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Clinical Echocardiography

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  1. Introduction to echocardiography and ultraound imaging
    12 Chapters
  2. Principles of hemodynamics
    5 Chapters
  3. The echocardiographic examination
    3 Chapters
  4. Left ventricular systolic function and contractility
    11 Chapters
  5. Left ventricular diastolic function
    3 Chapters
  6. Cardiomyopathies
    6 Chapters
  7. Valvular heart disease
    8 Chapters
  8. Miscellaneous conditions
    5 Chapters
  9. Pericardial disease
    2 Chapters
Section 6, Chapter 1
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Heart failure

Heart failure is a major public health problem worldwide. While the incidence of coronary heart disease and acute myocardial infarction has been reduced by approximately 50% during the past few decades, the incidence of heart failure has remained stable. New data actually suggest that the incidence of heart failure among young adults has increased in recent years (Nabel et al, Savarese et al). This is a paradoxical and worrisome trend, particularly in the light of the improvements in the management of hypertension (coronary heart disease and hypertension are traditionally viewed as the main drivers of heart failure). It is believed that the aging population, increased prevalence of obesity, diabetes and dysglycemia are propelling the heart failure pandemic. Indeed, a growing body of evidence suggests that heart failure is now the most frequent complication of diabetes (Shah et al, McMurray et al).

Management of heart failure progressed rapidly during the 1970s and 1980s. Beta blockers, ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARB) were introduced and improved survival dramatically. When the pioneers Waagstein, Hjalmarsson, and Swedberg proposed the use of beta blockers – which have negative inotropic and negative chronotropic effects – to treat heart failure, they were met with skepticism. Their landmark studies proved that beta blockers prolong life, alleviate symptoms and reduce the risk of hospitalization for patients with heart failure. Several landmark studies followed and proved that beta blockers, ACE inhibitors and ARBs were effective for the treatment of heart failure. The rapid advances in the 1970s and 1980s were followed by almost two decades without any major breakthrough in the management of heart failure. In 2014 the PARADIGM-HF study introduced a new drug class, the ARNI (Angiotensin–Neprilysin Inhibitors), which was a long-awaited breakthrough.

Heart failure is a serious condition with poor long-term prognosis. The 5-year survival rate after hospitalization for heart failure is 60%, which is comparable to common cancers (Stewart et al). In addition, heart failure is a disabling condition with a very negative impact on quality of life. Approximately half of all patients with heart failure die suddenly, as a result of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation). Early diagnosis and aggressive management can prolong survival, improve quality of life, reduce hospitalizations and reduce the risk of sudden death.

According to the American Heart Association (ACA) and the European Society for Cardiology (ESC), there are three types of heart failure: HFPEF, HFmrEF and HFREF. This classification is based primarily on measurement of left ventricular ejection fraction (LVEF). The vast majority of all clinical trials, epidemiological studies and mechanistic studies have been carried out in HFREF (heart failure with reduced ejection fraction). Thus, our current knowledge of heart failure is virtually synonymous with knowledge of HFREF. HFPEF (heart failure with preserved ejection fraction) and HFmrEF (heart failure with mid-range ejection fraction) are relatively new entities and there are currently no effective treatments that modify the natural course in these conditions. Yet, long-term survival is slightly better among patients with HFPEF, as compared with patients with HFREF.

Table 1. Types of heart failure.

TypeDescriptionEjection fraction (%)
HFREFHeart Failure with Reduced Ejection Fraction<40%
HFmrEFHeart Failure with midrange Ejection Fraction40–49%
HFPEFHeart Failure with Preserved Ejection Fraction≥50%
Types of heart failure.

In HEREF, left ventricular systolic function (ejection fraction) is impaired (defined as ejection fraction <40%). In HFPEF, there are clinical signs of heart failure despite normal ejection fraction (EF ≥50%). In HFMRef, there are signs of heart failure with ejection fraction in the range 40–49%.

