Introduction to Chronic Heart Failure

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Introduction to Chronic Heart Failure

OVERVIEW

Chronic heart failure is a complex progressing clinical condition caused by a structural and/or functional cardiac abnormality.

Ischaemic heart disease is the most underlying cause of heart failure. The prognosis of patients with heart failure due to ischaemic heart disease appears to be worse than that associated with many other aetiologies. This chapter reviews the definition, epidemiology, classification, diagnosis, prognosis, and clinical management of chronic heart failure due to ischaemic heart disease.

Definition of Chronic Heart Failure

Heart failure is a complex clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.

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Clinically, heart failure is characterised by typical symptoms (e.g.

breathlessness, ankle swelling, and fatigue), and may be accompa- nied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral oedema).

The current definition of heart failure restricts itself to the stages at which clinical symptoms are apparent. Before clinical symptoms become apparent, patients can present symptomatic structural and/or functional cardiac abnormalities (i.e. systolic or diastolic left ventricu- lar dysfunction), which are precursors of heart failure. Recognition of the precursors is important because they are related to poor outcomes, and starting treatment at the precursor stage may reduce mortality in patients with asymptomatic systolic left ventricular dysfunction.

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Classification of Heart Failure

Heart Failure with Preserved, Mid-range and Reduced Ejection Fraction

The main terminology used to describe heart failure is historical and is based on measurement of the left ventricular ejection fraction (LVEF), referring to the severity of heart failure with normal LVEF, preserved LVEF, or with reduced LVEF.

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Heart failure with preserved ejection fraction: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome defined as heart failure with normal ejection fraction (typically considered as

≥ 50%) and impaired diastolic function on objective imaging.

Heart failure with reduced ejection fraction: In heart failure with reduced ejection fraction (HFrEF), also known as systolic heart fail- ure, the heart muscle is not able to contract adequately and, therefore, expels less oxygen-rich blood into the body. Patients with this form of the disease will have lower-than-normal LVEF (< 40%) on an echocardiogram.

Heart failure with mid-range ejection fraction: Patients with a LVEF in the range of 40–49% represent a ‘grey area’, which we now define as heart failure with mid-range ejection fraction (HFmrEF).

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Differentiation of patients with heart failure based on the LVEF is important due to different underlying aetiologies, demographics, co- morbidities, and responses to therapies.

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Most clinical trials published after 1990 selected patients based on the LVEF (usually measured using echocardiography, a radionuclide technique, or cardiac magnetic reso- nance [CMR]), and it is only in patients with HFrEF that therapies have been shown to reduce both morbidity and mortality.

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Classification Based on the Symptomatic Severity of Heart Failure

The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It

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places patients in one of four categories based on how much they are limited during physical activity; the limitations/symptoms are in regard to normal breathing and varying degrees in shortness of breath and/or angina (see Table 1.1).

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This classification has been used to describe the severity of symptoms and exercise intolerance.

In 2001, the American Heart Association and American College of Cardiology (AHA/ACC) developed a rating system to evaluate the stages of heart failure development based on structural changes and symptoms.

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This rating system contains four stages:

· Stage A: Presence of heart failure risk factors but no heart disease or symptoms;

· Stage B: Heart disease is present but there are no symptoms (struc- tural changes in heart before symptoms occur);

· Stage C: Structural heart disease is present AND symptoms have occurred;

Table 1.1. New York Heart Association Functional Classification New York Heart

Association Class

Patients with Cardiac Disease (Description of Heart Failure Related Symptoms)

Class I (mild) Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation (rapid or pounding heartbeat), dyspnoea (shortness of breath), or angina (chest pain).

Class II (mild) Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea, or angina.

Class III (moderate)

Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnoea, or angina.

Class IV (severe) Patients with cardiac disease resulting in the inability to carry on any physical activity without discomfort. Symptoms of heart failure or the angina syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

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· Stage D: Presence of advanced heart disease with continued heart failure symptoms requiring aggressive medical therapy.

All these three types of classification systems are commonly used in clinical practice and clinical research. In this monograph, we did not exclude clinical studies based on which classification system was used.

Clinical Presentation

Symptoms and Signs of Heart Failure

Heart failure is a chronic phase of cardiac functional impairment secondary to much aetiology, and patients with heart failure experi- ence numerous symptoms that affect their quality of life including dyspnoea, fatigue, poor exercise tolerance, and fluid retention.

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Symptoms of heart failure are often non-specific and therefore it is not simple to discriminate between heart failure and other prob- lems (see Table 1.2).

