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Heart failure

Heart failure is a clinical syndrome where the patient has symptoms and/or signs of insufficient cardiac output and/or backwards congestion. This is due to an underlying decrease in systolic or diastolic function of the heart.

Decreased systolic function refers to decreased ability of the heart to eject blood, reflected as a decreased left ventricular ejection fraction (LVEF, usually shortened to simply EF), called heart failure with reduced ejection fraction (HFrEF). Decreased diastolic function refers to decreased ability of the heart to fill with blood, called heart failure with preserved ejection fraction (HFpEF).

Not all people with heart failure have symptoms of volume overload, and as such, the term “congestive” heart failure is no longer used to mean all cases of heart failure.

People may have decreased systolic function (decreased EF) or decreased diastolic function without having overt heart failure. However, these are precursors to heart failure and should be treated accordingly.

Heart failure is, much like COPD, a chronic disorder characterised by chronic symptoms with periods of exacerbation, called acute decompensated heart failure.

The mortality of heart failure has decreased significantly with modern treatment. According to one study, the 1-year mortality without medical therapy was approximately 52%, but with optimal modern medical therapy the 1-year mortality was approximately 7%.

Etiology

Heart failure is most common in persons with certain risk factors, especially coronary heart disease, cigarette smoking, hypertension, overweight, and diabetes. The most common causes of HF are ischaemic heart disease (like myocardial infarction) and hypertension.

This is a more comprehensive list of conditions which can cause heart failure:

In those who already have heart failure, many precipitators can trigger an episode of decompensation. This occurs most commonly due to excessive fluid intake or a myocardial infarction. However, any of the above mentioned causes can precipitate decompensation, in addition to:

  • Excessive salt intake
  • Physical or emotional stress
  • Infection

Pathophysiology

When the cardiac output becomes insufficient to supply the needs of the body, the body will try to increase the cardiac output by compensatory mechanisms. These compensatory mechanisms achieve the goal of increasing cardiac output initially and to some extent, but they’re deleterious in the long run. For this reason, many of the pharmacological targets in heart failure inhibit these compensatory mechanisms.

The most important compensatory mechanisms clinically are the neurohumoral systems, most importantly the sympathetic nervous system activation, the activation of RAAS, and the release of natriuretic peptides. Over time and as the result of these stimuli, myocardial remodelling occurs. This is also detrimental, as it causes the chambers to dilate, change their geometry, and accumulate fibrosis, causing systolic and/or diastolic dysfunction. Inhibition of the neurohumoral systems is shown to significantly decrease myocardial remodelling.

The body’s compensatory responses overshoot as well. The sympathetic nervous system gets so strongly activated that the vasoconstriction eventually decreases CO. The compensatory increase in heart rate increases the energy expenditure, increasing the demand for CO. Activation of RAAS causes fluid retention, which (after the Frank-Starling mechanism has been maxed out) worsens the myocardial contractility.

Types and classification

There are three types of heart failure, depending on the EF:

  • Heart failure with reduced ejection fraction (HFrEF) – EF < 40%
  • Heart failure with mildly reduced or mid-range ejection fraction (HFmrEF) – EF 40 – 50%
  • Heart failure with preserved ejection fraction (HFpEF) – EF > 50%

HFrEF was historically called “systolic heart failure” while HFpEF was called “diastolic heart failure”, which reflects the underlying pathophysiology of each type. This distinction is important because each type have different underlying cause, pathophysiology, and most importantly, response to therapy. It is only in HFrEF that research has shown that medical therapy reduces both morbidity and mortality. For HFpEF, science is not yet at a place where we know the optimal medical therapy.

We can also classify HF according to the severity. This is accomplished with the New York Heart Association (NYHA) classification of heart failure:

  • NYHA class I
    • Symptoms of heart failure only in excessive exercise, or no symptoms of heart failure at all
  • NYHA class II
    • Symptoms of heart failure during normal daily activity like climbing stairs, making food, etc.
  • NYHA class III
    • Symptoms of heart failure during easy daily activity like dressing, walking on flat surface
  • NYHA class IV
    • Symptoms present during rest

We can also artificially divide heart failure into “right” and “left” heart failure, depending on which ventricle is the offender, but this distinction offers no advantage. Failure of one side of the heart quickly causes failure of the other, and so in most patients, symptoms of both “right” and “left” heart failure is seen.

Clinical features

Some people with heart failure experience a stable course throughout their life, with no worsening of their symptoms. However, most people with HF experience at least one episode of worsening. This is called an acute decompensation or an exacerbation, and may occur over days or weeks or months. From there, the condition may continue to worsen or return to the baseline condition before the worsening.

The most characteristic symptoms of heart failure are dyspnoea, orthopnoea, and fatigue, although a wide variety of symptoms may occur. The most characteristic signs are elevated jugular venous pressure, lower extremity pitting oedema, and pulmonary crackles on auscultation.