The mechanisms causing HFPEF are unknown. Virtually all patients with HFPEF display diastolic dysfunction.

The majority of all patients with heart failure have extensive comorbidity. Ischemic heart disease, myocardial infarction, hypertension, arrhythmias, pulmonary disease, chronic kidney disease, diabetes (type 1 diabetes, type 2 diabetes), are common coexisting conditions. This complicates the treatment of heart failure due to the risk of drug interactions and complicates titration of medications (e.g ACE inhibitors in patients with renal failure). Cardiorenal syndrome is a particularly lethal combination, in which the patient has heart failure and kidney failure.

Epidemiology of heart failure

  • Heart failure is more common among men.
  • 6.5 million adults in the United States have heart failure (Benjamin et al)
  • Heart failure is a contributing cause of 1 in 8 deaths in 2017 (CDC).
  • Among individuals aged 65 years or older, 5–10% have heart failure.
  • The lifetime risk of developing heart failure is 20% for a 40 year old.
  • The incidence of heart failure has been stable for the past two decades, despite dramatic reductions in the incidence of acute myocardial infarction and improved management of hypertension.
  • Diabetes is probably one of the most common causes of heart failure (diabetic cardiomyopathy; Packer et al).

Prognosis

Table 2. Long-term survival after hospitalization for heart failure.

Time since hospitalizationSurvival (%)
1 year70%
5 year60%
Prognosis after hospitalization for heart failure.

Mortality in heart failure is equal to that observed in common cancers. Half of all deaths are explained by sudden cardiac arrest due to ventricular tachycardia and ventricular fibrillation. The remaining deaths are caused by a gradual deterioration of left ventricular function and thromboembolic complications.

Causes of heart failure

Mechanisms of heart failure

The underlying cause determines whether heart failure is transient or chronic. For example, heart failure due to myocardial infarction is chronic, whereas heart failure due to tachycardia (e.g atrial fibrillation) can be cured with restoration of sinus rhythm.

Refer to Tachycardia-induced cardiomyopathy.

Coronary artery disease and myocardial infarction

Myocardial infarction (STEMI, Non-STEMI) is the most common cause of heart failure. With regard to coronary heart disease, experts still debate whether chronic ischemia can cause heart failure in the absence of myocardial infarction (Camici et al, McMurray et al).

Hypertension

Hypertension is the most common cause of morbidity and mortality worldwide (Ezzati et al). Hypertension is also the second most common cause of heart failure. Hypertension causes heart failure by increasing afterload, which the left ventricle counteracts by developing hypertrophy. However, hypertrophy causes cardiac remodeling (see below), ultimately leading to impaired systolic function and chamber dilatation.

Diabetes

Diabetes is a common cause of heart failure and heart failure is viewed as a diabetes complication (diabetic cardiomyopathy; Packer et al). Diabetic cardiomyopathy is presumably caused by chronic hyperglycemia, which induces microvascular dysfunction and promotes the development of fibrosis in the myocardium.

Arrhythmias causing heart failure

Bradycardia (bradyarrhythmia) can cause heart failure when cardiac output (CO) drops below demands.

Prolonged tachycardia (tachyarrhythmia) can cause heart failure (tachycardia-induced heart failure). A common cause of tachycardia-induced heart failure is atrial fibrillation. However, any prolonged tachyarrhythmia can cause heart failure.

Atrial fibrillation and heart failure are strongly correlated. However, it is unclear whether heart failure causes atrial fibrillation, although it appears plausible; heart failure leads to ventricular dilation and elevated ventricular and atrial pressure. The latter may subsequently lead to left atrial enlargement and atrial fibrillation.

Structural heart disease

Structural heart disease refers to structural abnormalities in the myocardium, valves or greater vessels. Myocardial infarction, which results in structural changes (necrosis) in the myocardium, is also considered in this category. Other conditions include congenital heart disease and valvular heart disease (congenital or acquired). The most common valvular diseases that cause heart failure are as follows:

Pericardial disease (restrictive pericarditis, constrictive pericarditis) can also cause heart failure by impairing ventricular relaxation (diastole).