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Symptoms and signs of heart failure due to fluid retention may resolve quickly with diuretic therapy. Signs, such as elevated jugular venous pressure and displacement of the apical impulse, may be more specific but are more difficult to detect and have poor reproducibility.

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Furthermore, the symptoms and signs of heart failure may be particularly difficult to identify and interpret in obese individuals, in the elderly and in patients with chronic lung disease.

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Younger patients with heart failure often have a different aetiology, clinical presentation, and outcome compared to older patients.

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Heart failure can present itself as gradually increasing breathless- ness, fatigue, and oedema, or it may present acutely, either de novo or in an acute-on-chronic picture.

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Acute heart failure is character- ised by a rapid onset of signs and symptoms due to cardiac dysfunction. There may be pulmonary oedema due to back pressure into the lungs from the failing left ventricle. Once plasma oncotic pressure is exceeded, extravasation of fluid occurs, and hypoxia may ensue. Jugular venous pressure may be raised, reflecting elevated right

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ventricular filling pressure. The patient may be tachycardic, agitated, clammy, and peripherally cyanosed due to the actions of the sympa- thetic nervous system. If there is significant organ hypoperfusion, confusion and renal failure may occur, and the patient is said to be in cardiogenic shock — a condition with particularly poor prognosis.

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Chronic heart failure may present more insidiously with fatigue, breathlessness, and a more gradual build-up of fluid in the lungs and

Table 1.2. Symptoms and Signs Typical of Heart Failure

Symptoms Signs

Typical More Specific

Breathlessness Orthopnoea

Paroxysmal nocturnal dyspnoea Reduced exercise tolerance Fatigue, tiredness, increased

time to recover after exercise Ankle swelling

Elevated jugular venous pressure Hepatojugular reflux

Third heart sound (gallop rhythm) Laterally displaced apical impulse

Less Typical Less Specific

Nocturnal cough Wheezing Bloated feeling Loss of appetite

Confusion (especially in the elderly)

Depression Palpitations Dizziness Syncope Bendopnea

Weight gain (> 2 kg/week)

Weight loss (in advanced heart failure) Tissue wasting (cachexia)

Cardiac murmur

Peripheral oedema (ankle, sacral, scrotal)

Pulmonary crepitations

Reduced air entry and dullness to

percussion at lung bases (pleural effusion) Tachycardia

Irregular pulse Tachypnoea

Cheyne Stokes respiration Hepatomegaly

Ascites

Cold extremities Oliguria

Narrow pulse pressure Adapted from the European Society of Cardiology’s 2016 guidelines.¹ Evidence-based Clinical Chinese Medicine Downloaded from www.worldscientific.com by 134.122.89.123 on 11/26/21. Re-use and distribution is strictly not permitted, except for Open Access articles.

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periphery. In advanced stages, the patient may lose lean body mass and become cachectic. Many patients present first with an acute episode of heart failure, followed, if they survive, by evidence of ongoing ‘chronic’ heart failure. An acute ‘decompensation’ can then occur, where the syndrome rapidly becomes worse.

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Epidemiology

Heart failure is a rapidly growing public health issue with an estimated prevalence of > 37.7 million individuals globally.

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The prevalence of heart failure is related to how the definition is applied. It accounts for approximately 1–2% of the adult population in developed countries, with greater than 10% among people who are more than 70 years of age.

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Among people who are more than 65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognised heart failure (mainly HFpEF).

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The proportion of patients with HFpEF ranges from 22% to 73%, depending on the definition applied, the clinical setting (primary care, hospital clinic, and hospital admission), age and sex of the studied population, previous myocardial infarction, and the year of publication.

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Data on temporal trends, based on hospitalised patients, suggest that the incidence of heart failure may have been decreasing, more for HFrEF than for HFpEF.

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Heart failure with preserved ejection fraction and HFrEF seem to have different epidemiological and aetio- logical profiles. Compared with HFrEF, patients with HFpEF are older, more often women, and more commonly have a history of hyperten- sion and atrial fibrillation, while a history of myocardial infarction is less common.

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The characteristics of patients with HFmrEF are between those with HFrEF and HFpEF,

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but further studies are needed to better characterise this population.

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The prevalence of heart failure in Australia and China is consistent with the aforementioned information. A recently published systematic review showed that the prevalence of heart failure in the Australian population ranged between 1.0% and 2.0%, with a significant pro-

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portion of cases being previously undiagnosed. Heart failure was prevalent more in women than men, and in rural and remote regions, than in the metropolitan and capital territories.

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A survey conducted across 10 provinces in China showed that the prevalence of chronic heart failure is on average 0.9% among the population of 35 to 74 years old, with 0.7% in male and 1.0% in female. The average age of heart failure patients is 66 ± 15 years.

