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Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD)., Methods: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point., Results: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (N=187) or enalapril (N=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P =0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children., Conclusions: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312., Competing Interests: Dr Shaddy is a consultant for Novartis, American Regent Inc., CRI Biotech, and Rocket Pharmaceuticals. S. Solar-Yohay is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Garito is an employee of Novartis Pharma AG, Basel, Switzerland, and owns its shares. Dr Zhang is an employee of Novartis, Shanghai, China. M. Kocun is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Canter holds a Data and Safety Monitoring Board chairman position at the Mayo Research Foundation and has participated on an advisory board for CareDx. Dr Rossano reports receiving consulting fees from Bayer, Enzyvant, Merck, AskBio, American Regent, and Bristol Myers Squibb. Dr Halnon reports receiving consulting fees from Novartis and grants or contracts to her institution from Novartis. Dr Daly reports grants or contracts for the TEAMMATE multicenter trial of post–heart transplant immunosuppression (different patient population; Novartis holds the nonexclusive rights to one of the drugs that was studied [everolimus] but Novartis did not provide any support for the TEAMMATE study) and for American Heart Association/Enduring Hearts (ancillary studies to the TEAMMATE study in heart transplant recipients [different drug and patient population]); consulting fees from AstraZeneca (consultation regarding a different pediatric heart failure drug and possible study in children); payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from CareDx (pediatric research board related to the use of Allosure Heart in transplant recipients); leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid in ISHLT program committee 2021–2023 (developed ISHLT scientific sessions program) and AST trainee and young faculty community of practice chair (developed content for fellows and young faculty as part of the AST). Dr Singh is co-chair of the end point adjudication committee at Novartis for PANORAMA-HF. Dr Senni reports receiving consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Bayer, Merck, MSD, Abbott, AstraZeneca, Boehringer, Vifor, and Novo Nordisk. Dr Anjos reports an unpaid position as a board member of the pediatric cardiology section of the Portuguese Medical Association. Dr Bonnet reports consulting fees from Novartis paid to his institution for being the steering committee member for the current study and participating in an advisory board for the current study. The other authors declare no competing interests.

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles in heart failure are understood in adult patients, pediatric norms vary with age, complicating interpretation. Notably, the emergence of multi-system inflammatory syndrome in children (MIS-C) has highlighted the importance of these markers not only in the detection of acute heart failure but also as a marker of disease severity and even as a differential diagnosis tool. This review summarizes current knowledge on the utility of BNP and NT-proBNP in pediatric patients. Their unique physiology, including circulation and compensation mechanisms, likely influence BNP and NT-proBNP release, potentially even in non-heart failure states. Factors such as dynamic volemic changes accompanying inflammatory diseases in children may contribute. Thus, understanding the nuanced roles of BNP and NT-proBNP in pediatric populations is crucial for the accurate diagnosis, management, and differentiation of cardiac and non-cardiac conditions.

