Heart failure learning module 1: background, epidemiology, aetiology and pathophysiology

Released 24 May 2024     Expires: 24 May 2026      Programme:

Sponsorship Statement: Novartis Pharmaceuticals UK Ltd has provided OmniaMed Communications Ltd with an arm’s length sponsorship towards the update of the BJC e-learning programme for heart failure.

Background

Heart failure (HF) is a clinical syndrome of typical symptoms and signs (figure 1), which occur due to an abnormality of cardiac structure or function, combined with elevated serum natriuretic peptide concentrations and/or objective evidence of pulmonary or systemic congestion on examination.1,2

Heart failure module 1 2024 - Figure 1. Typical symptoms and signs of heart failure
Figure 1. Typical symptoms and signs of heart failure

Key: JVP = jugular venous pressure

Although everyone learns the mantra ‘HF is a syndrome, not a diagnosis’, HF is most commonly given as a specific diagnosis. This can be problematic as there are multiple possible causes of the syndrome of HF, many of which overlap, and only some of which are due to underlying (and treatable) cardiac dysfunction.

Patients with HF are classified into phenotypes based on the left ventricular ejection fraction (LVEF), most commonly measured using echocardiography. A LVEF ≤40% is classified as HF with reduced ejection fraction (HFrEF); LVEF 41–49% as HF with a mildly reduced ejection fraction (HFmrEF); and LVEF ≥50% as HF with a preserved ejection fraction (HFpEF) (further details will be discussed in module 2).

Epidemiology

Prevalence

The estimated global prevalence of HF is estimated to be 64 million people.2 In the UK, it is estimated that there are more than one million people with HF. HF affects between 1–2% of the general population, which is increasing at a rate of 200,000 new diagnoses every year,3 due to an ageing population, improved survival following myocardial infarction, increasing prevalence of risk factors such as diabetes and obesity – and better medical care. Although age- and sex-standardised prevalence is stable (1–2%), the crude number of patients living with HF has increased by 23% in the last decade.3

Incidence

In a population-based study from the UK including more than four million people, a decline of 7% in the incidence of HF was observed between 2002 and 2014 from 3.6 to 3.3 per 1,000 person-years.2 Whilst age- and sex-standardised incidence of HF has decreased in the last decade, the crude number of new cases has increased by 12%.3

National Heart Failure Audit 2024 Report

The recent National Institute for Cardiovascular Outcomes Research (NICOR) National Heart Failure Audit reports that the average age of HF patients in 2022/23 was 77.7 years (75.8 for men and 80.0 for women) with men being more numerous in every age category apart from over 85 years.5

The incidence of HF rises with age and has increased significantly amongst patients aged 85 years and older (figure 2), probably as a result of the increased use of screening and diagnostic tests (covered in module 2). The average age at diagnosis is approximately 77 years but is significantly lower in areas of economic deprivation.4 Typical patients are 15–20 years older than the average age of patients recruited to clinical trials.

Heart failure module 1 - Figure 2. Age and sex of HF patients in England and Wales at first admission, 2022/23 (NHFA data)
Figure 2. Age and sex of HF patients in England and Wales at first admission, 2022/23 (NHFA data)

Adapted with permission from NICOR’s National Heart Failure Audit 2024 Summary Report5
Key: HF = heart failure; NHFA = National Heart Failure Audit

Outcomes

Untreated, patients with HF have a poor quality of life and reduced life expectancy, more so than with some cancers.6 Most patients are diagnosed only after deteriorating to the point of requiring hospital admission during which approximately one in 10 will die.7 Of those who survive admission, approximately 15% will die during the month following discharge and 32% will die in the year following hospital admission.7 Effective treatment can improve symptoms and outcomes, but there are wide variations in the management of HF across the globe.2

Ischaemic heart disease (IHD) was responsible for one in 10 deaths in England and Wales in 2022, second behind dementia and Alzheimer’s disease as the leading cause of death (figure 3).8 HF is the common final end point for most forms of cardiovascular disease; most (50–70%) are due to IHD.9 Over the last two decades, researchers have seen a fall in the number of deaths due to IHD and huge improvements in the detection and management of HF,4,10,11 resulting in an increased incidence and prevalence of HF.12

Heart failure module 1 - Figure 3. Causes of adult deaths in England and Wales in 2022
Figure 3. Causes of adult deaths in England and Wales in 2022

Data obtained from the Office of National Statistics, 20238
Key: COVID-19 = coronavirus disease 2019
QOF indicators

The performance of general practices in managing patients with HF is monitored by the Quality and Outcomes Framework (QOF). Under the guidance of the National Institute for Health and Care Excellence (NICE), the QOF has developed ‘indicators’ for managing patients with HF that act as targets that are financially incentivised (table 1).