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It was also found that the incidence of heart failure increases along with ageing.

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Ischaemic heart disease (IHD) was the leading underlying cause of death globally in 2013, accounting for 15.7% of all age-standardised deaths, equating to a total of 8,139,900 deaths.

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The Global Burden of Disease Study estimates that the prevalence of IHD between 1990 and 2010 increased from 240 to 270 per 100,000 people per year in men, and was stable at 190 per 100,000 people per year in women.

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Using the estimated rate of myocardial infarctions as a surrogate for the incidence of IHD, there is evidence for epidemiological transitions among both industrialised and developing nations. Age-standardised rates of myocardial infarction decreased between 1990 and 2010 in high-income countries in Australasia, Europe, and North America.

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The decrease in the proportion of patients with HFrEF is likely to be attributable to a reduction in myocardial infarction through both pri- mary and secondary prevention strategies.

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Burden

Heart failure causes a significant burden for patients and healthcare systems due to its high prevalence and death rate. A thorough sys- tematic collection of data pertaining to the prevalence and burden of heart failure in Australia and China is lacking.

In high-income countries, heart failure is the most common diag- nosis in hospitalised elderly patients aged > 65 years.

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Heart failure hospitalisation represents 1–2% of all hospital admissions

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and the number of hospitalisations that included heart failure as a reason for admission has been increasing.

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Heart failure hospitalisations are projected to increase by > 50% by 2035, owing to an ageing popula-

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tion.

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It has been reported that in 2011, a total of 553,000 emergency department visits for heart failure were recorded in the United States, and in 2012, a primary diagnosis of heart failure was charted for 1,774,000 outpatient visits.

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Accurate estimates for the global financial burden of heart failure are challenging given data limitations. Attempts have been made to calculate the global cost of heart failure using known national health expenditures. A study published in 2014 estimated that US$108 bil- lion was spent globally on heart failure in 2012, 60% of which was spent directly on medical costs.

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A majority of the worldwide expenditure for heart failure (86%) was attributed to high-income regions that constitute only 18% of the global population.

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Aetiology and Pathological Processes

Aetiology

The aetiology of heart failure is diverse within, and among, world regions. There is no agreed single classification system for the causes of heart failure, with overlap between potential categories. Many patients will have several different pathologies (cardiovascular and non-cardiovascular) that conspire to cause heart failure. Identification of these diverse pathologies should be part of the diagnostic workup, as they may offer specific therapeutic opportunities.

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Ischaemic heart disease (IHD) is the most common underlying cause of heart failure. For example, according to the National Health and Nutrition Examination Survey, which relied on self-report data to define coronary disease, it was estimated than more than 60% of heart failure cases may be attributable to IHD.

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Furthermore, the prognosis of patients with heart failure due to IHD also appears to be worse than that associated with many other aetiologies.

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Many patients with heart failure and IHD have a history of myocardial infarction or revascularisation. However, a normal coronary angio- gram does not exclude myocardial scar (e.g. by cardiovascular magnetic resonance imaging) or impaired coronary microcirculation as alternative evidence for IHD.

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In clinical practice, the aetiology of heart failure has often been categorised into ischaemic or non-ischaemic cardiomyopathy.

Non-ischaemic cardiomyopathy may include cardiomyopathies due to volume or pressure overload, such as hypertension or val- vular heart disease, which are not conventionally accepted as dilated cardiomyopathy.

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Pathological Processes

Heart failure is caused by a loss of a critical quantity of functional myocardial cells after injury to the heart from a number of causes.

The most common aetiologies are IHD, hypertension, and diabetes.

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The amount of blood pumped by the heart over a given time period is known as cardiac output, which is in turn the product of heart rate and stroke volume and is typically 4–8 L/min. In addition, other factors such as synergistic ventricular contraction, ventricular wall integrity, and valvular competence all affect cardiac output.

Stroke volume is affected by three main factors: Preload, which is the amount of myocardial fiber stretch at the end of diastole; afterload, which is the resistance that must be overcome in order for the ventri- cle to eject blood; and contractility, which is the inotropic state of the heart independent of the preload or the afterload.

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Left Ventricular Dysfunction

Left ventricular dysfunction can be divided into two categories:

Systolic dysfunction (impaired ventricular contraction and ejection) and diastolic dysfunction (impaired relaxation and ventricular filling).

It is important, however, to understand that the symptoms of systolic and diastolic heart failure are the same, and whether a patient has systolic or diastolic dysfunction depends on the ejection fraction.