Cardiac toxicity

Substance abuse

Alcohol is the most common substance causing heart failure. Alcoholic cardiomyopathy is a common cause of heart failure worldwide. Alcohol causes dilated cardiomyopathy.

Cancer drugs and radiation therapy

Cancer drugs are an increasingly common cause of heart failure. The most common cancer drugs with known cardiotoxicity are as follows (Suter et al):

  • Doxorubicin
  • Daunorubicin (daunomycin)
  • Epirubicin
  • Mitoxantrone
  • Fluorouracil (5-FU)
  • Capecitabine
  • Cyclophosphamide
  • Cisplatin
  • Paclitaxel
  • Trastuzumab
  • Lapatinib
  • Bevacizumab
  • Sunitinib
  • Imatinib
  • Dasatinib
  • Nilotinib

Radiotherapy can cause myocarditis and pericarditis (constrictive pericarditis), resulting in heart failure.

Cardiac tumors and metastases

Cardiac tumors can cause heart failure, as can cardiac metastases.

Genetic causes of heart failure

In addition to mutations causing storage diseases (see below), heart failure may be the result of genetic mutations affecting cardiac myocytes. These mutations typically cause abnormalities in structural proteins, particularly actin, myosin, and proteins in the desmosome (intercalated discs). Such mutations lead to characteristic cardiomyopathies:

Other causes of heart failure

  • Heavy metals – Accumulation of heavy metals may cause heart failure. The following metals are known to cause heart failure:
    • Iron (hemochromatosis)
    • Copper
    • Lead
    • Cadmium
    • Cobolt
  • Storage diseases
    • Amyloidosis
    • Sarcoidosis
    • Pompe’s disease
    • Fabry’s disease
    • Hemochromatosis (accumulation of iron)
  • Immunological conditions
    • Rheumatoid arthritis (RA)
    • Systemic Lupus Erythematosus (SLE)
    • Giant cell myocarditis
    • Eosinophilic myocarditis
  • Endocrine causes
    • Hypothyreosis
    • Hyperthyreosis (thyrotoxicosis)
    • Hyperparathyroidism
    • Cushing’s syndrome
    • Acromegaly
    • Conn’s disease
    • Addison’s disease
  • Pregnancy
    • Postpartum cardiomyopathy (peripartum cardiomyopathy) is defined as new onset of heart failure between the last month of pregnancy and 5 months post-delivery, provided that no other causes of heart failure can be established.
  • Nutritional causes
    • Anorexia nervosa
    • Thiamin deficiency (cardiac beriberi)
  • Hemodynamic changes
    • Hypotension
    • Sepsis
    • Severe anemia
    • Volume overload (e.g renal failure)

Cardiac remodeling

Cardiac remodeling is observed in the majority of patients with heart failure, reglardless of etiology. Cardiac remodeling affects the natural course in heart failure. It ultimately leads to gradual dilatation (enlargement) of the left ventricle and thus worsening heart failure.

Cardiac remodeling results from changes in the genome expression of cardiac myocytes. These changes result in molecular, cellular and interstitial changes which gradually affect the size, shape and function of the heart. Cell death, interstitial fibrosis and reduced contractility are the hallmarks of cardiac remodeling.

The goal of heart failure therapy is to slow or reverse the progression of cardiac remodeling. ACE inhibitors, ARBs, ARNI and beta blockers all affect the remodeling process.