Background: Radiofrequency catheter ablation (RFCA) of the slow pathway in atrioventricular nodal reentry tachycardia (AVNRT) is associated with high efficacy and low risk of total perioperative or late atrioventricular block. This study aimed to evaluate the efficacy, safety, and feasibility of slow-pathway RFCA for AVNRT using a zero-fluoroscopy approach., Methods: Data were obtained from a prospective multicenter registry of catheter ablation from January 2012 to February 2018. Consecutive unselected patients with the final diagnosis of AVNRT were recruited. Electrophysiological and 3-dimensional (3D) electroanatomical mapping systems were used to create 3D maps and to navigate only 2 catheters from the femoral access. Acute procedural efficacy was evaluated using the isoproterenol and/or atropine test, with 15-min observation after ablation. Each case of recurrence or complication was consulted at an outpatient clinic during long-term follow-up., Results: Of the 1032 procedures, 1007 (97.5%) were completed without fluoroscopy. Conversion to fluoroscopy was required in 25 patients (2.5%), mainly due to an atypical location of the coronary sinus (n = 7) and catheter instability (n = 7). The mean radiation exposure time was 1.95 ± 1.3 min for these cases. The mean fluoroscopy time for the entire study cohort was 0.05 ± 0.4 min. The mean total procedure time was 44.8 ± 18.6 min. There were no significant in-hospital complications. The total success rate was 96.1% (n = 992), and the recurrence rate was 3.9% (n = 40)., Conclusion: Slow-pathway RFCA can be safely performed without fluoroscopy, with a minimal risk of complications and a high success rate., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The growing number of adult patients after the Fontan operation requires regular surveillance tests in specialized centers., Aims: Our study aimed to evaluate the current practice of care for Fontan patients in Poland using a multicenter survey., Methods: Eight centers were included in the study including 5 adult congenital heart disease (ACHD) and 3 pediatric centers for adolescents. To compare the centers and facilitate interpretation of results, the Fontan Surveillance Score (FSS) was developed. The higher score is consistent with better care, with a maximum of 19 points., Results: We included in the study 398 Fontan patients (243 adults and 155 adolescents [aged 14-18 years]). The median FSS was 13 points with variability between centers (interquartile range 7-14 points). Centers providing continuous care from the pediatric period until 18 years of age achieved a higher FSS compared to ACHD centers (median: 14 points vs. 12 points; P <0.001). Most of the patients, both in the ACHD (82.3%) and pediatric centers (89%), were seen annually and had a physical examination, electrocardiogram, and echocardiogram performed at each visit. However, we observed unsatisfactory utilization of tests identifying early stages of Fontan circulation failure (cardiopulmonary exercise tests, cardiac magnetic resonance, liver biochemistry and imaging, detection of protein-losing enteropathy)., Conclusions: Our results showed that there is no unified surveillance approach for Fontan patients in Poland. The practice of care for adults differs from that of adolescents.

Cases of severe heart damage in patients presenting with multisystem inflammatory syndrome in children are one of the most intriguing phenomena during the coronavirus disease of 2019 pandemic. The pathophysiology of myocardial changes in the course of this syndrome has not been fully understood yet. We present a case of a child with multisystem inflammatory syndrome in children and with cardiac changes corresponding to Takotsubo syndrome.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m ( n  = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml ( n  = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals., Competing Interests: H. G. A. reports fees for lectures and member of advisory boards for Bayer and Janssen. D. D. I. reports the University of Colorado contracts with Acceleron, Actelion/Janssen, Altavant, Bayer, Eli Lilly, GlaxoSmithKline, and United Therapeutics for D. D. I. to be a consultant and perform clinical trials. S. M. reports consultancy from Actelion/Janssen and GlaxoSmithKline. J. P. reports fees for lectures and/or consultancy from Actelion/Janssen. T. P. reports fees for lectures, member of advisory boards, and research grants from Actelion/Janssen, Bayer, GlaxoSmithKline, and Pfizer. H. Y. reports research grants and lecture fees from Actelion, AbbVie, and Teijin Pharma; research grants from Tanabe‐Mitsubishi; lecture fees from Bayer, GE Healthcare Japan, Merck Sharp and Dohme, Novo Nordisk, Nihon Seiyaku, Nihon Shinyaku, Pfizer, and Termo. G. C., M. G., S. L., A. R., S. S., S. W., G. W. are employees and stockholders of Bayer AG. D. B. is a steering committee member for Eli Lilly and Company, and steering committee and advisory board member for Actelion Pharmaceuticals, Bayer, and Novartis. M. B. reports fees for lectures and/or consultancy from Acceleron, Actelion/Janssen, AOP, Bayer, Eli Lilly, GlaxoSmithKline, and Gossamer; unrestricted research grants from Actelion and Bayer. The remaining authors declare no conflict of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

