NPC-QIC Registry data for prescribing angiotensin-converting enzyme inhibitors in patients with single ventricle physiology after stage-I Norwood palliation were reported by Hansen et al. ^{Reference Hansen, Brown and Hanke1} A cohort of 2180 patients was retrospectively analysed; 38% of the patients received angiotensin-converting enzyme inhibitors. The indications for prescribing angiotensin-converting enzyme inhibitors and the decision-making process of the participating institutions were not reported. The analysis of the non-prospective or randomised study showed no reduction in mortality, no improvement of ventricular dysfunction, or atrioventricular valve insufficiency. The authors’ final conclusion was that despite limited evidence of benefit for patients with hypoplastic left heart syndrome, prescription of angiotensin-converting enzyme inhibitors during interstage is still common. Our comment created as a mini review is focused on the immediate aroused question; what to expect from angiotensin-converting enzyme inhibitors following stage-I Norwood palliation? It would be too easy, and contrary to our own opinion, to reiterate that angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers as a whole are not effective in the single ventricle pathophysiology ^{Reference van der Bom, Winter and Bouma2} or in treating a right ventricle failure in a systemic position. ^{Reference Hsu, Zak and Mahony3} However, taking into account the predominant cardiovascular (patho) physiological regulation of newborns and young infants by circulating catecholamines, ^{Reference Ross, Daniels, Schwartz, Hannon, Shukla and Kaplan4} no real improvement is to be expected from angiotensin-converting enzyme inhibitor monotherapy, especially not in the fragile interstage after stage-I Norwood palliation. ^{Reference Schranz and Voelkel5} The aim of drug therapy during stage-I Norwood palliation in hypoplastic left heart syndrome is usually not the treatment of an already failing systemic right ventricle, but to prevent such a single ventricular failure. Another important purpose for using an angiotensin-converting enzyme inhibitor is to balance pulmonary (Qp) and systemic (Qs) blood flow by influencing pulmonary (Rp) and systemic (Rs) vascular resistances without endangering the perfusion pressures of the vital organs. In addition, oxygen consumption of the myocardium and the entire body should be reduced, since oxygen supply and the adaption to physical demands according to stage-I Norwood palliation are limited. ^{Reference Schranz and Voelkel5} Compared to adults, the fetal and neonatal heart has a less developed sympathetic nerve system and thus a lower intracellular storage of norepinephrine within nerve endings of the myocardium, while the adrenergic receptors are already fully developed. ^{Reference Friedman, Pool, Jacobowitz, Seargren and Braunwald6} Thus, the myocardial sensitivity to the adrenergic neurotransmitters released from adrenal gland and the aortal paraganglia (Zuckerkandl) is comparatively high. ^{Reference Friedman, Pool, Jacobowitz, Seargren and Braunwald6} The essential catecholamine for cardiovascular regulation in newborns and infants is norepinephrine. ^{Reference Friedman, Pool, Jacobowitz, Seargren and Braunwald6,Reference Nederend, Jongbloed, de Gues, Blom and ten Harkel7} The response to stress, even wall stress, hypoxaemia, and hypercapnia of the hypersensitive neonatal myocardium can be further intensified by the additional release of catecholamines. Almost decades ago, it was shown that infants with left-to-right shunts and preserved myocardial function, but with an activated neurohumoral axis, only ß-blockers improved heart failure scores, but not the treatment with angiotensin-converting enzyme inhibitors, especially not in combination with diuretics and digoxin. ^{Reference Buchhorn, Ross and Hulpke-Wette8} The profile of this neurohumoral activation was comparable to that of adults with myocardial pump failure. ^{Reference Buchhorn, Ross and Hulpke-Wette8} Haemodynamic and oxygen transport data from the early nineties, ^{Reference Gidding and Bessel9} which were obtained invasively during cardiac catheterisation, clearly show that infants with an isolated ventricular septal defect who received digoxin (D) and diuretics (D) had significantly higher heart rates and reduced oxygen saturation in the upper caval vein. The decreased systemic vein saturation was explained by a reduced systemic cardiac output. In addition, no beneficial effect on left-to-right shunt-dependent pulmonary congestion, heart rate, oxygen delivery, and consumption were shown. The result of this “double DD” (diuretics and digoxin) treatment, often combined with “diet” (fluid restriction), to a “triple D” treatment was growth failure in the young patients. ^{Reference Buchhorn, Ross and Hulpke-Wette8,Reference Ravishankar, Zak and Williams10} In terms of an additional angiotensin-converting enzyme inhibitor prescription, such a strategy means a potential risk of kidney failure. ^{Reference Fabiano, Carnovale and Gentili11}