In England and Wales, general practitioners (GPs) keep a HF registry as part of the QOF. These registers record a prevalence of HF of only 0.9%,13 suggesting that not all patients with HF in primary care are being recorded, or perhaps that the epidemiology is incorrect.14 Missing patients may be cases of undiagnosed or untreated HF.15 Improved coding of electronic records using simple automated methods can greatly increase the apparent prevalence of HF,15 and may yield financial rewards via the QOF framework.

Table 1. QOF indicators related to heart failure, their description and number of QOF points allocated14

QOF indicator Description Points allocated
HF001 The contractor establishes and maintains a register of patients with heart failure 4
HF003 60–92% of patients with a current diagnosis of heart failure due to left ventricular systolic dysfunction treated with an ACE inhibitor or ARB 6
HF005 50–90% of patients with a diagnosis of heart failure (diagnosed on or after 1 April 2006) confirmed by an echocardiogram or by specialist assessment 3 months before or 6 months after entering on to the register

If newly registered in the preceding 12 months, with no record of the diagnosis originally being confirmed by echocardiogram or specialist assessment, a record of an echocardiogram or a specialist assessment within 6 months of the date of registration

 6
HF006 60–92% of patients with a current diagnosis of heart failure due to left ventricular systolic dysfunction, who are currently treated with a beta blocker licensed for heart failure 9
HF007 50–90% of patients with a diagnosis of heart failure on the register, who have had a review in the preceding 12 months, including an assessment of functional capacity and a review of medication to ensure medicines optimisation at maximal tolerated doses. 7
Key: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; QOF = Quality and Outcomes Framework

The National Heart Failure Audit Report 2024: the burden of HF in the UK5

National Heart Failure Audit (NHFA) 2024 summary report

The National Heart Failure Audit was established in 2007 and produces annual reports (both as a summary and on a hospital-by-hospital basis) on the demographics, investigations, treatment, place of care, level of specialist input, follow up and outcome of all patients admitted with HF in England and Wales.

Records are submitted by individual institutions and, since 2016, have been financially incentivised by the Best Practice Tariff for HF (See Best Practice Tariffs for HF). The 2022/23 report captured data from around 86% of all hospital admissions coded as being for HF by Hospital Episode Statistics (HES/PEDW) coding in England and Wales. It is an invaluable source of information on the current ‘state-of-play’ for the quality of care given to patients admitted with HF.

Best Practice Tariffs for HF

In 2010, the Department of Health in the UK introduced ‘best practice tariffs’. Base payments for treating a certain condition were reduced overall, but additional money was available for hospitals meeting criteria based on national guidance and expert opinion that defined ‘best practice’ for managing that condition.19

The best practice tariff for HF is worth a 10% increase in payment for every admission, but it is not paid on a patient-by-patient basis: either the hospital meets the best practice tariff criteria and gets the 10% increase in payment for every admission coded as HF – or it does not.

The best practice tariff for HF, first introduced in 2016, includes two criteria21:

  • 60% of patients admitted with failure must receive specialist input during admission as recorded in the National Heart Failure Audit.
  • 70% of patients coded as having HF must be included in the National Heart Failure Audit.
HF has a profound negative impact and is costly to manage

Acute or decompensated HF is the leading cause of admission to hospital for patients aged ≥65 and causes or complicates 5% of all hospital admissions in the UK.5,16 Hospitalisation rates have increased by 33% in the last five years, three times greater than the increases seen for any other condition.17 Re-admission rates are high; as many as 23% will be re-admitted in the month after discharge (although not always for HF).18

Mortality is stubbornly high

There was an increase in the number of HF patients admitted to hospital who died to 11% in 2022/23 (from 9% in 2021/22) but 30-day and one-year mortality decreased to 13% and 30%, respectively, down from 14% and 33%, respectively, in 2021/22.5 Perhaps, surprisingly, non-cardiovascular hospitalisation or death accounts for the majority of admissions and deaths in patients with HF,20 which might reflect improvement in HF care, or the fact that HF predominantly affects older people with multiple competing risks.