Other clinical features include:

  • General features
  • Features of left-sided heart failure
  • Features of right-sided heart failure
    • Congestive symptoms dominate
    • Peripheral pitting oedema
    • Jugular vein distension
    • Hepatosplenomegaly
    • Jaundice
    • Ascites
    • Loss of appetite

Diagnosis and evaluation

Physical examination

Physical examination is important for determining the volume status of the patient. A patient with peripheral pitting oedema, pulmonary crackles on auscultation, elevated jugular pressure, hepatosplenomegaly and/or a recent increase in body weight has fluid overload (hypervolaemia).

Assess the functional capacity

Assessing the functional capacity of the patient is important, as it allows us to stratify the patient into one of the four NYHA types. This is based on the patient history and/or a simple walk test.

Chest X-ray

Chest X-ray is essential for the evaluation of HF, as it’s a quick and low-impact tool which can give a lot of information. The most common findings are pulmonary congestion, pleural effusion, enlarged heart, etc.

Echocardiography

Echocardiography is also essential for the evaluation of HF, as it can directly show the systolic and diastolic function of the heart. It also gives us the information necessary to determine whether the HF is HFrEF, HFmrEF, or HFpEF, which is important for prognosis and treatment.

Echo can also give valuable information on the etiology. It can show valvular abnormalities, hypertrophy, regional hypo/akinesia (due to infarction), etc.

Natriuretic peptides

The most important biomarkers for heart failure are the natriuretic peptides, NT-proBNP and BNP. Of these, NT-proBNP is the most used. These biomarkers have high negative predictive value, so NT-proBNP in a normal range makes HF very unlikely. They also have prognostic value and value in monitoring progression.

The level of NT-proBNP correlates with the severity of the HF, and a high value is associated with a worse prognosis. However, while it’s a sensitive biomarker, it’s not a specific one. NT-proBNP can be elevated in other conditions, like renal failure, pulmonary embolism, etc. NT-proBNP can be false negative in HFpEF.

Brain natriuretic peptide (BNP) is a hormone produced in the ventricles (initially discovered in the brain, hence the name). It increases natriuresis (sodium excretion in the kidneys) in response to pressure and volume overload in the ventricles, which occurs in heart failure.

Electrolytes

Hyponatraemia is a common feature in heart failure, due to reduction in circulating blood volume from oedema. This increases ADH secretion, giving hyponatraemia. Hyponatraemia also increases due to natriuretic peptide secretion.

ECG

There are no specific ECG findings for heart failure, but the ECG is abnormal in more than 90% of cases of LV systolic dysfunction. Findings may include conduction abnormalities, arrhythmias, ST-T changes, etc.

Treatment of HFrEF

Objectives

The objectives of treatment in heart failure are to reduce the number of hospitalisations, increase survival and quality of life, and slow the progression of the disease while reducing the symptoms. For HFrEF, we know of many medications which achieve all these objectives.

For HFrEF, the four most important drugs are beta blockers, ACE inhibitors or ARNIs, MRAs, and SGLT2 inhibitors. The higher the dose, the greater the benefit. These drugs are initiated in a low dose which is then increased until the maximum tolerated dose by the patient is reached. Usually, side effects like bradycardia, hypotension, and/or hyperkalaemia prevent further increase. Previously, one would gradually titrate the doses up over many months, but nowadays it's recommended to titrate up over 4-6 weeks. The patient taking all four of these drugs in the maximum tolerated dose is called optimal medical therapy (OMT). Unfortunately, many heart failure patients are using suboptimal doses of medications.

Non-pharmacological treatment

Patient education is important. When they know the signs and symptoms of worsening HF, they can seek a physician earlier and treat the problem earlier rather than waiting until they’re in such poor condition that they’re admitted to the hospital, which unfortunately occurs in many cases due to poor education.

Self-weighing regularly is important. During an exacerbation patients become fluid overloaded, and one of the earliest signs of this is rapid unintentional weight gain.

Reducing risk factors for HF and cardiovascular disease is important, and includes weight loss, normalising blood pressure, alcohol restriction, smoking cessation, and physical activity.

To avoid fluid overload, salt and water restriction is often used. Guidelines recommend avoiding excessive salt and fluid intake, but where exactly to draw the line of what’s excessive is difficult. The evidence of the efficacy in salt and water restriction is weak. The European Society of Cardiology recommends eating less than 6 g salt daily and “avoiding excessive fluid intake”, with consideration of fluid restriction of 1,5 – 2 L daily in those with severe HF.

Any infection can cause a HF exacerbation. As such, taking the pneumococcal, COVID-19, and seasonal influenza vaccines is recommended.

Cardiac rehabilitation is as important for all types of HF as it is for AMI, as it improves quality of life and reduces mortality.

Iron deficiency, especially with anaemia, worsens outcomes in HF. Patients should be regularly screened for iron deficiency and anaemia, and managed with IV iron supplementation if present.

Beta blockers

Beta blockers block the sympathetic nervous system overactivation which occurs in HF and is indicated in all patients with HF (class I recommendation). Extended-release (ER) metoprolol (metoprolol depot, Selo-Zok®), carvedilol, and bisoprolol are most frequently used. The target dose of ER metoprolol is 200 mg once daily.

