest. If any physical activity is undertaken, discomfort is increased.  

===Physical examination===

There are several key features in the clinical examination of a patient presenting with HF. The physical examination should focus on the general appearance of the patient, pulse and blood pressure, signs of fluid overload (increased jugular venous pressure, peripheral edema, ascites and hepatomegaly), the lungs, and the heart (apex, Gallop rhythm, third heart sound, murmurs).

===Additional diagnostic test===

===Electrocardiogram===

In every patient suspected of HF, an electrocardiogram (ECG) should be performed. Several common abnormalities (including possible causes) indicative of HF on the ECG include but are not limited to: sinus tachy- or bradycardia, atrial tachycardia, -flutter, or –fibrillation, ventricular arrhythmias, ischemia (including myocardial infarction), abnormal Q waves, left ventricular hypertrophy, micro voltages, and QRS length >120 ms. Although an abnormal ECG (excluding arrhythmias) has a low positive predictive value for HF, a normal ECG is highly indicative of the absence of HF.

 

 

 

 

===Exercise test===  

An exercise test is not diagnostic for heart failure, but may be used to objectify ischemia as the cause of heart failure, or can be used to assess severity of heart failure, usually in conjunction with maximal oxygen uptake (VO_2max) measurement. This test is performed on a treadmill or on an bicycle ergo meter. The patient is asked to give maximal effort while the work load gradually increases. During the test, ECG is monitored for ischemia. When possible, oxygen consumption should be measured during the test. Not only is an oxygen consumption test a good tool to discriminate between lung- peripheral- or heart problems, the obtained maximal oxygen uptake (VO_2max) also has an important prognostic value.  

===Heart catheterization===

Heart catheterization is not always part of the routine diagnosis and work-up of patients with HF. It should be considered however to exclude coronary heart disease (Class of recommendation IIa, level of evidence C, see table 4). Coronary angiography is recommended in patients at high risk of coronary artery disease  (Class of recommendation I, level of evidence C) and in HF patients with significant valvular disease (Class of recommendation IIa, level of evidence C).

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!colspan="3"|Table 3 Common echocardiographic abnormalities in heart failure

|Left ventricular ejection fraction (LVEF)

|Reduced (< 50%)

|Left ventricular global systolic dysfunction

|Left ventricular wall motion

|Akinesis, hypokinesis, dyskinesis

|Myocardial infarction/ischaemia, cardiomyopathy, myocarditis

|Left ventricular end-diastolic diameter

|Increased (≥60 mm/>32 mm/m2))

|Volume overload HF likely

|Left ventricular end-systolic diameter

|Increased (≥45 mm/>25 mm/m2,)

|Volume overload

HF likely

|Left ventricular fractional shortening

|Reduced (<25%)

|Left ventricular systolic dysfunction

|Left atrial volume index

|Increased (volume >34 mL/m2)

|Increased filling pressures, mitral valve dysfunction

|Left ventricular thickness

|Hypertrophy (>11 – 12 mm)

|Hypertention, aortic stenosis, hypertrophic cardiomyopathy

|Valvular structure and function

|Valvular stenosis or regurgitation (especially aortic stenosis and mitral insufficiency)

|May be primary cause of HF or complicating factor

 

 

|Mitral diastolic flow profile

|Abnormalities of the early and late diastolic filling patterns

|Indicates diastolic dysfunction and suggests mechanism

|Tricuspid regurgitation peak velocity

|Increased (>3.4 m/s)

|Increased right ventricular systolic pressure

|Pericardium

|Effusion, haemopericardium, calcification

|Consider tamponade, malignancy, systemic disease, acute or chronic pericarditis, constrictive pericarditis

|Aortic outflow velocity time integral

|Reduced (<15 cm)

|Reduced low stroke volume

|Right ventricular function (e.g. TAPSE)

|Reduced (TAPSE < 16 mm)

|RV systolic dysfunction

|Inferior vena cava

|Dilated, with no respiratory collapse

|Increased right atrial pressures, right ventricular dysfunction, volume overload Pulmonary hypertention possible

{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="100%"

|

|'''Class I'''

|'''Class IIa'''

|

|Procedure/treatment should be performed/administered

|It is reasonable to perform/administer treatment

|Procedure/treatment may be considered

|Procedure/treatment should not be performed/administered since it is not helpful and may be harmful

|-

|'''Level A'''

|

*Recommendation that procedure or treatment is useful/effective

*Greater conflicting evidence from single randomized trial or non-randomized studies |

|

*Recommendation in favor of treatment or procedure being useful/effective

The most important cause (50% of the cases) of HF in the Western world is ischemic heart disease including myocardial infarction. These patients mainly suffer from systolic HF due to wall motion abnormalities of the affected and due to remodeling of the non-affected parts of the myocardium.