Death rates following diagnosis in the community are 19%, 49% and 71% at one, five and 10 years, respectively, with little appreciable change in the last decade.22

HF mortality and hospitalisation rates are increasing worldwide

There has been a worrying upward trend in HF death rates recently reported in the USA between 2012 and 2017.23 Although drawing comparisons between our state-run health service in the UK and the insurance-based model in the USA is difficult, the increase in hospital admissions with HF and the unchanging high death rates during and after admission are concerning.

HF creates a huge burden on patients and healthcare systems

Admission is associated with long hospital stays (approximately nine days for patients treated on cardiology wards).5 HF accounts for 2% of the entire National Health Service (NHS) annual budget (around £625 million per year); 70% is spent on in-patient care and only about 9% on drugs.12

Specialist input improves HF outcomes

In-patient mortality is lower for those admitted to cardiology wards and for those who receive specialist care (see figure 4).

Data from 2022/23 show that:

  • Overall 30-day mortality improved to 13% compared to 14% during the 2021/22 audit
  • The 60% prescribing target of the three standard outcome-improving drugs for HFrEF (i.e. ACE inhibitors/angiotensin receptor blockers [ARB]/angiotensin receptor-neprilysin inhibitors [ARNI] + mineralocorticoid receptor antagonists [MRA] + beta blocker) was achieved by 54% of hospitals compared to 42% of hospitals in 2021/22. Patients cared for in cardiology wards or seen by specialist teams were more likely to receive outcome-improving drug therapy, including sodium-glucose co-transporter-2 (SGLT2) inhibitors.
  • Specialist follow-up within two weeks of discharge was received by 81% of HF patients, similar to 2021/22, but remains short of the 100% target.
Heart failure module 1 - Figure 4. Kaplan Meier plot of all-cause mortality following discharge from hospital according to place of care during admission, 2022/23
Figure 4. Kaplan Meier plot of all-cause mortality following discharge from hospital according to place of care during admission, 2022/23

Adapted with permission from NICOR’s National Heart Failure Audit 2024 Summary Report5
A wide variation exists in the level of specialist input

The proportion of patients being admitted to cardiology wards is falling and only 40% of HF patients were cared for on a cardiology ward in 2022/23. Only 15% of hospitals reached the target of 60% of patients being admitted to a cardiology ward and almost 40% of hospitals failed to reach the target of 80% of all HF patients being seen by a specialist HF team. There was wide regional variation with more than a three-fold difference in HF admissions across different health boards in England and Wales.5

Length of stay affected by level of specialist input

Median length of stay was higher for patients on cardiology wards compared to those treated on general medical wards (9 days vs. 7 days).

Likelihood of undergoing all necessary investigations increased with level of specialist input

Patients undergoing echocardiography remained at 89-92% for those receiving specialist care or for those cared for on cardiology wards but this decreased to 65% for those patients not receiving this care.5 The audit does not record the availability and use of natriuretic peptide measurements, which is probably now the best tool to rule-out HF as a cause of presentation. Details of natriuretic peptides can be found in module 2.

Of those who had an echocardiogram, 51% had left ventricular systolic dysfunction, with it being less commonly found in women (40%) than men (59%).5

Prescription of guideline-directed therapy correlates to place of care and level of specialist input

In 2022/23, more patients received drug therapy that improves longer-term outcomes5:

  • Beta blockers were prescribed to 91% of patients
  • An ACE inhibitor, ARB or ARNI were prescribed to 85% of patients
  • MRAs were prescribed to 68% of patients
  • SGLT2 inhibitors were prescribed to 59% of patients
  • Only 44% of patients received all four classes of outcome-improving drug therapy
  • There was considerable variation in prescribing these drugs in different ward settings with highest prescribing rates seen on cardiology wards (figure 5) and with specialist heart failure teams (see figure 6)
  • Fewer older patients received disease-modifying drug treatments.
Heart failure module 1 - Figure 5. Percentage of patients with HFrEF who received disease-modifying drugs alone and in combination at discharge from hospital, by place of care (2022/23)
Figure 5. Percentage of patients with HFrEF who received disease-modifying drugs alone and in combination at discharge from hospital, by place of care (2022/23)

Adapted with permission from NICOR’s National Heart Failure Audit 2024 Summary Report5
Key: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BB = beta blocker; MRA = mineralocorticoid receptor antagonist; SGLT2i = sodium-glucose co-transporter-2 inhibitor
Heart failure module 1 - Figure 6. Percentage of patients with HFrEF who received disease-modifying drugs alone or in combination, at discharge from hospital (2022/23)
Figure 6. Percentage of patients with HFrEF who received disease-modifying drugs alone or in combination, at discharge from hospital (2022/23)