It has to be considered that the activated neurohumoral axis in newborns and infants is best and most easily reflected in the children’s heart rate and heart rate variability. Fetuses and newborns with hypoplastic left heart syndrome almost generally have decreased heart rate variability. ^{Reference Nederend, Jongbloed, de Gues, Blom and ten Harkel7,Reference Buchhorn, Hulpke-Wette, Nothroff and Paul12} Any additional stress, such as surgical interventions like a simple sternotomy, has substantial impact on the autonomic nervous system and worsens somatic and cognitive development, especially if it occurs in the neonatal period. ^{Reference Nederend, Jongbloed, de Gues, Blom and ten Harkel7,Reference Buchhorn, Hulpke-Wette, Nothroff and Paul12} In young patients, heart failure can mimick a norepinephrine storm. ^{Reference Hasking, Esler, Jennings, Burton, Johns and Korner13} Contrary to the catecholamines-driven myocardial function in young patients, in adults, increased sympathetic nervous system activity has contributed to the recognition that beta-blockers are useful in the treatment and prophylaxis of heart failure by blocking the cascade of failing. Taking into account of the age- and disease-related pathophysiologic and molecular knowledge in context of the pharmacological profile of the medical drugs, it remains a mystery why ß-blockers, specifically a differentiated ß-blocker therapy, are rarely or not at all used in children and especially infants with cardiovascular circumstances as after stage-I Norwood palliation. ^{Reference Schranz and Voelkel5,Reference Buchhorn, Hulpke-Wette, Hilgers, Bartmus, Wessel and Bürsch14,Reference Esmaeili and Schranz15} Regardless of the surgical/interventional stage-I Norwood palliation technique used, the following interstage remains a fragile shunt vitium with a functional single (right) ventricle. Angiotensin-converting enzyme inhibitor reduces preferentially the Rs and can thus have a favourable effect of Qp/Qs without significant impact on systemic blood pressure if an intravascular volume depletion is excluded. In terms of side effects, the combination of angiotensin-converting enzyme inhibitor treatment with ß-blockers, ideally with a highly specific ß1-adrenoceptor -antagonist, ^{Reference Schranz and Voelkel5,Reference Esmaeili and Schranz15} can prevent the risk of angiotensin-converting enzyme inhibitor induced and counteracting sympathetic stimulation, including renal renin release. ^{Reference Holmer, Hense, Danser, Mayer, Riegger and Schunkert16} The highly sensitive and easily verifiable surrogate parameter heart rate, which reflects oxygen consumption and cardiac filling time, can best be monitored at least by the ratio of systolic–diastolic time interval. ^{Reference Mienert, Esmaeili and Steinbrenner17} At the Children’s Heart Center in Giessen, a retrospective evaluation over a 5-year period demonstrated that all patients following a Hybrid stage-I Norwood palliation received ß-blockers. From a cohort of 51 newborns with hypoplastic left heart syndrome and variants, 90% of the patients received bisoprolol or 10% the non-specific ß-blocker propanolol, which was indicated for atrial tachyarrhythmias. ^{Reference Mienert, Esmaeili and Steinbrenner17} With regard to the risk–benefit ratio, but also taking into account the compliance of the parents, the long-acting, highly specific ß1-adrenoreceptor blocker bisoprolol has been the ß-blocker of our choice for more than a decade now, administered in a single dose of 0.1–0.2 mg/kg once per day. In 70% of the newborns, the similarly long-acting tissue angiotensin-converting enzyme inhibitor lisinopril was also prescribed, but in no patient without an additional ß-blocker therapy. The dose of lisinopril was even between 0.1 and 0.2 mg/kg once per day. The basic prerequisite for using the angiotensin-converting enzyme inhibitor is that there is no risk of obstruction of the aortic flow and that the coronary