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Right Ventricular Dysfunction

The most common cause of right ventricular failure is left ventricular failure. As the right ventricular fails, there is a similar increase in the

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amount of blood in the ventricle, which in turn leads to elevated right atrial pressure and increased pressure in the vena caval system that impairs venous drainage from the body. This leads to increased pres- sure in the liver, the gastrointestinal tract, and the lower extremities, and to the clinical signs and symptoms of abdominal pain, hepato- megaly, and peripheral oedema.

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Compensatory Mechanisms

Mean arterial pressure is defined as the product of cardiac output and total peripheral resistance. A patient with heart failure has decreased cardiac output, which in turn leads to a decrease in the mean arterial pressure and therefore decreased tissue perfusion. The body thus tries to maintain adequate tissue perfusion and compen- sates to bring the mean arterial pressure back to normal using several mechanisms including the Frank–Starling mechanism, neurohormo- nal activation, and ventricular remodelling. While initially beneficial, the long-term effects of these mechanisms serve to worsen heart failure in a vicious cycle.

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Diagnosis

Algorithm for the Diagnosis of Heart Failure in the Non-acute Setting

For patients presenting symptoms or signs for the first time, either non-urgently in primary care or in a hospital outpatient clinic, the probability of heart failure should first be evaluated based on the patient’s prior clinical history (e.g. IHD, arterial hypertension, diu- retic use), presenting symptoms (e.g. orthopnoea), a physical examination (e.g. bilateral oedema, increased jugular venous pres- sure, displaced apical beat), and resting electrocardiography (ECG).

If all elements are normal, heart failure is highly unlikely and other diagnoses need to be considered. If at least one element is abnormal, plasma natriuretic peptides (NPs) should be measured, if available, to

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identify those who need echocardiography (an echocardiogram is indicated if the NP level is above the exclusion threshold or if circu- lating NP levels cannot be assessed).

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The Diagnosis of Heart Failure with Preserved, Mid-range and Reduced Ejection Fraction

The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF. In the case of HFpEF, a patient’s LVEF is normal and the signs and symptoms for heart failure are often non-specific and do not discriminate well between heart failure and other clinical conditions.

Patients who have an LVEF that ranges from 40% to 49% are described with the term HFmrEF. Details of these three categories are presented in Table 1.3.

Table 1.3. Definition of Heart Failure with Preserved, Mid-range, and Reduced Ejection Fraction

Type of HF HFrEF HFmrEF HFpEF

Criteria 1. Symptoms ± signsâ Symptoms ± signsâ Symptoms ± signsâ 2. LVEF < 40% LVEF 40–49% LVEF ≥ 50%

3. N/A 1. Elevated levels of NPs^b;

2. At least one additional criterion:

a. Relevant structure heart disease (LVH and/or LAE), b. Diastolic

dysfunction

1. Elevated levels of NPs^b;

2. At least one additional criterion:

a. Relevant structure heart disease (LVH and/or LAE), b. Diastolic

dysfunction Adapted from the European Society of Cardiology’s 2016 guidelines.¹

Note: (a) Signs may not be present in the early stages of heart failure (especially in HFpEF) and in patients treated with diuretics; (b) BNP > 35 pg/mL and/or NT-proBNP > 125 pg/mL.

Abbreviations: BNP: B-type natriuretic peptide; HF: heart failure; HfmrEF: heart failure with mid-range ejection fraction; HfpEF: heart failure with preserved ejection fraction; HfrEF: heart failure with reduced ejection fraction; LAE: left atrial enlargement; LVEF: left ventricular ejection fraction; LVH: left ventricular hypertrophy; NP: natriuretic peptides; and NT-proBNP:

N-terminal pro-b-type natriuretic peptide.

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Essential Initial Investigations: Natriuretic Peptides, Electrocardiogram, and Echocardiography

The plasma concentration of NPs can be used as an initial diagnostic test, especially in the non-acute setting when echocardiography is not immediately available. Elevated NPs help establish an initial working diagnosis and identify those who require further cardiac investigation;

patients with values below the cut off point for the exclusion of impor- tant cardiac dysfunction do not require echocardiography. Patients with normal plasma NP concentrations are unlikely to have heart failure. The upper limit of normal in the non-acute setting for B-type natriuretic peptide (BNP) is 35 pg/mL and for N-terminal pro-BNP (NT-proBNP) it is 125 pg/mL; in the acute setting, higher values should be used (BNP < 100 pg/mL, NT-proBNP < 300 pg/mL, and mid-regional pro A-type natriuretic peptide [MR-proANP] < 120 pmol/L). Diagnostic values apply similarly to HFrEF and HFpEF; on average, values are lower for HFpEF than for HFrEF.