During the winter months of 2020/2021 a wave of multisystem inflammatory syndrome in children (MIS-C) emerged in Poland. We present the results of a nationwide register aiming to capture and characterise MIS-C with a focus on severity determinants. The first MIS-C wave in Poland was notably high, hence our analysis involved 274 children. The group was 62.8% boys, with a median age of 8.8 years. Besides one Asian, all were White. Overall, the disease course was not as severe as in previous reports, however. Pediatric intensive care treatment was required for merely 23 (8.4%) of children, who were older and exhibited a distinguished clinical picture at hospital admission. We have also identified sex-dependent differences; teenage boys more often had cardiac involvement (decreased ejection fraction in 25.9% vs. 14.7%) and fulfilled macrophage activation syndrome definition (31.0% vs. 15.2%). Among all boys, those hospitalized in pediatric intensive care unit were significantly older (median 11.2 vs. 9.1 years). Henceforth, while ethnicity and sex may affect MIS-C phenotype, management protocols might be not universally applicable, and should rather be adjusted to the specific population., (© 2021. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Hypoplastic left heart syndrome (HLHS) was first described by Lev in 1952, but it was not until 1958 that it received a name from Noonan and Nadas. For the next several decades, the defect was considered untreatable. In 1979, William Norwood and his colleagues from Boston initiated a program to evaluate staged surgical management for infants with HLHS. The Norwood operation has became a milestone in the effective palliation for neonates born with HLHS. Today, the Norwood procedure is the first step of a three-stage heart surgery aimed at creating a new circulatory pathway (i.e., the Fontan pathway)., (© 2021 Wiley Periodicals LLC.)

Competing Interests: Competing interests: None declared.

The COVID-19 pandemic has impacted healthcare systems worldwide. Little is known about the impact of the pandemic on medical and psycho-social aspects of children with rare diseases such as pulmonary arterial hypertension and their parents. The study is based on children registered in The Database of Pulmonary Hypertension in the Polish Population and a parent-reported survey deployed during the first 6 months of the pandemic. The questionnaire consisted of six question panels: demographic data, fear of COVID-19, General Anxiety Disorder-7 (GAD-7), social impact of pandemic, patients' medical status, and alarming symptoms (appearance or exacerbation). Out of 80 children registered, we collected 58 responses (72.5% response rate). Responders (parents) were mostly female ( n = 55; 94.8%) at a mean age of 40.6 ± 6.9 years. Patients (children) were both females ( n = 32; 55%) and males with a mean age of 10.0 ± 5.1 years. Eleven (19%) children had symptoms of potential disease exacerbation. Eight parents (72.7%) decided for watchful waiting while others contacted their GPs or cardiologists ( n = 6; 54.5%). Three children had to be hospitalized (27.3%). Most planned hospitalizations (27/48; 56.2%) and out-patient visits (20/35; 57.1%) were cancelled, delayed, or substituted by telehealth services. Among the participating parents, the study shows very high levels of anxiety ( n = 20; 34.5%) and concern ( n = 55; 94.8%) and the need for detailed information (52; 89.6%) regarding COVID-19 and medical service preparedness during the pandemic. The COVID-19 pandemic has influenced child healthcare and caused high levels of anxiety among parents.

Competing Interests: Competing interests: None declared.

Atrial septal defect is the most common congenital heart lesion in adults. Although atrial septal defect closure is recommended in those with right heart enlargement or paradoxical embolism, data informing such indications in adults are quite limited. This population has many unique characteristics and needs. In recent years, significant progress has been made with regard to diagnostic modalities that facilitate the diagnostic workup of these patients. However, the decision‑making process, especially in selected adult patients population (advanced age, various concomitant diseases, poor LV function [both systolic and diastolic], pulmonary hypertension, concomitant arrhythmias or multiple defects, or deficient rims) is still not easy. Available data are predominantly focused on imaging endpoints and short‑term morbidity and mortality rather than long‑‑term. The evidence base for outcomes with or without defect closure comes from various studies with different observation periods. Moreover, the clinical experience in diagnosing and treating that subgroup of patients is inhomogeneous between individual physicians (cardiologists, imaging specialists, operators) and between small and large experience centers. In the view of the above, the joint group of experts from the Association of Cardiovascular Interventions and the Grown‑Up Congenital Heart Disease Section of the Polish Cardiac Society developed the following consensus opinion in order to standardize the principles of diagnosis, indications for treatment, methods of performing procedures, and tenets of postoperative care in Poland.

We report the successful use of levosimendan in the treatment of heart failure in a patient with the univentricular heart. The presented case was atypical because our patient had systemic right ventricle. To our knowledge, it is the first reported such case with intermittent levosimendan administration as an effective treatment and bridge to successful heart transplant in a patient with functionally univentricular heart.