Valvular disease, especially mitral- or aortic, can cause volume and pressure overload of the left ventricle of the heart. This overload causes dilation and / or hypertrophy of the left ventricle which in the long term decreases the pump function.

Dilated cardiomyopathy (DCM) is characterized by dilatation of one or both of the ventricles of the heart, with a general decrease in contractility and consequently a decreased pump function. In about 30% of the cases, DCM is hereditary.

Hypertrophic cardiomyopathy (see also Hypertension), is characterized by hypertrophy, which may be concentric or asymmetric. The asymmetric form is usually hereditary. 

Restrictive cardiomyopathy is characterized by a primary diastolic dysfunction of one or more of the ventricles, leading to increased filling pressures and hypertrophy, and initially a preserved systolic function.

Arrhythmogenic right ventricular cardiomyopathy is characterized by fatty infiltration and fibrosis of the right ventricle or the left ventricle or both and is usually hereditary.

Restriction of ventricular filling by a tight (inflammated or constrictive) pericardium or by pericardial effusion and tamponade can be the cause of diastolic HF.

*Hypo- or hyperthyroidism *Cushing syndrome

Deficiency of thiamine, selenium, or camitine, in states of severe cachexia.

*Viral, bacterial or protozoal diseases causing myocarditis.

*Assess ischemia: are there indications of ischemic etiology (ECG: Q’s or significant and changing ST segments, laboratory: troponins, and echocardiogram: segmental wall motion abnormality in coronary territory areas) ? If yes, then proceed with further coronary artery or myocardial perfusion imaging.

#In case of fever look for infectious etiology, MRI confirmation for possible myocarditis, plasma serology.

#Coronary arteriography or coronary CT scan to exclude coronary artery disease

#Myocardial biopsy in cases where the suspicion of severe underlying disease is high (e.g. fulminant myocarditis, sarcoidosis suspicion on MRI with no other organ involved).

The therapeutic management of HF involves both pharmacological and non-pharmacological treatment. The goal is reduction in mortality and morbidity, prevention of the progression of HF, and the treatment of (non-)cardiovascular co-morbidities.

Non-pharmacological management is of great importance for HF patients. It can have a significant impact on symptoms, functional capacity, wellbeing, morbidity, and prognosis. The most important non-pharmacological options are described below.

Education of both the patient and their family about HF and its symptoms is important. The patient and/or the caregiver should be able to undertake appropriate actions such as adjusting the diuretic dose or contact the physician when necessary. (Class I recommendation, level of evidence C; see table 4) Education on the importance  and (side) effects of medication should be provided to the patient in order to increase compliance. (Class I recommendation, level of evidence C)

In patients with severe symptoms of HF, restriction of fluid intake (to 1500 ml/day) may be considered. (Class IIa recommendation, level of evidence C) Also, patients should be educated on salt content of food and minimize intake (< 2 gram/ day) in order to prevent fluid retention. (Class I recommendation, level of evidence C)

CHF patients should carefully monitor their body weight. A sudden increase in weight is a potential consequence of fluid retention and deterioration of HF. When patients notice a weight gain of >2kg in 3 days they should consult a physician. (Class I recommendation, level of evidence C) In obese patients (body mass index of > 30 kg/m2), weight reduction should be promoted to prevent progression of HF, decrease symptoms and improve the overall wellbeing of the patient. (Class IIa recommendation, level of evidence C) Also, attention should be paid to weight loss due to malnutrition which is frequently observed in severe HF. An altered metabolism, inflammatory mechanisms or a decreased food intake may be important factors in the pathophysiology of cardiac cachexia in HF. (Class I recommendation, level of evidence C)

Alcohol intake should be minimized, as it may increase blood pressure and/or have a negative inotropic effect. (Class IIa recommendation, level of evidence C) Smoking cessation should be encouraged. It is recommended that patients with HF receive support and advice on this topic. (Class I recommendation, level of evidence C). A reduction in alcohol and tobacco intake might also improve co-morbidities including sleep disorders.