Symptoms of heart failure

Symptoms of heart failure are often nonspecific, especially in the early phase. Distinguishing heart failure from other common cardiopulmonary conditions may be challenging, particularly in the following patients:

  • Patients with pulmonary disease (e.g., chronic obstructive pulmonary disease [COPD]), as dyspnea and poor exercise capacity are common in chronic pulmonary disease.
  • Overweight, obese or diabetic patients (type 2 diabetes): these patients frequently experience dyspnea and poor exercise capacity due to body weight and abdominal obesity.
  • Elderly individuals: dyspnea and poor exercise capacity are common in the elderly.
  • Ankle and lower limb edema are common side effects of calcium channel blockers and glitazones.
  • Ankle and lower limb edema may be caused by venous insufficiency.

Typical symptoms of heart failure

  • Dyspnea (shortness of breath)
  • Orthopnea (shortness of breath in supine position)
  • Paroxysmal nocturnal dyspnea (sudden attacks of dyspnea occurring at night, typically a few hours after falling asleep)
  • Poor exercise capacity (exercise intolerance)
  • Fatigue
  • Ankle edema, lower limb edema

Less typical symptoms of heart failure (non-specific)

  • Palpitations
  • Weight gain
  • Weight loss (advanced heart failure)
  • Dizziness
  • Syncope
  • Cough
  • Loss of appetite
  • Confusion
  • Depression

Weight gain due to fluid retention is common in the early phase. However, in advanced heart failure, weight loss is also common, which is explained by the development of cachexia.

Symptoms of decompensated (acute) heart failure

Heart failure is a chronic condition characterized by gradual deterioration of cardiac function. Clinically stable periods may be interrupted by sudden worsening of heart failure (i.e decompensation), with increased fluid retention, worsening dyspnea and need for hospitalization. Figure 1 presents typical symptoms in patients with decompensated heart faailure (Goldberg et al).

Figure 1. Frequency of symptoms in patients with acute decompensated heart failrue (Goldberg et al).

New York Heart Association (NYHA) functional classification of heart failure

Heart failure patients are classified according to the severity of the symptoms. The New York Heart Association (NYHA) Functional Classification is the most commonly used classification system (Table 3).

Table 3. New York Heart Association (NYHA) functional classification of heart failure

NYHA ClassPatient Symptoms
INo limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea.
IISlight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea.
IIIMarked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.
IVUnable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994.

Clinical signs of heart failure

Physical examination may reveal any of the following in patients with heart failure:

  • Hepatojugular reflux: With the patient sitting at an angle of 45°, pressing on the liver leads to dilation of the jugular vein. The jugular vein is distended because blood flow through the right ventricle is impaired in patients with heart failure.
  • Wide jugular vein, due to distension of the vein (increased jugular venous pressure). This implies right heart failure.
  • Presence of a third heart sound (S3), also known as the “ventricular gallop”.
  • Lateral displacement and enlargement of the apical (apex) impulse.
  • Pulmonary ausculation: Fine or coarse crackles, depending on the severity of pulmonary edema.
  • Pulmonary percussion: dull percussion note.
  • Tachycardia: cardiac output is maintained by increasing the heart rate.
  • Irregular pulse: extrasystoles (supraventricular extrasystole, ventricular extrasystole), supraventricular arrhythmias (atrial fibrillation, atrial flutter, atrial tachycardia, etc) are common in heart failure. Ventricular arrhythmias (ventricular tachycardia) are less common but occur in most patients with heart failure.
  • Tachypnea
  • Hepatomegaly
  • Ascites
  • Cold extremities
  • Oliguria
  • Narrow pulse pressure

Diagnosing heart failure: criteria & guidelines

Diagnosis of chronic heart failure

Patients with symptoms or signs of heart failure may be evaluated in primary care or the outpatient clinic. The initial evaluation should determine the probability of heart failure by assessing the following components:

  • Medical history
  • Physical examination
  • 12-lead resting ECG

A detailed medical history is fundamental to assess the risk of heart failure. Presence of coronary artery disease, previous myocardial infarction, hypertension, and other risk factors and causes of heart failure should be carefully reviewed. Physical examination should focus on signs noted above. Resting ECG must be obtained in all patients.

Figure 2. Evaluation of patients with symptoms or signs of heart failure.