Adapted with permission from NICOR’s National Heart Failure Audit 2024 Summary Report5
Key: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BB = beta blocker; MRA = mineralocorticoid receptor antagonist; SGLT2i = sodium-glucose co-transporter-2 inhibitor
The rate of referral to cardiac rehabilitation has fallen

The rate of referral to cardiac rehabilitation after discharge was under 10% in 2022/23; down 3% from the previous year. This may be because the Quality and Outcomes Framework indicators no longer reward practices for referring patients to an exercise-based cardiac rehabilitation programme, despite recommendations made in both European Society of Cardiology and NICE chronic HF guidelines. This is perhaps a reflection of service-underfunding and the so-called ‘postcode lottery’; exercise-based cardiac rehabilitation can improve symptoms and reduce the risk of HF hospitalisation in patients with HFrEF,24,25 but access to such programmes varies greatly nationwide.

Quality standards

NICE has produced ‘quality standards’ for acute and chronic HF that define the standard of care that should be provided.

Acute HF: The NICE acute HF quality standards – updated 201526 – recommend that:

  • Adults presenting to hospital with new, suspected acute HF have a single measurement of natriuretic peptide
  • Adults admitted to hospital with new, suspected acute HF and raised natriuretic peptide levels have a transthoracic Doppler 2D echocardiogram within 48 hours of admission
  • Adults admitted to hospital with acute HF have input within 24 hours of admission from a dedicated specialist HF team
  • Adults with acute HF due to left ventricular systolic dysfunction (LVSD) are started on, or continue with, beta-blocker treatment during their hospital admission
  • Adults admitted to hospital with acute HF and reduced LVEF are offered an ACE inhibitor and a MRA
  • Adults with acute HF have a follow up clinical assessment by a member of the community – or hospital-based specialist HF team within two weeks of hospital discharge.

Chronic HF: The NICE chronic HF quality standard – updated 202327 – recommend that:

  • Adults presenting in primary care with suspected HF have their N‑terminal pro‑B‑type natriuretic peptide (NT‑proBNP) measured
  • Adults with suspected HF have specialist assessment and transthoracic echocardiography within two weeks of referral if they have a very high NT‑proBNP level, or six weeks if they have a high NT‑proBNP level.
  • Adults with chronic HF who have reduced ejection fraction receive all appropriate medication at target or optimal tolerated doses, including:
    • ACE inhibitor (or ARB, if ACE inhibitor not tolerated) and/or an ARNI e.g. sacubitril/valsartan
    • Beta blocker
    • MRA
    • SGLT2 inhibitor
  • Adults with chronic HF have a review within two weeks of any change in the dose or type of their HF medication
  • Adults with stable chronic HF have a review of their condition at least every six months
  • Adults with chronic HF receive a personalised programme of cardiac rehabilitation.

The quality standards require significant resources and do not take into account patient variables that may limit their treatment. Many centres struggle to attain these very high standards; quality standards require that all patients should have specialist input from a dedicated specialist heart failure team within the first 24 hours of admission, but only 82% of patients get any input from HF specialists while an inpatient.5 The standards suggest that all patients should get a transthoracic echocardiogram within 48 hours of admission, but only 85% of patients get an echocardiogram at all during admission.

The requirement that all patients have follow-up with either their GP, a cardiologist, or HF specialist nurse within two weeks of discharge must be one of the most unrealistic targets in the modern NHS.

Aetiology, precipitants and comorbidities

Aetiology28

HF is a syndrome and not a diagnosis. Once a patient has been identified as having the HF syndrome, a cause must be sought. For example, in the majority of patients with HFrEF, the underlying cause will be IHD. However, determining the aetiology of HF is often complex, and many causative factors may overlap.

National Heart Failure Audit 2024 Report5

The top five causes and comorbidities in both heart failure with reduced and preserved ejection fraction (prevalence, %), respectively, are:

• Hypertension (54%; 65%)
• Atrial fibrillation (AF) (38%; 52%)
• Diabetes (34%; 36%)
• Valve disease (24%; 35%)
• IHD (38%; 32%)

Possible aetiologies of HF:

  • IHD
  • Hypertension
  • Valve disease (acquired and congenital)
  • Arrhythmias (atrial and ventricular brady- and tachyarrhythmias)
  • Dilated cardiomyopathy (DCM)
    • Viral
    • Idiopathic
    • Lyme disease
    • Chagas’ disease
  • Infective
  • Congenital heart disease
  • Drug-induced
  • Infiltrative
  • Storage disorders
  • Endomyocardial disease
  • Pericardial disease
  • Metabolic (autoimmune, nutritional deficiencies, endocrine disease)
  • Neuromuscular disease.