We present the results from the pediatric arm of the Polish Registry of Pulmonary Hypertension. We prospectively enrolled all pulmonary arterial hypertension (PAH) patients, between the ages of 3 months and 18 years, who had been under the care of each PAH center in Poland between 1 March 2018 and 30 September 2018. The mean prevalence of PAH was 11.6 per million, and the estimated incidence rate was 2.4 per million/year, but it was geographically heterogeneous. Among 80 enrolled children (females, n = 40; 50%), 54 (67.5%) had PAH associated with congenital heart disease (CHD-PAH), 25 (31.25%) had idiopathic PAH (IPAH), and 1 (1.25%) had portopulmonary PAH. At the time of enrolment, 31% of the patients had significant impairment of physical capacity (WHO-FC III). The most frequent comorbidities included shortage of growth ( n = 20; 25%), mental retardation ( n = 32; 40%), hypothyroidism ( n = 19; 23.8%) and Down syndrome ( n = 24; 30%). The majority of children were treated with PAH-specific medications, but only half of them with double combination therapy, which improved after changing the reimbursement policy. The underrepresentation of PAH classes other than IPAH and CHD-PAH, and the geographically heterogeneous distribution of PAH prevalence, indicate the need for building awareness of PAH among pediatricians, while a frequent coexistence of PAH with other comorbidities calls for a multidisciplinary approach to the management of PAH children.

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1802). The authors have no conflicts of interest to declare.

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared.

In 1708, Adam Christian Thebesius, a 22-year-old student at Leiden University, presented his graduate thesis, Disputatio medica inauguralis de circulo sanguinis in corde . More than a doctoral dissertation, this groundbreaking work opened new channels into the study of the human coronary venous system. Thebesius' theory about the vascular communication between the coronary arteries and the chambers of the heart helped to advance understanding of hemodynamic principles and to clarify the physiologic pathways of the coronary circulation. The following article-the third in a trilogy about Lower Silesian scientists-provides an overview of the life story and achievements of this Silesian physician and innovator, whose name was immortalized in 2 cardiac eponyms: the Thebesian veins and the Thebesian valve., (© 2019 by the Texas Heart® Institute, Houston.)

Purpose: During incremental atrial pacing in patients with atrioventricular nodal reentrant tachycardia, the PR interval often exceeds the RR interval (PR > RR) during stable 1:1 AV conduction. However, the PR/RR ratio has never been evaluated in a large group of patients with pacing from the proximal coronary sinus and after isoproterenol challenge. Our study validates new site of pacing and easier method of identification of PR > RR., Material and Methods: A prospective protocol of incremental atrial pacing from the proximal coronary sinus was carried out in 398 patients (AVNRT-228 and control-170). The maximum stimulus to the Q wave interval (S-Q = PR), SS interval (S-S), and Q-Q (RR) interval were measured at baseline and 10 min after successful slow pathway ablation and after isoproterenol challenge (obligatory)., Results: The mean maximum PR/RR ratios at baseline were 1.17 ± 0.24 and 0.82 ± 0.13 (p < 0.00001) in the AVNRT and controls respectively. There were no PR/RR ratios ≥1 at baseline and after isoproterenol challenge in 12.3% of the AVNRT group and in 95.9% of the control group (p < 0.0001). PR/RR ratios ≥1 were absent in 98% of AVNRT cases after slow pathway ablation/modification in children and 99% of such cases in adults (P = NS). The diagnostic performance of PR/RR ratio evaluation before and after isoproterenol challenge had the highest diagnostic performance for AVNRT with PR/RR > = 1 (sensitivity: 88%, specificity: 96%, PPV-97%, NPV-85%)., Conclusions: The PR/RR ratio is a simple tool for slow pathway substrate and AVNRT evaluation. Eliminating PR/RR ratios ≥1 may serve as a surrogate endpoint for slow pathway ablation in children and adults with AVNRT., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patients with complex congenital heart defects may have different hemodynamic prob-lems which require a variety of interventional procedures including angioplasty which involves using high-pressure balloons. After failure of conventional balloon angioplasty, cutting balloon angioplasty is the next treatment option available. The purpose of this study was to evaluate the safety and efficacy of cutting balloon angioplasty in children with different types of congenital heart defects., Methods: Cutting balloon angioplasty was performed in 28 children with different congenital heart defects. The indication for cutting balloon angioplasty was: pulmonary artery stenosis in 17 patients, creating or dilatation of interatrial communication in 10 patients, and stenosis of left subclavian artery in 1 patient., Results: In the pulmonary arteries group there was a significant decrease in systolic blood pressure (SBP) in the proximal part of the artery from the average 74.33 ± 20.4 mm Hg to 55 ± 16.7 mm Hg (p < 0.001). Distal to the stenosis there was an increase in SBP from 19.8 ± 3.82 mm Hg to 30.3 ± ± 13.3 mm Hg (p = 0.04). This result remained constant in the follow-up. In atrial septal defect/fenestra-tion group, cutting balloon angioplasty was performed after an unsuccessful classic Rashkind procedure. After cutting balloon angioplasty there was a significant widening of the interatrial communication., Conclusions: Cutting balloon angioplasty is a feasible and effective treatment option in different con-genital heart defects.