Algorithm for the investigation of heart failure according to the European Society for Cardiology (ESC).

If medical history, physical examination and ECG are all normal, then heart failure is unlikely and other diagnoses should be considered. If any component is abnormal, plasma natriuretic peptides should be measured. The upper normal limit for natriuretic peptides (NT-proBNP and BNP) is the threshold for excluding heart failure.

NT-proBNP and BNP in heart failure

Plasma natriuretic peptides are assessed in patients with abnormal medical history, physical examination or resting ECG. The American Heart Association and European Society for Cardiology recommend measurement of BNP (Brain Natriuretic Peptide) or NT-proBNP (N-Terminal proBNP). If NT-proBNP or BNP is higher than the threshold (for excluding heart failure), echocardiography should be performed. Echocardiography should also be performed if NT-proBNP and BNP are not available.

NT-proBNP or BNP levels above the threshold strongly suggest heart failure and require further investigation with echocardiography.

Table 4. Thresholds for NT-proBNP and BNP

BiomarkerThreshold for exclusion of heart failure
Chronic heart failure
NT-proBNP125 pg/mL
BNP35 pg/mL
Acute (decompensated) heart failure
NT-proBNP300 pg/mL
BNP100 pg/mL
Thresholds for NT-proBNP and BNP. Levels above the threshold are abnormal.

High levels of NT-proBNP or BNP strongly suggests heart failure. However, there are numerous other causes of elevated levels of natriuretic peptides (Table 5). The value of measuring NT-proBNP and BNP is greatest when the probability of heart failure is low to moderate. Note that the threshold for natriuretic peptides is higher in the acute setting (Table 5). The same thresholds are applied to HFREF and HFPEF. Generally, patients with HFREF have higher levels of NT-proBNP and BNP.

According to current (2020) guidelines from the ESC, AHA and ACC, heart failure is excluded if NT-proBNP or BNP levels are below the threshold.

Note that obesity results in lower levels of NT-proBNP and BNP. Furthermore, patients with heart failure who are well-treated may exhibit normal, or near-normal, levels of natriuretic peptides.

Table 5. Causes of increased levels of natriuretic peptides (NT-proBNP, BNP)

CARDIAC CAUSES
Heart failure
Atrial fibrillation
Acute coronary syndromes
Pulmonary embolism
Left ventricular hypertrophy (LVH)
Hypertrophic Cardiomyopathy (HCM, HOCM)
Myocarditis, Perimyocarditis
Electrical conversion, defibrillation
Congenital heart disease
Heart surgery
Pulmonary hypertension
Tachyarrhythmias
NON-CARDIAC CAUSES
Kidney failure
Aging
Stroke
Subarachnoid bleeding
Liver cirrhosis
COPD (chronic obstructive pulmonary disease)
Anemia
Severe infection (sepsis, pneumonia)
Ketoacidosis
Thyreotoxicosis
Paraneoplastic syndrome
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)

ECG in heart failure

A completely normal ECG strongly speaks against heart failure (Mant et al). It is often difficult to determine whether the ECG is completely normal. There are numerous normal variants and non-significant abnormalities that may be ambiguous.

The ECG can not confirm nor exclude heart failure, but a completely normal ECG strongly speaks against heart failure.

Echocardiography in heart failure

Echocardiography is the preferred modality to investigate cardiac function. Traditionally, ejection fraction (EF) has been the predominant parameter for assessing cardiac function. Nowadays, diastolic function, systolic ventricular function, ventricular size, atrial size, etc are all investigated with numerous methods. Although a diagnosis of HFREF is based solely on ejection fraction, multiple other parameters for chamber size and diastolic function are needed to establish a diagnosis of HFPEF (heart failure with preserved ejection fraction).

Echocardiography can determine the type of heart failure (HFREF, HFPEF, HFmrEF) and assess structural and functional parameters with regards to the myocardium, valves, pericardium and chamber dimensions.