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An abnormal ECG increases the likelihood of the diagnosis of heart failure but has low specificity.

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Some abnormalities on the ECG provide information on aetiology (e.g. myocardial infarction), and findings on the ECG might provide indications for therapy. Heart failure is unlikely in patients presenting a completely normal ECG, therefore, the routine use of an ECG is mainly recommended to rule out heart failure.

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Echocardiography is the most useful, widely avail- able test in patients with suspected heart failure to establish the diagnosis. It provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve func- tion, and pulmonary hypertension.

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Other Diagnostic Tests Chest X-ray

Chest X-ray is probably most useful in identifying an alternative, pul- monary explanation for a patient’s symptoms and signs, i.e. pulmonary malignancy and interstitial pulmonary disease, although computed tomography (CT) of the chest is currently the standard of care.

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A chest X-ray is of limited use in the diagnostic work-up of patients with suspected heart failure. It is important to note that sig- nificant left ventricular dysfunction may be present without cardiomegaly on the chest X-ray.

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The chest X-ray may, however, show pulmonary venous congestion or oedema in a patient with heart failure, and is more helpful in the acute setting than in the non- acute setting.

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Transthoracic Echocardiography

A broader range of echocardiography refers to all cardiac ultrasound imaging techniques, including two-dimensional/three-dimensional echocardiography, pulsed and continuous wave doppler, colour flow doppler, tissue doppler imaging (TDI) contrast echocardiography, and deformation imaging (strain and strain rate). Transthoracic echo- cardiography (TTE) is the method of choice for assessment of myocardial systolic and diastolic function of both the left and right ventricles.

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Transoesophageal Echocardiography

Transoesophageal echocardiography (TOE) is not needed in the rou- tine diagnostic assessment of heart failure. However, it may be valuable in some clinical scenarios of patients with valve disease, suspected aortic dissection, suspected endocarditis or congenital heart disease, and for ruling out intracavitary thrombi in atrial fibril- lation patients requiring cardioversion. When the severity of mitral or aortic valve disease does not match the patient’s symptoms using TTE alone, a TOE examination should be performed.

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Stress Echocardiography

Exercise or pharmacological stress echocardiography may be used for the assessment of inducible ischaemia and/or myocardium viabil- ity,

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and in some clinical scenarios of patients with valve disease (e.g. dynamic mitral regurgitation or low-flow–low-gradient aortic

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stenosis).

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There are also suggestions that stress echocardiography may allow the detection of diastolic dysfunction related to exercise exposure in patients with exertional dyspnoea, preserved LVEF, and inconclusive diastolic parameters at rest.

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Cardiac Magnetic Resonance

Cardiac magnetic resonance (CMR) is acknowledged as the gold standard for the measurements of volumes, mass, and ejection fraction of both the left and right ventricles. It is the best alterna- tive cardiac imaging modality for patients with nondiagnostic echocardiographic studies (particularly for imaging of the right heart).

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Cardiac magnetic resonance may also be used for the assessment of myocardial ischaemia and viability in patients with heart failure and IHD (considered suitable for coronary revascularisation).

Single-photon Emission Computerised Tomography and Radionuclide Ventriculography

Single-photon emission computerised tomography (SPECT) may be useful in assessing ischaemia and myocardial viability.

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Gated SPECT can also yield information on ventricular volumes and func- tion but exposes the patient to ionising radiation. In addition, 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy may be useful for the detection of transthyretin cardiac amyloidosis.

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Positron Emission Tomography

Positron emission tomography (PET) (alone or with CT) may be used to assess ischaemia and viability, but the flow tracers (N-13 ammonia or O-15 water) require an on-site cyclotron.

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Rubidium is an alterna- tive tracer for ischaemia testing with PET, which can be produced locally at relatively low cost. Limited availability, radiation exposure, and cost are the main limitations.

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Coronary Angiography

For several decades invasive coronary angiography has been the reference standard test for the assessment of IHD. Coronary magnetic resonance angiography allows non-invasive visualisa- tion of the coronary arteries without exposing the patient to ionising radiation.

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Coronary angiography should be considered in patients with heart failure, intermediate to high pre-test prob- ability of IHD, and the presence of ischaemia in non-invasive stress tests in order to establish the ischaemic aetiology and IHD severity.

Cardiac Computed Tomography

The main use of cardiac computed tomography (CT) in patients with heart failure is a non-invasive means to visualise the coronary anat- omy in patients with heart failure with low intermediate pre-test probability of IHD. Alternatively, those with equivocal non-invasive stress tests in order to exclude the diagnosis of IHD, in the absence of relative contraindications. However, this test is only required when the results might affect a therapeutic decision.