However, beta blockers cause a temporary decrease in myocardial contractility, before the contractiliy later increases. For this reason, it's recommended to titrate up the dose of other medications before beta blockers.

ACE inhibitors

ACE inhibitors block the RAAS overactivation which occurs in HF and is indicated in all patients with HF (class I recommendation). If ACE inhibitors are not tolerated due to angioedema or dry cough, ARBs should be used as an alternative.

Ramipril is most frequently used. The target dose is 5 mg twice daily.

Mineralocorticoid receptor antagonists

MRAs like spironolactone block the aldosterone overproduction which occurs in HF and is indicated in all patients with HF who remain symptomatic despite beta blocker and ACE inhibitor treatment (class I recommendation).

Angiotensin receptor-neprilysin inhibitor

Sacubitril is a first-in-class neprilysin inhibitor. Neprilysin is an enzyme which degrades the vasoactive peptides (ANP, BNP) in the body. These peptides are beneficial in heart failure. Neprilysin inhibitors must be combined with an ARB, the combination of which is known as angiotensin receptor-neprilysin inhibitor (ARNI).

The only ARNI available at the time of writing is Entresto® (valsartan/sacubitril). In the 2021 guidelines it is recommended as a replacement for ACE-I (class IB recommendation) as part of optimal medical therapy, as they’re better than ACE inhibitors alone. Because ARNIs contain an ARB, they can’t be combined with an ACE inhibitor and must therefore replace it. However, they may be combined with MRAs.

Diuretics

Diuretics, most often loop diuretics like furosemide and bumetanide, are important in the management of heart failure, as fluid overload and congestion is a frequent problem. Research has not shown diuretics to improve survival in HF, but it does alleviate symptoms and reduce hospitalisations.

As such, diuretics are only recommended when there are signs or symptoms of congestion. They may also be used regularly to prevent fluid overload in patients who are prone to this.

Bumetanide has better and more predictable absorption from the GI tract, which is beneficial in heart failure as backward congestion can significantly impair absorption of furosemide.

Overuse of diuretics may cause prerenal AKI and/or a decline in cardiac output, and so care must be used.

SGLT2 inhibitors

SGLT2 inhibitors like dapagliflozin and empagliflozin were initially discovered as treatment of diabetes mellitus. Nowadays we have evidence that these drugs are effective in treating HF as well, even in the absence of DM.

As of the 2021 guidelines, SGLT2 inhibitors are recommended (class 1 recommendation) for the treatment of HFrEF as it reduces risk of hospitalisation and death.

Potassium binders

An integral part of HF treatment is RAAS blockade, which increases the risk for hyperkalaemia. In the case of hyperkalaemia, rather than stopping these medications, other measures to prevent hyperkalaemia should be tried first. A potassium-reduced diet is always indicated.

Nowadays so-called potassium binders, drugs which bind to potassium in the food and prevents absorption, may also be used. These may be patiromer calcium or sodium zirconium cyclosilicate.

Cardiac resynchronisation therapy

CRT is indicated for patients with HF and left bundle branch block. Having a LBBB and heart failure worsens the heart failure because of the desynchronised contraction of the right and the left ventricle. CRT may be considered for other conduction blocks as well.

Implantable cardioverter-defibrillator

Primary prevention of sudden cardiac death with an ICD is indicated in all HF with an underlying ischaemic etiology and EF < 35% despite optimal medical therapy. This is a class I recommendation, as it’s effective in reducing SCD. In those with a non-ischaemic etiology, ICD implantation is a class IIa recommendation.

However, in reality, this is evaluated on a case-by-case basis, as ICDs are expensive and not risk-free to implant. The patient's estimated life expentancy must also be taken into account, as ICDs are rarely used for those with estimated short life expectancy (< 1 year).

Digoxin

Digoxin is nowadays one of the last-line interventions for HF, as we know that it increases the risk for sudden cardiac death and the therapeutic range is very narrow. It may be considered in patients who remain symptomatic despite all the above mentioned therapies.

Heart transplant

Heart transplantation is a last-line intervention for HF. It’s recommended for patient with medical and device-refractory advanced HF who have no contraindications to transplant.

Treatment of HFpEF

While there is much research on effective medications for HFrEF, the same cannot be said for HFpEF. For HFpEF and HFmrEF, we have much less research on effective treatment. For these patients, the only interventions which are known to be effective are:

  • Controlling hypertension
  • Controlling tachycardia
  • Treating fluid retention
  • Preventing myocardial ischaemia
  • Exercise training

In fact, exercise training is the only intervention known to consistently improve quality of life in HFpEF. Recently, SGLT2 inhibitors were also shown to improve prognosis, and have become a class I recommendation for use in HFpEF.

Notably, ACE inhibitors, ARBs, ARNIs, and beta blockers have shown to have very little to not benefit in HFpEF. Ongoing trials will reveal whether other drugs are useful for HFpEF.