Cardiac MRI (Cardiac Magnetic Resonance Imaging)

Cardiac MRI is considered the gold standard for the majority of parameters of cardiac function. Although the use of cardiac MRI is increasing, it is still not widely available and therefore not recommended as part of routine evaluation of patients with suspected heart failure.

Diagnostic criteria for heart failure

Heart Failure with Reduced Ejection Fraction (HFREF)

Criteria for heart failure with reduced ejection fraction (HFREF):

  1. Symptoms of heart failure, with or without objective signs of heart failure.
  2. Ejection fraction <40%.

Heart Failure with mid-range Ejection Fraction (HFmrEF)

Criteria for HFmrEF:

  1. Symptoms of heart failure, with or without objective signs of heart failure.
  2. Ejection fraction 40–49%
  3. Elevated levels of NT-proBNP or BNP.
  4. One or two of the following:
    • Structural Heart Disease (left ventricular hypertrophy and/or left atrial enlargement)
    • Diastolic dysfunction

Heart Failure with Preserved Ejection Fraction (HFPEF)

It is relatively difficult to diagnose heart failure with preserved ejection fraction. This is partly because there is no clear consensus regarding how diastolic function should be determined. A range of echocardiographic techniques exists to assess diastolic dysfunction. The vast majority of patients with HFPEF exhibit structural abnormalities, most notably left ventricular hypertrophy (LVH) or left atrial enlargement (LAE).

  • A diagnosis of HFPEF is difficult to establish.
  • Symptoms are less pronounced in patients with HFPEF, as compared with patients with HFREF.
  • HFPEF is more common among women, elderly, diabetics, people with sleep apnea, obesity, overweight, COPD, pulmonary hypertension, metabolic syndrome, atrial fibrillation, hypertension and chronic kidney disease.

Criteria for heart failure with preserved ejection fraction (HEFPEF):

  • Symptoms of heart failure, with or without objective signs of heart failure.
  • Ejection fraction ≥50% (normal).*
  • Elevated levels of NT-proBNP or BNP.
  • One or two of the following:
    • Structural abnormalities (LVH and/or LAE)
    • Diastolic dysfunction

*In some clinical studies, the cut-off for ejection fraction is ≥40%, which is classed as HFmrEF according to ESC.

Structural changes consistent with heart failure, according to ESC:

  • Left atrial volume index (LAVI) >34 ml/m²
  • Left ventricular mass index (LVMI) ≥ 115 g/m² for males and ≥ 95 g/m² for females.
  • E/E′ ≥13
  • Mean e’ septal and lateral wall <9 cm/s.

Treatment of heart failure

Treatment goals

The ideal treatment for heart failure should have beneficial effect on all four following elements:

  1. Alleviate symptoms, reduce suffering and increase quality of life.
  2. Reduce the rate of hospitalizations.
  3. Improve functional capacity.
  4. Prolong survival.

Generally, treatments that prolong survival (e.g beta blockers) will also alleviate symptoms, reduce the risk of hospitalization and improve functional capacity. Diuretics, on the other hand, have a marked effect on symptoms but no effect on survival.

Current evidence-based therapy for heart failure is based almost solely on patients with HFREF. There are no evidence-based treatment available for HFPEF.

Treatment of heart failure with reduced ejection fraction (HFREF)

Figure 3. Algorithm for treatment of heart failure with reduced ejection fraction.

Adapted from Ponikowski et al (ESC Guidelines, 2019).

Diuretics

  • All patients with heart failure require diuretics to alleviate dyspnea and eliminate excess fluid.
  • It is recommended that the lowest possible dose be used to avoid hypokalemia and hyponatremia. Higher doses are necessary in advanced heart failure.
  • Consider the increased risk of gouty arthritis.