and cerebral perfusion pressure is not endangered. ^{Reference Mienert, Esmaeili and Steinbrenner17} As mentioned earlier, the clinical parameters to demonstrate the effectiveness of the treatment were a lowest effective heart rate, a normal respiratory rate, and body weight gain up to comprehensive stage II. The therapeutic goal was to achieve a heart rate of less than 120/min, better one of less than 110/min during sleep of the patient. Side effects such as hypotension were not observed due to the avoidance of intravascular volume depletion, in particular by avoiding diuretics in almost all patients. It was mandatory to educate the parents about the administration of medication and to observe their baby’s respiratory rate during sleep, oral feeding behaviour, and body weight gain. In addition, fixed professional controls were advised in close at short intervals of 8–10 days were recommended. The clinical data were re-checked, and systolic and diastolic blood pressures values and SaO2 were measured by experienced nurses. Despite such a close and in generally effective surveillance, which included periodic echocardiographic examinations, ^{Reference Mienert, Esmaeili and Steinbrenner17,Reference Alphonso, Angelini and Barron18} one patient suffered cardiogenic shock and died of neurological sequalae. From our point of view, zero mortality during the interstage is not achievable regardless of any drug treatment. However, the stage-I Norwood palliation survivors deserve respect for the best, especially long-term outcome. Minimising early stressors, especially neonatal stress factors, therefore plays an important role. However, this point is still overly neglected due to the focus on mortality. For the stage-I Norwood palliation-interstage and thus in turn also for the long-term outcome, adequate nutrition and tailored concurrent medication are essential, which promote cardio-vascular economy and in particular cardiac proliferation. Both of these can best be achieved by providing beta-adrenoceptor-blockers with a low risk but high efficacy profile. Waiting for evidence-based large cohort studies is unrealistic. With regard to drug treatment as a prophylactic and preventive measure, age- and disease-specific treatment is required. ^{Reference Esmaeili and Schranz15} Thus, infants with hypoplastic left heart syndrome differ fundamentally from DCM patients with regard to the local cardiac stem cell population and thus in terms of reduced regeneration potential of the right ventricular hypoplastic left heart syndrome myocardium. ^{Reference Traister, Patel and Huang19} If one continues to consider the control of the cytokinesis of cardiomyocytes by ß-adrenergic receptors and the inhibition of cardiac proliferation by catecholamine-related stress, but instead induced cardiomyocyte hypertrophy, then infants with complex CHDs and high cardiac wall-stress, particularly of the RV, are especially vulnerable when cardiomyocytes are highest in mitosis and cytokinesis. ^{Reference Liu, Zhang and Ammanamanchi20–Reference Mollova, Bersell and Walsh22} Regulation of the cardiomyocyte milieu, simply through the use of beta-blockers, is overdue particularly in the interests of young patients currently affected. Therefore, the use of a beta-blockers make sense far beyond the blocking effect of the neuro-humoral axis for preventing arrhythmias and influencing haemodynamics. However, instead of ß-blockers, diuretics and digoxin are consistently discussed, as if they were the substances of choice. Especially digoxin, since a retrospective analysis seemed to show that the use of digoxin on discharge after stage-I Norwood palliation resulted in reduced interstage mortality. ^{Reference Brown, Mangeot and Anderson23} Digoxin usually is used for patients after stage-I Norwood palliation assuming that it not only has a positive inotropic but also negative chronotropic effects. However, contrary to ß-blockers as bisoprolol, digoxin has a narrowed therapeutic range with less impact on heart rate, but increase of Rs. Some editorial comments summarise the use of digoxin for interstage single ventricle patients that possibly some goes wrong. ^{Reference George24} Secondary analysis of the Pediatric Heart Network Infant Single Ventricle Trial Public Use Dataset has shown a probably negative effect of digoxin on patient’s growth during the interstage period. ^{Reference Truong, Menon and Lambert25} When comparing digoxin with the specific ß1-recptor blocker, bisoprolol, has multiple advantages due to