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Molecular Genetic Analysis

Molecular genetic analysis in patients with cardiomyopathies is rec- ommended when the prevalence of detectable mutations is sufficiently high and consistent to justify routine targeted genetic screening. In most patients with a definite clinical diagnosis of heart failure, there is no confirmatory role for routine genetic testing to establish the diagnosis.

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In summary, patients with heart failure should be diagnosed by comprehensive assessments, besides medical history and physical examination, including adequate imaging techniques and a set of additional diagnostic tests, including laboratory variables, ECG, chest X-ray, and exercise testing, etc.

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Management

Guideline-recommended therapy includes use of angiotensin- converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers, beta-blockers, mineralocorticoid-receptor antagonists, anticoagulant therapy for atrial fibrillation or flutter, cardiac resynchronisation therapy, implantable cardioverter-defibrillators, and education on self-management of heart failure.

The two main categories of heart failure are HFrEF and HFpEF. The body’s responses to these two types of left ventricular abnormalities may be very similar, but the evidence base for therapy is much better established for HFrEF.

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It should be noted that the presence of IHD may influence both the efficacy and choice of treatment for heart fail- ure. Agents such as digoxin and amlodipine appear less effective in heart failure patients with IHD, while ACEIs and beta-blockers appear to be equally (if not more) effective in patients with IHD.

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Objectives in the Management of Heart Failure

The goals of treatment in patients with heart failure are to improve their clinical status, functional capacity and quality of life, prevent hospital admission, and reduce mortality. The fact that several drugs for heart failure have shown detrimental effects on long-term outcomes, despite showing beneficial effects on shorter-term surrogate markers, has led regulatory bodies and clinical practice guidelines to seek mortality/

morbidity data for approving /recommending therapeutic interventions for heart failure. However, it is now recognised that preventing heart failure hospitalisation and improving functional capacity are important benefits to be considered if a mortality excess is ruled out.

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Treatments Recommended in all Symptomatic Patients with Heart Failure with Reduced Ejection Fraction

Angiotensin-converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to reduce mortality and morbidity in patients with HfrEF,

^54,55

and are

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recommended unless contraindicated or not tolerated in all sympto- matic patients. Angiotensin-converting enzyme inhibitors should be up-titrated to the maximum tolerated dose in order to achieve ade- quate inhibition of the renin–angiotensin–aldosterone system (RAAS).

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Angiotensin-converting enzyme inhibitors are also recommended in patients with asymptomatic left ventricular systolic dysfunction to reduce the risk of heart failure development, heart failure hospitalisa- tion, and death.

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Beta-blockers

Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF, despite treatment with an ACEI and, in most cases, a diuretic.

^57–61

There is consensus that beta-blockers and ACEIs are complementary and can be started together as soon as the diag- nosis of HFrEF is made.

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Beta-blockers should be initiated in clinically stable patients at a low dose and gradually titrated up to the maxi- mum tolerated dose.

Mineralocorticoid/aldosterone Receptor Antagonists

Mineralocorticoid/aldosterone receptor antagonists (MRAs) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone (e.g. corticosteroids or androgens) receptors.

Spironolactone or eplerenone are recommended in all symptomatic patients (despite treatment with an ACEI and a beta-blocker) with HFrEF and LVEF (despite treatment with an ACEI and a beta-blocker)

≤ 35%, to reduce mortality and heart failure hospitalisation.

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Other Treatments Recommended in Selected Symptomatic Patients with Heart Failure with Reduced Ejection Fraction Diuretics

Diuretics are recommended to reduce the signs and symptoms of congestion in patients with HFrEF, but their effects on mortality and

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morbidity have not been studied in randomised controlled trials.

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The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to the individuals needs over time. In selected asympto- matic euvolaemic/hypovolaemic patients, the use of a diuretic drug might be (temporarily) discontinued. Patients can be trained to self- adjust their diuretic dose based on monitoring the symptoms/signs of congestion and daily weight measurements.

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Angiotensin Receptor Neprilysin Inhibitor

A new therapeutic class of agents acting on the RAAS and the neutral endopeptidase system (angiotensin receptor neprilysin inhibitor [ARNI]) has been developed and recommended as the first-in-class treatment for heart failure.

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By inhibiting neprilysin, the degradation of NPs, bradykinin, and other peptides is slowed. Sacubitril/valsartan is a combination drug for use in heart failure, which consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan in a 1:1 ratio. The combination of the ARNI and ARB results in increasing levels of NPs that counterbalance the neurohor- monal activation underlying HFrEF.