Table 6. Diuretics

Intial dose (mg)Regular daily dose (mg)
LOOP DIURETICS
Furosemide20–4040–240
Bumetanide0.5–1.01–5
Torasemide5–1010–20
TIAZIDES
Hydrochlorothiazide2512.5–100
Metolazone2.52.5–10
lndapamidec2.52.5–5

Table 7. Potassium sparing diuretics

Initial dose if using ACEi/ARB (mg)Initial dose if not using ACEi/ARB (mg)Regular dose if using ACEi/ARB (mg)Regular dose if not using ACEi/ARB (mg)
Spironolactone/ eplerenone12.5–255050100– 200
Amiloride2.555–1010–20
Triamterene2550100200
POTASSIUM SPARING DIURETICS.
ACEi = ACE inhibitor; ARB = angiotensin II receptor antagonist.

ACE inhibitors (ACEi)

  • ACE inhibitors have beneficial effects on all treatment goals, including prolonging survival and should therefore be considered in all patients with heart failure.
  • ACE inhibitors reduce the production of angiotensin II, which exerts multiple deleterious effects in patients with heart failure.
  • ACE inhibitors cause a dry, persistent cough in 10–30% of patients. Consider switching to ARBs if cough is unbearable.
  • Other common side effects include hypotension and renal failure. Electrolytes should be assessed in patients susceptible to electrolyte disturbances.
  • ACE inhibitors should be used with caution in patients on NSAID (non-steroidal anti-inflammatory drugs).

Table 8. ACE inhibitors

Initial dose (mg)Target dose (mg)
Captopril6.25 × 350 × 3
Enalapril2.5 × 210–20 × 2
Lisinopril2.5–5.0 × 120–35 × 1
Ramipril2.5 × 110 × 1
Trandolapril0.5 × 14 × 1
ACE inhibitors.

Beta blockers

  • All patients should have beta-blockers, which have a positive effect on all treatment goals in heart failure. Beta blockers reduce mortality by 33%.
  • Beta-blockers reduce the harmful effect of norepinephrine (noradrenaline) and epinephrine (adrenaline) in the myocardium.
  • Start low, go slow and titrate to maximally tolerated dose.
  • A temporary worsening of cardiac function may occur but is transient and left ventricular function improves gradually; a temporary dose reduction can be advised if necessary.

Table 9. Beta blockers

Beta blockerInitial dose (mg)Target dose (mg)
Bisoprolol1.25 × 110 × 1
Carvedilol3.125 × 2.25 × 2 d
Metoprolol succinate12.5–25 × 1200 × 1
Nebivolol1.25 × 110 × 1
Beta blockers

Angiotensin II receptor blockers (ARBs)

  • Effects similar to ACE inhibitors. Prolongs survival. Some data suggests that ARBs are slightly more effective than ACE inhibitors (McMurray et al).
  • ARBs prevent angiotensin II from binding to its receptor, thus interrupting the RAAS axis.
  • ARBs do not cause cough and is preferred in patients bothered by cough induced by ACE inhibitors.
  • ARBs can be added to ACE inhibitors, which further reduces mortality (McMurray et al). Combining ARBs and ACE inhibitors, however, requires repeated controls of kidney function and electrolytes.
ARBsInitial dose (mg)Target dose (mg)
Candesartan4–8 × 132 × 1
Valsartan40 × 2160 × 2
Losartan50 × 1150 × 1

Aldosterone antagonists

  • Aldosterone is part of the RAAS system. Blocking the effect of aldosterone results in inhibition of the harmful RAAS axis.
  • Spironolactone and eplerenone reduce mortality in heart failure.
  • Clinical studies have been conducted in patients with NYHA class II, III and IV. The effect of aldosterone antagonism is unknown in heart failure with NYHA class I.
  • Spironolactone and eplerenone are recommended if ACE/ARB and beta-blockers are insufficient.
  • Spironolactone and eplerenone can cause hyperkalemia and impairment of renal function.
  • Spironolactone can cause gynecomastia in men.
Initial dose (mg)Target dose (mg)
Eplerenone25 × 150 × 1
Spironolactone25 × 150 × 1

ARNI (Sacubitril-valsartan)

Sacubitril-valsartan is the only substance in the ARNI (Angiotensin Receptor Neprilysin Inhibitor) drug class. Sacubitril-valsartan is a combination drug consisting of an ARB (valsartan) and sacubitril, which inhibits neprilysin, thus blocking the breakdown of natriuretic peptides. Use of ARNI results in increased levels of natriuretic peptides. Sacubitril-valsartan reduces morbidity and mortality in heart failure (NYHA II, III and IV).