Complications and comorbidities

HF is predominantly a disease of the elderly and most patients have multiple comorbidities5; approximately 60% of patients with heart failure have at least one comorbidity.29 Some comorbidities may cause HF in the first place, for example, chemotherapy after treatment for cancer.30 Others are risk factors for developing HF, such as obesity or hypertension (see below). Polypharmacy is common and can be very challenging.

The most common comorbidities include the following:

  • Arrhythmias
    Arrhythmias are common complications of HF, especially AF (figure 7), which can increase the risk of stroke, thromboembolism and ventricular arrhythmias.31

    Figure 7. ECG showing atrial fibrillation (click to enlarge)
    Figure 7. Electrocardiogram showing atrial fibrillation (click to enlarge)
    • AF

      • Patients with HF who develop AF (figure 7) should be assessed for potentially reversible causes (see below) and stroke risk. Unless there is a very strong contraindication, patients with HF and AF should always be anticoagulated.31

      Potential reversible causes of AF in HF

      • hyperthyroidism
      • electrolyte disorders
      • uncontrolled hypertension
      • mitral valve disease.

      Potential precipitating factors of AF in HF

      • recent surgery
      • chest infection or exacerbation of chronic obstructive pulmonary disease (COPD)/asthma
      • acute myocardial ischaemia
      • alcohol binge.
    • Ventricular arrhythmias

      • Episodes of asymptomatic, non-sustained ventricular tachycardia are common.1 ‘Complex ventricular arrhythmias’, including frequent premature ventricular complexes and non-sustained ventricular tachycardia, are associated with a poor outcome.1

  • Anxiety and depression

    • Anxiety and depression are common in patients with HF with around one in three patients reporting symptoms of low mood and one in five patients meeting diagnostic criteria for a depressive illness. Depression in patients with HF is associated with a worse clinical status, poor prognosis, poor adherence to treatment and social isolation.32

  • Anaemia

    • Chronic HF (CHF) and anaemia frequently co-exist – up to 40% of patients with CHF are anaemic (Hb <13 g/dL in men and <12 g/dL in women).33 The cause of anaemia in patients with CHF is multifactorial34; a combination of disease severity, co-morbidities (such as renal dysfunction), poor diet, haematinic deficiencies and side-effects of treatment. Anaemia in patients with CHF is associated with more severe symptoms and poorer prognoses.35,36

  • Diabetes

    • Diabetes affects approximately one third of patients with HF and is associated with a poorer prognosis and reduced functional status.37 Hyperglycaemia is associated with endothelial dysfunction, myocardial fibrosis, and increased activation of the sympathetic nervous system and renin-angiotensin-aldosterone system.38

  • Chronic kidney disease

    • Chronic kidney disease (CKD) is very common amongst patients with chronic HF – ~50% of patients with CHF have an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.39 Both CKD and worsening renal function during treatment are associated with a poor prognosis.40 Patients with CHF and CKD have worse symptoms, higher levels of circulating renin-angiotensin-aldosterone system hormones and natriuretic peptides, are more likely to take a diuretic, but are less likely to be treated with an ACE inhibitor/ARB, beta blockers or MRAs.9,41 Despite concerns regarding renal function, treatment with disease-modifying therapies at the expense of renal function is better than the preservation of a ‘normal’ eGFR or creatinine. Additionally, newer drug treatments for HFrEF, such as sacubitril/valsartan and SGLT2 inhibitors, may reduce the rate of decline of renal function.42,43

  • Chronic obstructive pulmonary disease

    • Chronic obstructive pulmonary disease is another common co-morbidity affecting around 10% of patients but may have negligible impact on prognosis.44 There is much overlap in risk factors and symptoms, prompting concerns about misdiagnosis of a patient with exertional dyspnoea.45 The concern is that a diagnosis of COPD in patients with HFrEF will lead to under-prescription of beta blockers.46

  • Hyperuricaemia and gout

    • Gout is common in patients with heart failure; diuretics can either cause or aggravate gout.47

  • Hypertension

    • Hypertension is more common in patients with HFpEF.31 Among people with hypertension, the incidence of HF is reduced by antihypertensive therapy, with the exception of alpha-adrenoreceptor blockers which are associated with an increased risk and should be discontinued whenever possible.48

  • Obesity

    • Obesity is a risk factor for HF, independent of lifestyle factors that may contribute to, or are associated with being obese, such as physical inactivity, diabetes and hypertension.49 There is potential for misdiagnosis in an obese patient with exertional dyspnoea and ankle swelling. Obesity often makes an echocardiogram challenging and sometimes, uninterpretable.