⁶¹

I

_f

-Channel Inhibitor

The I

_f

ion current is highly expressed in the sinoatrial node. Ivabradine slows the heart rate through inhibition of the I

_f

-channel in the sinoatrial node.

Angiotensin II Type I Receptor Blockers

Angiotensin receptor blockers are recommended only as an alterna- tive in patients intolerant of an ACEI.

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The combination of the ACEI/

ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker who are unable to tolerate an MRA and must be used under strict supervision.

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Other Treatments with Less Certain Benefits in Symptomatic Patients with Heart Failure with Reduced Ejection Fraction Other treatments that have shown benefits in terms of symptomatic improvement, reduction in heart failure hospitalisations, or both, and are useful additional treatments in patients with HFrEF are listed:

Digoxin and Other Digitalis Glycosides

Digoxin may be considered in patients in sinus rhythm with sympto- matic HFrEF to reduce the risk of hospitalisation (both all-cause and heart failure hospitalisations).

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In patients with symptomatic heart failure and atrial fibrillation, digoxin may be useful to slow a rapid ventricular rate, but it is only recommended for the treatment of patients with HFrEF and atrial fibrillation with rapid ventricular rate when other therapeutic options cannot be pursued.

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N-3 Polyunsaturated Fatty Acids

The n-3 polyunsaturated fatty acids (n-3 PUFA) may be considered as an adjunctive therapy in patients with symptomatic HfrEF, who are already receiving optimised recommended therapy with an ACEI (or ARB), a beta-blocker, and an MRA.

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Non-surgical Device Treatment of Heart Failure with Reduced Ejection Fraction

Implantable Cardioverter-defibrillator

An implantable cardioverter-defibrillator is recommended to reduce the risk of sudden death and all-cause mortality in patients with sympto- matic heart failure (NYHA Class II–III), and an LVEF ≤ 35% despite greater or equal to three months of optimal medical therapy. This is provided they are expected to survive substantially longer than a year with good functional status, and they have IHD (unless they have had a myocardial infarction in the prior 40 days) or dilated cardiomyopathy.

¹

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Cardiac Resynchronisation Therapy

Cardiac resynchronisation therapy (CRT) improves cardiac perfor- mance in appropriately selected patients, improves symptoms and well-being,

⁶⁷

and reduces morbidity and mortality.

⁶⁸

Treatment of Heart Failure with Preserved Ejection Fraction According to the definition provided in the European Society of Cardiology’s (ESC’s) 2016 guidelines,

¹

the diagnosis of HFpEF requires an LVEF ≥ 50%, whereas patients with a LVEF between 40%

and 49% are considered to have HFmrEF. The treatment recom- mended by the ESC’s 2016 guidelines

¹

applies to patients with both HFmrEF and HFpEF.

Effect of Treatment on Symptoms in Heart Failure with Preserved Ejection Fraction

Diuretics will usually improve congestion, if present, thereby improv- ing symptoms and signs of heart failure. The evidence that diuretics improve symptoms is similar across the spectrum of LVEF.

⁶⁹

Effect of Treatment on Hospitalisation for Heart Failure in Heart Failure with Preserved Ejection Fraction

For patients in sinus rhythm, there is some evidence that nebivolol,

^61,70

digoxin,

⁷¹

spironolactone, and candesartan

⁷²

might reduce heart failure hospitalisations. For HFpEF patients in atrial fibrillation, beta-blockers do not appear to be effective and digoxin has not been studied.

¹

The evidence in support of either ARBs or ACEIs is inconclusive.

¹

Effect of Treatment on Mortality in Heart Failure with Preserved Ejection Fraction

Trials of ACEIs, ARBs, beta-blockers, and MRAs have all failed to reduce mortality in patients with HFpEF or HFmrEF.

¹

However, in older patients with HFrEF, HFpEF or HFmrEF, nebivolol reduced the combined

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endpoint of death or cardiovascular hospitalisation,

^61,70

with no signifi- cant interaction between treatment effect and baseline LVEF.

⁷³

Management of Angina and Ischaemic Heart Disease

As mentioned earlier, IHD is the most common underlying cause of heart failure and serves as the leading underlying cause of death globally. For patients with IHD who also developed heart failure symptoms, their treatment should be altered.

Pharmacological Management

Trimetazidine has been shown to exert some beneficial effect as an add-on to beta-blockers in patients with heart failure and angina.

^74,75

There is data suggesting that it may improve NYHA functional capac- ity, exercise duration, and left ventricular function in patients with HFrEF.

^74,75

Certain other effective anti-anginal drugs have been studied in sizeable numbers of HFrEF/left ventricular dysfunction patients and shown to be safe (e.g. amlodipine, nicorandil, and nitrates).