Angiotensin receptor neprilysin inhibitors (ARNI)Initial dose (mg)Target dose (mg)
Sacubitril/valsartan (Entresto)49/51 × 297/103 × 2

Ivabradine

Ivabradine blocks If (funny channels) channels, causing the intrinsic frequency (automaticity) of the sinoatrial node to decrease. This results in a reduced heart rate. Ivabradine is indicated for patients with NYHA class II-IV with impaired systolic function, provided that the patient has sinus rhythm at ≥75 beats per minute.

If kanalblockerareInitial dose (mg)Target dose (mg)
Ivabradine5 × 27.5 × 2

Digoxin (digitalis)

  • Digoxin (digitalis) has a positive inotropic effect, thus increasing myocardial oxygen consumption. The role of digoxin in heart failure has been questioned in recent years.
  • digoxin may be considered in patients with atrial fibrillation and ventricular rate >70 beats per minute.

Treatment of heart failure with preserved ejection fraction (HFPEF)

  • Diuretics, ACE inhibitors, ARBs, aldosterone antagonists, beta-blockers, ARNI, ivabradine and digoxin do not affect survival in HFPEF.
  • Current evidence-based therapy suggests targeting comorbidities and risk factors.
  • Conventional heart failure drugs may be used on an individual basis, but a general recommendation lacks scientific evidence.

Other treatments for heart failure

  • Smoking cessation and weight loss.
  • Vaccinations: pneumococci, influenza, COVID-19 (SARS-COV-2) when available.
  • Avoid antiarrhythmic drugs (amiodarone can be used in atrial fibrillation), antipsychotics, corticosteroids, NSAIDs.
  • Restricting salt consumption is common although scientific support is limited.
  • Moderate intake of alcohol is probably not harmful.
  • Encourage physical activity.

Device therapy for heart failure

  • ICD reduces mortality by 23% at HFREF (Bardy et al).
  • CRT reduces mortality by 20% (McMurray et al).

The purpose of CRT (cardiac resynchronization therapy) is to achieve resynchronization of right and left ventricular depolarization (i.e activation, contraction). Approximately 25% of heart failure patients exhibit ventricular dyssynchrony, which implies that the activity of the left and right ventricle is not synchronized, resulting in ineffective contractions. The hallmark of dyssynchrony is the wide QRS complex on ECG (QRS duration >120 ms). CRT allows for significant resynchronization of ventricular activation.

Figure 5. Cardiac resynchronization therapy (CRT)
Cardiac resynchronization therapy (CRT)

Refer to ICD and CRT Therapy.

References

Nabel et al: A Tale of Coronary Artery Disease and Myocardial Infarction. N Engl J Med 2012; 366:54-63

Savarese et al: Global Public Health Burden of Heart Failure. Card Fail Rev. 2017 Apr; 3(1): 7–11.

McMurray et al: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993-1004

McMurray et al: Heart failure. Lancet 2005; 365: 1877–89

Stewart et al: Population Impact of Heart Failure and the Most Common Forms of Cancer A Study of 1 162 309 Hospital Cases in Sweden (1988 to 2004)

Packer et al: Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care 2018 Jan; 41(1): 11-13.

Camici et al. Hibernation and heart failure. Heart 2004; 90: 141–43. 

Ezzati et al: Behavioral and Dietary Risk Factors for Noncommunicable Diseases. N Engl J Med 2013; 369:954-964

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