===Exercise===

Exercise training is recommended to all chronic stable HF patients. Twenty years ago, exercise was strongly discouraged in patients with HF as the general conception was that it was harmful. Nowadays, numerous studies have shown the opposite. Rehabilitation programmes have shown to increase exercise capacity and health related quality of life and decrease hospitalization rates and symptoms. (Class I recommendation, level of evidence A)

===Other===

Other non-pharmacological treatment recommendations include immunization of HF patients (pneumococcal- and influenza vaccination should be considered), the consulting of a physician around pregnancy, the screening for depression and sleep disorders which require additional medical attention.  

 

{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="100%"

|bgcolor="99FFCC"|'''ACE-inhib'''

|bgcolor="33660|

|bgcolor="33660|

|bgcolor="33660|

|bgcolor="33660|

|bgcolor="99FFCC"|'''AT-II antagonist'''

|bgcolor="99FFCC"|

|bgcolor="33660|Alternative

|bgcolor="33660|Alternative

|bgcolor="33660|Alternative

|bgcolor="99FFCC"|'''Betablocker'''

===Angiotensin-converting enzyme (ACE) inhibitors===

An ACE inhibitor (in addition to beta blocker) is indicated for every patient with symptomatic systolic HF and an EF≤40 % (NYHA class II-IV). (Class I recommendation, level of evidence A) Contraindications for the use of ACE inhibitors are:

 

ACE inhibitors relieve the heart by decreasing the preload and afterload. This is achieved through two mechanisms. Firstly, conversion of angiotensin-I to angiotensin–II is inhibited, which reduces vasoconstriction and lowers BP. Secondly, production of aldosterone is decreased, as angiotensin II induces this production. Aldosterone stimulates sodium- and water retention. Possible side effects are symptomatic hypotension (dizziness), hyperkalaemia, worsening renal function and cough.

 

 

===ß-Blockers===

ß-Blockade (in addition to an ACE inhibitor or ARB when ACE inhibitor is not tolerated) is indicated for every patient with symptomatic systolic HF and an EF ≤40 % (NYHA class II-IV) and in asymptomatic patients with a LVEF ≤40% after a MI . (Class I recommendation, level of evidence A)(19) Contraindications are:

 

*Second- or third degree heart block, sick sinus syndrome, sinus bradycardia

 

 

 

In patients with persistent symptoms after treatment with a combination of beta blocker and ACE inhibitor or ARB, an mineralocorticoid/aldosterone receptor antagonist (MRA) is recommended. (Class I recommendation, level of evidence A)

===Diuretics (Loop of Henle diuretics, Thiazides, Aldosterone antagonists)===

Diuretics reduce preload by venous vasodilatation and by increasing diuresis. As a result, filling pressures of the heart and the lung vasculature decrease . Although the effects of diuretics on mortality and morbidity have not been studied in patients with HF (irrespective of EF), it is recommended in patients with signs and symptoms of congestion as diuretics relieve dyspnoea and oedema. Figure 6 depicts the nephron and sites where different diuretics work.

===Loop of Henle diuretics===

Loop of Henle diuretics act on the ascending loop of Henle in the kidney tubules to inhibit sodium and chloride (and indirectly calcium and magnesium) reabsorbtion. This will ultimately result in increased urine production of sodium and water. Compared to thiazides, loop diuretics produce a more intense and shorter diuresis.

===Thiazides===

Thiazide increases urine production by decreasing reabsorbtion of sodium in the distal tubule. This type of diuretic  is often used in combination with loop diuretics to enhance their effects, but may be less effective in patients with a severely reduced kidney function.  

===Aldosterone antagonists===

Adding this drug is suggested for patients with moderate to severe symptomatic HF (NYHA class II to IV, refer to table 2)  and an LVEF < 35%. (Class I recommendation, level of evidence A) Contraindications:

*Serum potassium concentration > 5.0 mmol/L

*Serum creatinine > 220 µmol/L

*Combination of an ACEI and ARB

Aldosterone antagonists reduce sodium retention by the kidney, and inhibit fibrosis formation in the heart.

Possible side effects include hyperkalaemia, hyponatremia, worsening renal function, and breast tenderness and/or enlargement. Eplerenon has less mastopathy side effects and is alternative to spironolacton. In patients with severe heart failure, spironolactone in addition to standard therapy, reduces morbidity and mortality (20).