Nearly 50 years after the pioneering procedure performed by Francis Fontan and Eugene Baudet, which has saved the lives of thousands of children, there are still more questions than answers regarding therapeutic management. The complex pathophysiology of Fontan circulation, the lack of clear guidelines, and the shift in the care of such patients from pediatric cardiological and cardiac surgical centers to ones dealing with adult patients, cause new threats. This paper outlines the fundamental issues related to the pathophysiology of Fontan circulation and reviews the literature on the methods of treating complications characteristic of this group of patients.

The year 2016 was the 180th anniversary of Wilhelm Ebstein's birth and the 150th anniversary of his description of the congenital tricuspid valve malformation that came to be known as Ebstein anomaly. We present a brief history of the life and work of Dr. Wilhelm Ebstein. Despite his distinguished career, he is seemingly forgotten in his own birthplace. We include a review of the relevant historical medical literature.

Aim: Evaluation of possibilities of percutaneous closure of recanalised left superior caval vein after total cavopulmonary connection., Methods and Results: We analysed 19 patients after total cavopulmonary connection catheterised because of a sudden increase of desaturation. In four of them, the recanalisation of the left superior caval vein was identified. For this reason, the balloon occlusion tests of the veins were made temporarily. In all cases, the haemodynamic status of patients did not change, and arterial oxygen saturation increased significantly. Thus, using different types of implants, these veins were closed effectively in all patients. During the short-term follow-up, the effectiveness of treatments and constantly maintaining a high level of saturation were confirmed., Conclusions: Meticulous investigation of unclear causes of desaturation in cyanotic patients after Fontan completion is necessary. Almost all causes of desaturation, including recanalised additional left superior caval vein, can be effectively treated percutaneously.

Given the increasing popularity of aliskiren, particularly in combination with angiotensin converting enzyme inhibitor (e.g. enalapril), it is important to determine whether its use in combination with these agents is associated with potentially life threatening safety events. Analytical methods for the simultaneous determination of both drugs in plasma and urine utilized in clinical studies on efficacy and safety have not been fully described in the literature. In this work, a new, fast and reliable method using a digitally controlled microextraction by packed sorbent (eVol(®)-MEPS) followed by ultra-high performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS) was developed and validated to quantify an aliskiren, enalapril and its active metabolite in both human plasma and urine. Chromatographic separation was accomplished on a Poroshell 120 EC-C18 column with a gradient elution system consisting of 0.1% formic acid in water and acetonitrile (1.5min of total analysis). Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. This assay method has been fully validated in terms of selectivity, linearity, accuracy, precision, stability, recovery and matrix effect. The developed method can be applied to the routine determination of selected compounds in human plasma and urine and can be useful to elucidate the mechanisms of the potential risks triggered by the combination of aliskiren and enalapril as well as its active metabolite enalaprilat., (Copyright © 2014 Elsevier B.V. All rights reserved.)