Introduction - Professor Richard Kirk 2023

Professor Richard Kirk
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Definition & Classification
A definition and classification of heart failure describes heart failure (HF) as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. The classification is dependent upon the ejection fraction. In contrast the pediatric community generally uses the guidelines published in 2019 "Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement from the American Heart Association" (see below) based on the morpho functional phenotypes of dilated, hypertrophic, restrictive, non compaction and arrhythmogenic cardiomyopathy.

There are two main physiologies that lead to heart failure in children. They often coexist but there some are differences in their primary management.

  1. Most pediatric heart failure patients present with symptoms of congestion due to reduced myocardial contractility documented by a reduced ejection fraction on echocardiography. This clinical presentation is commonly referred to as "Dilated Cardiomyopathy" (DCM) but increasingly it called "Heart Failure with Reduced Ejection Fraction" (HFrEF). The causes of DCM include genetic mutations, inflammation (myocarditis), toxins (e.g. chemotherapy), metabolic disorders (e.g. Propionic acidemia), congenital heart disease (e.g. anomalous coronary arteries), persistent arrhythmias (e.g. persistent junctional re-entrant tachycardia) and nutritional deficiencies (e.g. Vitamin D). However many causes remain unknown.

  2. Heart failure may occur when there is impairment of diastolic filling, often in combination with hypertrophy which may lead to obstruction of the left ventricle outflow tract. It is referred to as "Restrictive Cardiomyopathy" (RCM) or "Heart Failure with preserved Ejection Fraction" (HFpEF). Many patients remain asymptomatic until the late stages of the disease when the reduction in cardiac output is manifested by lethargy and often right sided congestion due to the high left atrial pressure. It may also present with syncope or cardiac arrest. Causes of RCM include genetic disorders (e.g. sarcomeric and desmin mutations), infiltrative disorders (e.g. mucopolysaccharidosis), endocardial fibroelastosis (usually in association with CHD), iron overload, transplant cardiac allograft vasculopathy and the consequences of myocardial fibrosis following cancer treatment with chemotherapy and thoracic radiotherapy.

The effects of decompensated heart failure are a reduction in cardiac output coupled with an increased metabolic demand, which leads to pulmonary ± systemic venous congestion. Congestion is a consequence of the natural compensatory mechanisms resulting from circulatory failure. These mechanisms, from our evolutionary past, were designed to deal with circulatory failure as a result of intravascular depletion either from blood loss due to injury or fluid loss from dehydration. Circulatory failure from pump failure, as a consequence of modern longevity, diet and lifestyle, would be rare in our ancestors. The compensatory mechanisms thus designed to reduce the impact of a reduction in circulating volume, through fluid retention, tachycardia, increasing myocardial contractility and vasoconstriction, become counterproductive when the underlying cause is cardiac (pump) failure itself.

An understanding of these compensatory mechanisms is useful in defining the rationale for therapy but control of the cardiovascular system is extremely complex and further reading advised. Neurohormonal control begins with the autonomic nervous system and baroreceptors in the aortic arch, carotid body and atria which respond to blood pressure and atrial stretch. In the case of heart failure these sensors trigger the sympathetic nervous system (SNS) and inhibit the parasympathetic nervous system (PNS).

  • The principal mediator of SNS is the adrenergic neurotransmitter norepinephrine. This triggers β1 receptors (principally in the heart) to increase the heart rate and contractility, β2 receptors (principally in the peripheral circulation) causing vasodilation and α1 receptors (principally on the peripheral circulation) causing vasoconstriction. α1 receptors are more common than β2 receptors so the net effect of norepinephrine is vasoconstriction. Activation of the SNS also triggers norepinephrine and epinephrine release from the adrenal gland - both thus acting in this capacity as hormones. α1 receptors are less sensitive to epinephrine than β2 receptors thus at low levels, epinephrine causes vasodilation but at higher levels the α1 receptors are activated and override the β2 receptors thus vasoconstriction then predominates. Constriction of the renal arteries, increases renin production - a major component of the Renin-Angiotensin-Aldosterone System (RAAS). Renin converts angiotensinogen, in the liver, to angiotensin I and then angiotensin-converting enzyme (ACE) cleaves two peptides to form angiotensin II, a potent vasoconstrictor. Angiotensin II also stimulates the adrenal gland to produce aldosterone. Both angiotensin II and aldosterone act on the nephron to cause fluid retention.
  • The vasoactive peptides Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are produced in atria and ventricles in response to myocyte stretch. Along with other vasoactive peptides e.g. Endothelin-1, their effects counter activation of the RAAS system by causing vasodilation and increased sodium and water excretion. The concentration of vasoactive peptides is controlled by a balance between production and breakdown - Neprilysin is an endopeptidase that cleaves a variety of vasoactive peptides including natriuretic peptides (ANP and BNP), reducing their effectiveness to counter the SNS & RAAS activation.

The net effect of these neurohumoral responses is to attempt to maintain arterial pressure through arterial vasoconstriction and increase ventricular filling by venous constriction and increased blood volume. However these haemodynamic changes contribute to adverse LV remodelling, worsening ventricular function and a vicious circle of increased neurohormonal activation. The final consequences are fibrosis, maladaptive hypertrophy and dilation, oxidative stress and arrhythmogenesis.

Treatment of cardiac failure is thus aimed at reducing these maladaptive responses, principally by targeting the neurohumoral response. Diuretics reduce congestion and β blockers mitigate the effects of SNS activation. RAAS activation is reduced by an angiotensin-converting enzyme inhibitor (ACEi) e.g. captopril, or an angiotensin receptor blocker (ARB) e.g. valsartan, and a mineralocorticoid receptor antagonist (MRA) e.g. spironolactone. Neprilysin inhibitors e.g. sacubitril are available and usually used in combination with an angiotensin receptor blocker (ARNi) e.g. sacubitril/valsartan (Entresto). Newer classes of drugs are also emerging such as the SGLT2 inhibitors (sodium-glucose transporter-2) e.g. Dapagliflozin, which impair the absorption of sodium and glucose in the kidney and enhance diuresis and Vericiguat which stimulates soluble Guanylate Cyclase (sGC) to produce cyclic Guanosine Monophosphate (cGMP) which plays a role in vasodilation and acts as an anti-proliferation and anti-fibrotic agent.

The treatment of heart failure can be divided into 3 phases:

  1. Acute: maintenance of an adequate cardiac output and preservation or restoration of end organ function are the priorities - this may paradoxically require catecholamine infusion, ventilation and mechanical cardiac support
  2. Transition: assuming the cardiac failure is controlled then cautious transition to oral therapies is indicated with close monitoring to prevent deterioration of function. In this period additional therapies e.g. necessity for an ICD should be considered and preparations made for safe discharge
  3. Chronic: it is essential to ensure appropriate clinic visits and adjustments of medication with growth to reduce the likelihood of cardiac decompensation

Heart failure presentation in children is often acute and many present late in the disease process. "Rescue" therapy with inotropes and mechanical support may be required to maintain life while other therapies are instituted. Heart failure presents many treatment challenges due to different underlying mechanisms, the lack of clinical trials necessitating the use of adult data despite the differences in the etiology and the medication pharmacokinetics, and the lack of recent guidelines and considerable practice variation between cardiologists and institutions.
These web pages are a practical guide to the clinical management of children with heart failure. They are based on the clinical practice of our team, led by Dr Rachele Adorisio. However clinical management of patients is always the responsibility of the attending doctor and the information presented here are not a substitute for seeking advice from more experienced colleagues.
Further Reading
Last Updated: May 2023
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