its effectiveness and safety profile. In contrast to a ß-blocker, the effectiveness of angiotensin-converting enzyme inhibitor therapy cannot be proven so easily by a surrogate parameter, such as heart rate. In the interstage after stage-I Norwood palliation, only side effects, such as angiotensin-converting enzyme inhibitor-related hypotension, can actually be recorded particularly in a volume-depleted patient particularly if the angiotensin-converting enzyme inhibitor is adequately dosed. Acute efficiency may only be based on SaO2 values related to blood pressure amplitude and urine output. Since infants have a low risk of myocardial fibrosis, ^{Reference Nakano, Siomos and Garcia26} therapy with angiotensin-converting enzyme inhibitors is therefore not prescribed to prevent cardiac fibrosis, but rather to reduce a possible AV-valve regurgitation ^{Reference Castro, Khalil and Schwender27} or to influence an excessively high SaO2 that will become caused by an unbalanced Qp/Qs and resulting increased Rs. The generalised conclusion by Hansen et al ^{Reference Hansen, Brown and Hanke1} that prescribing angiotensin-converting enzyme inhibitors is still common despite limited evidence of efficacy in the interstage could misinterpret that angiotensin-converting enzyme inhibitor is generally unsuitable for treating infants during the interstage after stage-I Norwood palliation. Breaking down complex mechanisms into relative rough results and referring them to a single intervention (here angiotensin-converting enzyme inhibitor therapy) will not sufficiently exclude a possible benefit of this therapy, especially since it should be part of a therapeutical concept and not as a single therapeutic principle. It should be avoided that a good drug like the angiotensin-converting enzyme inhibitor enalapril for single ventricle physiology ^{Reference Hsu, Zak and Mahony3} or the ß-blocker carvedilol for the treatment of children with heart failure ^{Reference Shaddy, Boucek and Hsu28} gets again a bad reputation. In summary, our core statement is that every drug treatment, particularly after stage-I Norwood palliation, requires an individualised indication that takes into account the age- and disease-related (patho)physiological and molecular characteristics as well as the pharmacological ingredient profile of the drugs to be used. ^{Reference Esmaeili and Schranz15,Reference Garcia, Beatty and Nakano29} This is especially true because large cohort studies are lacking and will likely never be made possible. In view of the vulnerable interstage after stage-I Norwood palliation and the harmful effects of endogenous but also exogenously caused high catecholamine concentrations with profound acute and chronic effects on the cardiac function as well as somatic and cognitive development, we recommend the use of a long-acting and highly specific ß1-adrenoreceptor blocker bisoprolol for almost all patients with stage-I Norwood palliation. However, there is no monotherapy with an angiotensin-converting enzyme inhibitor. ^{Reference Schranz and Voelkel5,Reference Esmaeili and Schranz15,Reference Mienert, Esmaeili and Steinbrenner17} This is consistent with the knowledge that infants with hypoplastic left heart syndrome may have adrenoreceptor genotypes associated with higher catecholamine release and sensitivity and then lower event-free survival after stage-I Norwood palliation. ^{Reference Ramroop, Manase and Lu30} Excessive catecholamine activation is postulated to an adverse affected cardiovascular adaption after the Norwood surgery. ^{Reference Ramroop, Manase and Lu30} Despite the lack of prospective controlled studies but many years of experience with the beneficial therapy regimen, especially with bisoprolol for patients with hypoplastic left heart syndrome in the interstage after stage-I Norwood palliation, our recommendations have to be assessed in the interest of the currently affected newborns with hypoplastic left heart syndrome receiving stage-I Norwood palliation. The next step for a structured approach is the subsequent translation of the accumulated knowledge into an improved prescription of cardiovascular drugs. Novel diagnostic tools as receptor genotyping ^{Reference Garcia, Beatty and Nakano29,Reference Ramroop, Manase and Lu30} or based on single cell analysis ^{Reference Stuart, Butler and Hoffman31,Reference Nicin, Abplanalp and Schänzer32} will play a key role in the management of accurate and tailored pharmacological therapy in paediatric cardiovascular diseases.