[[Image:Image1.jpg|thumb|Figure 6 diuretics and site of action in the nephron.]]

===Choice and combination of diuretics===

Patients with heart failure may be treated with a thiazide diuretic, which should be switched to a loop diuretic in case of a suboptimal response. In patients with a decreased renal function, a loop diuretic is the mainstay of treatment. Addition of a thiazide diuretic to a loop diuretic can be considered in case of a suboptimal response of loop diuretic alone, when given in sufficient doses (furosemide 250 mg twice daily), suggesting diuretic resistance because of distal tubular increased activity of retaining sodium. In all patients with NYHA II or more, except in those with a creatinin clearance < 20 ml/min (creatinin > 220 micromol/L), addition of an aldosterone antagonist should be considered . In special cases in which hypercapnia plays a role, metabolic alkalosis can result from diuretics, and acetazolamide, a reversible carbonic anhydrase inhibitor, is then a solution as alternative diuretic.  

===Angiotensin receptor blockers (ARBs)===

ARBs are recommended in patients who do not tolerate an ACE inhibitor. Until recently, addition of ARBs were the first choice recommendation in patients with HF and EF ≤40% who remained symptomatic despite optimal treatment with ACE inhibitor and beta blocker.  As aldosteron antagonists have also proven their effects in NYHA class II patients, aldosteron antagonists have become first choice additional therapy after an ACE inhibitor and betablocker. Whether ARBs may still be recommended in this patient group as added therapy after the addition of aldosteron anatagonist, is not known.

Contraindications are:

*Serum potassium concentration > 5.0 mmol/L

*Serum creatine > 220 µmol/L

*Severe aortic stenosis

===Digoxin===

In the past digoxin has been standard treatment in HF. Digoxin inhibits sodium-potassium ATPase in the cellmembrane of the myocytes, and by decreasing the sodium extrusion, also inhibits the exchange of calcium out of the cell for sodium into the cell. More calcium remains in the myocyte and increases contractility of the heart. In contrast to other inotropics, digoxin does not increase mortality.

 

In patients with symptomatic HF and atrial fibrillation (AF) with a ventricular rate at rest of >80 beats per minute, use of digoxin may be considered to slow the ventricular rate. (Class I recommendation, level of evidence C)

 

Digoxin may be considered to reduce  HF hospitalization in patients with symptomatic (NYHA class II-IV) systolic HF in sinus rhythm with an EF ≤45% . These patients should also use an ACE inhibitor (or ARB) and an MRA (or ARB) and preferably a beta blocker. (Class IIb recommendation, level of evidence B) This may also be considered in patients with an EF ≤45% and persisting symptoms despite treatment  with an ACE inhibitor (or ARB) and an MRA (or ARB). (Class IIb recommendation, level of evidence B)

*Second- or third degree heart block without a permanent pacemaker, sick sinus syndrome

*Pre-excitation syndromes  

 

===Ivabradine===

Ivabradine lowers heart rate through inhibition of the If channel in the sinus node. This drug can be used in patients who are still in NYHA class II-IV after treatment with ACE inhibitor (or ARB), beta blocker and an MRA (or ARB), who have a LVEF≤35%, are in sinus rhythm and have a heart rate≥75 beats/min. Ivabradine may also be used in patients who do not tolerate, or have contraindications for the use of beta blockers.

 

===Hydralazine and isosorbide dinitrate (H-ISDN)===

H-ISDN can be used as an alternative treatment when both ACEI and ARBs are not tolerated in symptomatic HF patients with a LVEF≤45% and dilated LV (or EF≤35%). These patients should also receive a beta blocker and MRA. (Class IIb recommendation, level of evidence B). H-ISDN can be used in addition to the standard HF treatments (ACEI, beta blocker and MRA) in patients of Afro-American descent (Class .. recommendation).  H-ISDN may reduce risk of HF hospitalization and risk of premature death in patients with a LVEF≤45% and dilated LV (or EF≤35%)with persisting symptoms despite treatment with beta blocker, ACEI (or ARB), and an MRA (or ARB). (Class IIb recommendation, level of evidence B)

 

Contraindications for the use of H-ISDN are:

*Symptomatic hypotension

*Lupus syndrome  

*Severe renal failure

 

The H-ISDN combination acts by decreasing peripheral vascular resistance.  

===Other===  

*Anticoagulants