¹

The safety of other anti-anginal agents in HFrEF, such as ranolazine, is uncertain while other drugs, specifically diltiazem and verapamil, are thought to be unsafe in patients with HFrEF (although they may be used in HFpEF).

¹

Dihydropyridine (Calcium-channel blockers) may all increase sympathetic tone, and their safety in HFrEF and HFpEF is uncertain.

¹

Myocardial Revascularisation

Percutaneous and surgical revascularisation are complementary approaches for symptomatic relief of angina in HFpEF, but whether these interventions improve outcomes is not entirely clear.

¹

Coronary artery bypass grafting (CABG) is recommended in patients with HFrEF, signifi- cant IHD (left anterior descending artery or multivessel disease) and LVEF

≤ 35% to reduce death and hospitalisation for cardiovascular causes.

¹

The choice between CABG and Percutaneous Cardiovascular Intervention (PCI) should be made by the Heart Team after a careful evaluation of the patient’s clinical status and coronary anatomy, expected completeness of revascularisation, coexisting valvular disease, and co-morbidities.

¹

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Prognosis

Estimation of prognosis for morbidity, disability, and death helps patients, their families, and clinicians decide on the appropriate type and timing of therapies (in particular, decisions about a rapid transi- tion to advanced therapies), and assists with planning of health and social services and resources. Numerous prognostic markers of death and/or heart failure hospitalisation have been identified in patients with heart failure. However, their clinical applicability is limited and precise risk stratification in heart failure remains challenging.

¹

Ischaemic heart disease is a major risk factor for heart failure.

¹

Damage from ongoing myocardial ischaemia may adversely affect disease progression and prognosis in chronic heart failure. The find- ings of a recent study demonstrate that in patients with advanced chronic systolic heart failure, a history of IHD was a strong and inde- pendent predictor of all-cause and cardiovascular mortality.

⁷⁶

Delaying or Preventing the Development of Overt Heart Failure or Preventing Death Before the Onset of Symptoms

There is considerable evidence that the onset of heart failure may be delayed or prevented through interventions aimed at modifying risk factors for heart failure or treating asymptomatic left ventricular sys- tolic dysfunction.

¹

For example, effective control of hypertension will delay the onset of heart failure and may prolong life.

^77,78

Different antihypertensive drugs (diuretics, ACEIs, ARBs, and beta-blockers) have been shown to be effective, especially in older people, both in patients with, and without, a history of myocardial infarction.

⁷⁷

Statins reduce the rate of cardiovascular events and mortality, and there is also reasonable evidence that they prevent, or delay, the onset of heart failure.

¹

Recently, empaglifozin (an inhibitor of sodium-glucose cotransporter 2), has been shown to improve outcomes (including the reduction of mortality and heart failure hospitalisations) in heart failure patients with type 2 diabetes.

⁷⁹

Obesity is also a risk factor for heart

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Table 1.4. Chapter Summary

Definition · Heart failure is a complex clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress;

· Heart failure is classified as HFpEF, HFrEF, and HFmrEF;

· Chronic heart failure may present more insidiously with fatigue, breathlessness, and a more gradual build-up of fluid in the lungs and periphery;

· Ischaemic heart disease is the most common underlying cause of heart failure, and the prognosis of patients with heart failure due to ischaemic heart disease also appears to be worse than that associated with many other aetiologies.

Diagnosis · The probability of heart failure should first be evaluated based on the patient’s prior clinical history, presenting symptoms, physical examination, and electrocardiography;

· The plasma concentration of natriuretic peptides can be used as an initial diagnostic test;

· Echocardiography is the most useful, widely available test in patients with suspected heart failure to establish the diagnosis.

failure but the impact of treatments of obesity on the development of heart failure is unknown.

¹

Although smoking cessation has not been shown to reduce the risk of developing heart failure, the epidemiological associations with the development of cardiovascular disease

⁸⁰

suggest that such advice, if followed, would be beneficial. The association between alcohol intake and the risk of developing de novo heart failure is U-shaped, with the lowest risk with modest alcohol consumption (up to seven drinks/week).

^81–83

Greater alcohol intake may trigger the development of toxic cardiomyopathy; complete abstention from alcohol is recommended.

A recent meta-analysis found that doses of physical activity in excess of the guideline-recommended minimal levels might be required for more substantial reductions in heart failure risk.

⁸⁴

(Continued) Evidence-based Clinical Chinese Medicine Downloaded from www.worldscientific.com by 134.122.89.123 on 11/26/21. Re-use and distribution is strictly not permitted, except for Open Access articles.

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