  • Sleep disturbances

    • Disturbed sleep is a common complaint of patients with HF and sleep-disordered breathing affects up to one third.9 Obstructive sleep apnoea is associated with intermittent hypoxaemia, hypercapnia, sympathetic activation, pulmonary and systemic hypertension, and atrial fibrillation.50

Classifications of HF

In classifying HF syndromes, patients were historically grouped into those with acute HF and chronic HF. Various classifications exist, depending on the presentation of the patient, the underlying cause and the pathophysiology particular to that patient. The terminology surrounding HF is sometimes confusing and often unhelpful. Current terms used to classify HF include the following:

  • Acute HF versus chronic HF versus acute decompensated/hospitalised HF

    • ‘Acute HF’ means different things to different clinicians. To some, it is synonymous with acute pulmonary oedema; to others, it encompasses all patients being admitted to hospital with HF and includes those (the majority with ‘acute’ HF) with fluid retention as their dominant problem.

    ‘Acute decompensated’ HF is also unsatisfactory – it is not acute (fluid having taken weeks or months to accumulate); nor is it ‘decompensated’ (which implies prior compensation, when it is, in fact, often the presenting feature of HF).

    Pulmonary oedema is a dramatic event with an identifiable cause (such as myocardial ischaemia or arrhythmia). It is an uncommon mode of hospitalisation for patients with HF, and requires entirely different treatment from those with severe fluid retention – anasarca. Like patients presenting with pulmonary oedema, those presenting with fluid retention are likely to have an underlying cause.

    In this module, we will use the terms ‘acute pulmonary oedema’ and ‘anasarca’ to encompass those patients presenting acutely or subacutely; and ‘chronic HF’ to describe those patients stabilised after an initial presentation and between any exacerbations.

  • High output versus low output
  • Systolic versus diastolic HF
  • Right-sided versus left-sided HF
  • Phenotype based on LVEF i.e. HFrEF/HRmrEF/HFpEF (See figure 8). This will be discussed in further detail in Module 2.

    • Patients with HF are often sub-divided in relation to their LVEF, which is most commonly measured using transthoracic echocardiography (TTE or ‘echo’).

    Heart failure module 1 - Figure 8. Infographic of the phenotypic classification of HF according to left ventricular ejection fraction
    Figure 8. Infographic of the phenotypic classification of HF according to left ventricular ejection fraction

    Key: HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction

Despite much debate surrounding the value of LVEF as a measure of cardiac function, there is no doubt that it is helpful in identifying patients who are likely to respond to specific therapies.

Clinical trials have unequivocally demonstrated the benefit of medical and device therapy for patients with HF, particularly amongst those with reduced ejection fraction, whichever way that is defined.

The latest ESC 2023 Focused update to the ESC 2021 Guidelines on the assessment and management of heart failure focuses on the phenotypic classification to determine management.

Syndromes and pathophysiology

As described above, the most useful distinction to make is between decompensated (either with pulmonary oedema or anasarca) and chronic HF. Chronic HF describes the syndrome patients have once decompensated HF has been medically treated.

Pulmonary oedema

Pulmonary oedema is an acute medical emergency, which can be precipitated by the following:

Table 2. Common precipitants of acute pulmonary oedema

Myocardial ischaemia Acute infarction
Acute coronary syndrome
Angina
Arrhythmia Atrial fibrillation
Ventricular tachycardia
Mechanical disaster Ventricular septal rupture
Papillary muscle rupture
Intercurrent illness Pneumonia
Thyrotoxicosis
Environmental Lack of compliance with medication
Acute salt loading
Pathophysiology of pulmonary oedema28

Pulmonary oedema is best understood in haemodynamic terms. Fluid is held in the pulmonary capillaries by the balance between the hydrostatic pressure in the capillary (tends to push fluid out) and the colloid osmotic pressure, which is largely generated by plasma proteins (tending to hold fluid in the vascular space).

