Endothelins (ET-1,-2,-3) are molecules produced by the endothelium acting as vasoconstrictors and mitogenic factors. In patients with heart failure, their plasma concentrations are increased, and their concentration is proportional to the severity of the disease [14]. Endothelins promote vasoconstriction, inflammation, fibrosis, and hypertrophy in the pulmonary and systemic vasculature.

Plasma ET-1 levels are elevated in patients who have cardiomyopathy or chronic heart failure, and they correlate with severity and prognosis. In particular, the degree of plasma elevation of endothelin correlates with the magnitude of alterations in cardiac hemodynamics and functional class.

Endothelin receptor antagonists cause vasodilation via increased nitric oxide and prostacyclin production, which have antiproliferative properties. Nitric oxide and prostacyclin reduce ET-1 activity by inhibition of pre-pro-ET production. Increased levels of ET-1 have been demonstrated in patients with pulmonary hypertension (PAH) and Eisen­menger syndrome and after cardiopulmonary bypass in children with PAH.

The renin-angiotensin-aldosterone axis exerts many effects on the cardiovascular system (Table 39.2). Neural connexion of the brain and kidneys is stimulated by low sodium, decreased perfusion, and increased alpha-adrenergic activity. It can affect the juxtaglomerular apparatus, increasing renin-protease transforming angiotensinogen to angiotensin I, which is converted within the endothelial cells (particularly concentrated in the lungs) to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is the most potent vasoconstrictor increasing vascular resistance in stress situations (especially in hypovolemia) and affecting the adrenal cortex, increasing aldosterone production, which increases reclaiming of sodium and water. Its major role is to maintain the circulating volume status [15].

To influence the RAAS axis, ACE inhibitors are used in children with congenital heart defects. Several studies in ventricular level shunts have suggested a possible benefit from ACE inhibitors, presumably due to their relatively selective effect of afterload reduction, increasing systemic blood flow and reducing pulmonary blood flow [16]. A few small studies reported mixed results with respect to the use of ACE inhibitors in patients with single ventricle physiology. Perioperative ACE inhibitor treatment was shown to decrease the severity and duration of pleural effusions after bidirectional cavopulmonary anastomosis surgery [17], although no benefit on exercise performance or cardiac autonomic activity after the Fontan operation was observed [18].

Insufficiency of the hypothalamic-pituitary-adrenal axis after pediatric cardiac surgery has been observed, best described as a critical illness related to corticosteroid insufficiency (CIRCI). Together with derangement of other axes, it is considered one of the causes of low cardiac output syndrome in the postoperative period. Many causes of this phenomenon were proposed: brain hypoperfusion, central hypothalamus and pituitary gland insufficiency, tissue resistance to adrenocorticotropic hormone (ACTH), adrenal dysfunction, cyanosis, and tissues immaturities. The CIRCI is diagnosed by a delta cortisol level of 9 g/dl (after 250 g cosyntropin) or a random total cortisol of 10 g/dl. To treat adrenal dysfunction, adrenal function prior to hydrocortisone administration should be tested. Hydrocortisone should be considered in patients with septic shock who have responded poorly to fluid resuscitation and vasopressor agents [19]. Treatment of adrenal dysfunction reduces inotrope requirements, which may reduce low output syndrome in intensive care units and morbidity and improve the neurodevelopmental outcome. The detrimental effects of glucocorticoid therapy should always be considered.

Vasopressin is released by the hypothalamus as a result of baroreceptor, osmotic, and neurohormonal stimuli. It normally maintains body fluid balance, vascular tone, and regulates contractility. Heart failure causes a paradoxical increase in AVP. The increased blood volume and atrial pressure in heart failure suggest inhibition of vasopressin secretion, but it does not occur. This phenomenon is related to SNS and RAAS activation overriding the volume and low-pressure cardiovascular receptors and osmotic vasopressin regulation causing an increase in AVP secretion. It contributes to the increased systemic vascular resistance (V1 receptors) and to renal retention of fluid (V2 receptors) [20]. Stimulation of V1 receptors can also cause vasoconstriction of the peripheral vessels, platelet aggregation, and adrenocorticotrophic hormone stimulation. Low-dose arginine infusion initiated in the operating room after complex neonatal cardiac surgery was associated with decreased fluid resuscitation and catecholamine [21].

Growth hormone is secreted by the anterior pituitary and mediates its effects via insulin growth factor-1 (IGF-1). Levels of growth hormone are elevated in patients with heart failure as well as in patients with cardiac cachexia. In particular, a recent study showed that treating heart failure patients with growth hormone may result in normalization of the abnormal immunological responses and in suppression of the excessive activation of biochemical apoptotic pathways in the human cardiovascular system.

Thyroid hormones are stimulated by TSH anterior pituitary secretion. The many actions of thyroid hormones on cardiovascular system are exerted mainly by triiodothyronine (T3). These effects can be divided into genomic and extragenomic actions. T3 binds to the nuclear receptors and activates many genes corresponding to key myocardial functions: myosin heavy chain (MHC), sarcoplasmic reticulum Caţţ-ATPase (SERCA2) and its inhibitor phospholamban (affecting cardiac contractile function and diastolic relaxation), voltage-gated Kt channels, b1-adrenergic receptor, guanine nucleotide regulatory proteins, adenylate cyclase, NAt/Kt-ATPase, and Na/Ca exchanger [22]. The main cardiovascular effects of T3 are increased cardiac contractility, reduction of afterload, reduction of vascular resistance, chronotropic effects (increased heart rate), and increased sodium reabsorption, and water improves the atrial filling pressure. All of this increases cardiac output. Low TH levels are common in critical illness of multiple causes, e.g., sepsis, myocardial infarction, and after surgery. Euthyroid sick syndrome is common in pediatric cardiac surgery intensive care units, and the typical physiologic disruptions are reduced, non-pulsatile TSH secretion and T3 reduced by increased conversion of T4 rT3 vs. T3. The total T3  <  0.6 nmol/l can predic: longer mechanical ventilation, longer O₂ supplementation, longer ICU stay, greater use of epinephrine, and greater use of furosemide [23]. Main causes of hypothyroidism in congenital heart surgery population are hemodilution, iodine skin preparations, dopamine administration, and secondary hypothyroidism related to abnormal cerebral perfusion. Transient secondary hypothyroidism occurs in a large number of children after cardiopulmonary bypass operations [24]. The postoperative increase in cardiac output and systolic ventricular function variables was significantly greater after tri-iodothyronine treatment. Patients given tri-iodothyronine after longer cardiopulmonary bypass operations showed improvement in cardiac function. It was also observed after a modified Fontan procedure [25]. T3 has genomic effects that maintain endothelial integrity, such as angiotensin receptors in vascular smooth muscle cells (VSMC). This supports the hypothesis that the vasculature is a principal target for T3 action. T3 decreases resistance in peripheral arterioles. Extragenomic actions include modulating cellular metabolic activities, such as glucose and amino acid transport, ion fluxes at the level of the plasma membrane, and mitochondrial gene expression and function.

Low T3 is also frequently associated with a catabolic pattern characterized by lower insulin levels, higher cortisol levels, lower plasma lipid levels, lower body weight, and lower albumin levels. Furthermore, in asymptomatic and mildly symptomatic patients with non-ischemic left ventricular dysfunction, T3 values and the T3/T4 ratio are linked to both the severity of the left ventricular dysfunction and clinical status, being progressively lower in patients with more depressed ventricular dysfunction (and higher brain natriuretic peptide values).