There is a net (small) constant transudation of fluid from the pulmonary capillaries which is removed by the lymphatics (figure 9).

Heart failure module 1 - Figure 9. Increased hydrostatic pressure resulting in transudation into the intravascular space, resulting in increased fluid accumulation
Figure 9. Increased hydrostatic pressure resulting in transudation into the intravascular space, resulting in increased fluid accumulation

Left ventricular work (and cardiac output) is determined by left ventricular filling pressure (end-diastolic pressure). This is the Frank-Starling relationship (figure 10): as filling pressure rises, so does cardiac output. In the acutely failing LV, the relation is shifted downward and to the right so that to maintain any given cardiac output, a higher filling pressure is required.

Heart failure module 1 - Figure 10. Starling’s law of the heart. In the normal heart (blue), ventricular work increases as a function of preload. The horizontal lines show the ventricular work required at rest, then for mild and finally severe exertion. With increasing severity of HF (brown lines), a greater preload is needed for a given level of activity. Note the ‘descending limb’ of the Starling curve for patients with severe HF: the implication is that a reduction in preload might (paradoxically) increase ventricular work
Figure 10. Starling’s law of the heart. In the normal heart (blue), ventricular work increases as a function of preload. The horizontal lines show the ventricular work required at rest, then for mild and finally severe exertion. With increasing severity of HF (red lines), a greater preload is needed for a given level of activity. Note the ‘descending limb’ of the Starling curve for patients with severe HF: the implication is that a reduction in preload might (paradoxically) increase ventricular work

Adapted McDonagh et al. 2011.9

Left ventricular filling pressure is the same as the pulmonary venous pressure (assuming no mitral valve stenosis). As the left ventricle becomes impaired, the end diastolic pressure and pulmonary venous pressure increase. The rise results in an increase in the rate of transudation from the pulmonary capillaries into the lung tissues. The rate of influx eventually exceeds the rate at which fluid can be removed by the lymphatics. Fluid then accumulates in the interstitium of the lung and then the alveoli.

A point often ignored is that the increase in filling pressure requires an input of energy – this can only come from the right ventricle. In acute pulmonary oedema, there must be a temporary imbalance between the output of the two ventricles; the relative excess output from the right results in the increase in left ventricular diastolic pressure and represents the fluid accumulating in the lungs.51

Decompensated HF28

More common than pulmonary oedema as a cause of hospitalisation is fluid retention (table 3). In contrast to patients with pulmonary oedema (who may have a low circulating volume due to accumulation of fluid in the lungs), patients with peripheral oedema have an absolute excess of body fluid and an increased circulating volume. The fluid tends to accumulate gradually over many days or weeks; it takes around 5 L of excess fluid before peripheral oedema appears.

Table 3. Comparison between patients with acute pulmonary oedema and those with peripheral oedema

Pulmonary oedema Fluid retention
Onset Minutes – hours Days – weeks
Precipitant Always Rarely
Circulating volume Normal or reduced Increased
Total water volume Normal Increased
Blood pressure Increased Normal or low

Fluid accumulates with gravity, so for most patients it starts in the ankles and works upward – and may involve the abdominal, and even thoracic, wall. However, patients who are bed bound may have oedema around the sacrum and thighs but little around the feet and ankles. Patients are usually not breathless at rest, although are unable to do much exercise.

On physical examination, the patient may have a tachycardia with a low volume pulse and a low blood pressure. Around 25% will be in AF. The jugular venous pressure is invariably raised, but may be so high that the top of the column of blood cannot be seen, even with the patient sitting upright.

In most patients, the heart is dilated and there is a loud third, and often fourth, heart sound. Some degree of pulmonary venous hypertension is almost invariable and patients may have basal crackles in both lung fields.

Pathophysiology of decompensated HF28

Salt and water are retained by the kidneys in response to decreased renal perfusion, which in turn, leads to renin-angiotensin-aldosterone activation coupled with an increase in antidiuretic hormone production. The increased circulating volume is accommodated largely in the compliant venous side of the circulation; venous hydrostatic pressure thus rises (with gravity ensuring that the hydrostatic pressure is highest in the feet). The capacity of the lymphatics to drain away the transudate is exceeded, and oedema starts to form.

What is less certain is why there is salt and water retention in the first place. It may be related to the primary need for the body to maintain blood pressure. This cannot be the whole explanation, as in some patients, oedema develops despite normal blood pressure and in others, there is fluid retention despite aggressive treatment with neurohormonal antagonists.

Chronic HF28

Although some patients with fluid retention are thought of as having chronic HF – particularly if they do not actually need to be hospitalised – the term is best reserved for patients with treated, decompensated HF.

Successful treatment of acute/decompensated HF leads to chronic HF – patients usually have some degree of exercise limitation – but where HF is well-treated, patients do not have congestion and oedema.

Chronic HF is iatrogenic in the sense that before modern therapies were available, decompensated HF had a very bleak prognosis. Diuretics and treatment with neurohormonal antagonists allow chronic HF to develop.

The cardinal symptom of chronic HF is exercise limitation. Patients complain of breathlessness or fatigue on exertion, with the dominant symptom varying with the kind of exercise performed. The origin of symptoms is not clear and is likely to be a result of abnormal haemodynamics, neurohormonal activation and skeletal muscle changes.

Pathophysiology of chronic HF
  • Haemodynamics
    In most patients with chronic HF, remodelling causes progressive dilation of the LV. Stroke volume is maintained by an increase in left ventricular wall tension by the law of Laplace. Cardiac output is usually normal at rest and during submaximal exercise, but may not be able to rise normally during more strenuous activity. However, there is little correlation between haemodynamic variables – particularly when measured at rest – and exercise capacity.
  • Neurohormonal activation
    The insight that many neurohormonal systems are activated in chronic HF has been the key to the success of modern medical therapy for HF.
  • Renin-angiotensin-aldosterone system activation
    The renin-angiotensin-aldosterone system (RAAS) (figure 11) is activated by reduced renal perfusion. Plasma concentrations of renin, angiotensin II, and aldosterone are higher in those with worse HF symptoms (higher New York Heart Association [NYHA] class). Diuretics – while essential for controlling symptoms – further increase RAAS activation. The consequences are, inter alia, vasoconstriction, salt and water retention, increased vascular fibrosis and a positive interaction with the sympathetic nervous system (figure 12), which is activated by a fall in cardiac output and RAAS activation. The consequences for the heart include tachycardia, myocardial fibrosis and apoptosis, increased risk of arrhythmia and peripheral vasoconstriction (figure 13).
    • Figure 11. The renin angiotensin aldosterone system
    Figure 11. The renin angiotensin aldosterone system (click to enlarge)

    Key: ACE = angiotensin-converting enzyme; AT1/2 = angiotensin receptor type 1 or 2; MR = mineralocorticoid receptor; NO = nitrous oxide
    Figure 12. Overactivity of sympathetic nervous system
    Figure 12. Overactivity of sympathetic nervous system (click to enlarge)
    Heart failure module 1 - Figure 13. The ‘vicious cycle’ of chronic HF pathophysiology (click to enlarge)
    Figure 13. The ‘vicious cycle’ of chronic HF pathophysiology (click to enlarge)
  • Natriuretic peptides and arginine vasopressin
    Natriuretic peptide concentrations rise as a homeostatic response to dilation of the cardiac chambers. They counteract many of the effects of the RAAS – inducing natriuresis, diuresis and vasodilation. Antidiuretic hormone (arginine vasopressin) is also increased, further enhancing water retention.

    Other hormone systems are activated, although their clinical relevance is not always clear. The potent vasoconstrictor, endothelin, is raised, and more intriguingly, there is activation of components of the immune system, with increases in tumour necrosis factor and C-reactive protein, for example.

  • Skeletal muscle changes
    These can be very prominent in some patients resulting in cachexia, but almost all patients have some degree of loss of lean muscle bulk. The skeletal muscle changes correlate closely with impaired exercise capacity, and appear to be implicated, at least in part, as the cause of sympathetic nervous system activation.
  • Peripheral changes
    These include the downregulation of baroreceptors (making them unlikely to be the source of sympathetic nervous system activation) and enhancement of chemoreceptors. The ergoreflex, a neurally mediated reflex arising from exercising muscle in proportion to work done, is increased.

Conclusion

HF has a profound impact on quality of life, prognosis and survival of those affected. Establishing a clear diagnosis can be difficult, especially given the broad and vague diagnostic criteria relating to HFpEF. Its incidence and prevalence rise with age, and both are rising in the population due to better healthcare and therapeutic advances. A large proportion of the healthcare budget is spent on HF hospitalisations.

The pathophysiology of HF remains key to understanding how to diagnose and manage the different types of HF accordingly.

In the following modules in this programme, we will explore investigations, diagnostic algorithms and pharmacological and non-pharmacological options for the management of HF.

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