Functional regeneration of dilated cardiomyopathy by transcatheter bilateral pulmonary artery banding: first-in-human case series.

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart transplantation (HTx) in children. Surgical pulmonary artery banding (PAB) is used worldwide to achieve functional heart regeneration and remodelling. Case summary: We report for the first-time successful bilateral transcatheter implantation of bilateral pulmonary artery flow restrictors in a case series of three infants with severe DCM based on left-ventricular non-compaction morphology associated with Barth syndrome in one and a non-classified syndrome in another. Functional cardiac regeneration was observed in two patients after almost 6 months of endoluminal banding, and in the neonate with Barth syndrome already after 6 weeks. Accompanied by an improvement in functional class (Class IV to Class I), the left ventricular end-diastolic dimensions z-score normalized, as did the elevated serum brain natriuretic peptide levels. A listing for HTx could be avoided. Discussion: Percutaneous bilateral endoluminal PAB is a novel minimally invasive approach that enables functional cardiac regeneration in infants with severe DCM and preserved right ventricular function. Interruption of the ventriculo-ventricular interaction, the key mechanism for recovery, is avoided. Intensive care for these critically ill patients is reduced to a minimum. However, investing in 'heart regeneration to avoid transplantation' remains a challenge.

A novel large in-frame FBN1 deletion causes neonatal Marfan syndrome.

Neonatal Marfan syndrome (nMFS) is a rare and severe form of Marfan syndrome (MFS) with a poor prognosis, that presents with a highly variable phenotype, particularly regarding skeletal, ocular, and cardiovascular manifestations. Mutations in the fibrillin-1 (FBN1) gene are known as the principal cause of MFS and MFS-related syndromes. Here, we report on a full-term female neonate with postnatal characteristics suggestive of nMFS, including severe cardiovascular disease resulting in cardiorespiratory failure and death by 4 mo of age. We identified a novel large genomic in-frame deletion of FBN1 exons 42-45, c.(5065 + 1_5066 - 1)_(5545 + 1_5546 - 1)del. Large FBN1 in-frame deletions between exons 24 and 53 have been associated with severe MFS. The deletion in our patient differs from the FBN1 region associated with the majority of nMFS cases, exons 24-32.

Applicability of a Host-mediated In Vivo/In Vitro Model in Screening for the Carcinogenic Potential of Chemicals.

Based on a publication of Tomasetti and Vogelstein in 2015, in which the risk of cancer development is postulated to be just one-third caused by genetic predisposition and environmental factors, it seemed worth focusing again on the value of test systems for screening chemicals for their carcinogenicity. This review aims to firstly summarize data on a host-mediated in vivo/in vitro assay developed by our working group to screen the tumorigenic potential of chemicals. Subsequently, in this article the importance and advantages of host-mediated in vivo/in vitro assays in general have been compared with in vivo and in vitro tests. The applicability of the host-mediated in vivo/in vitro assay system within broad screening strategies is discussed. The main intention of this review is to stimulate developments of newer approaches in the field of carcinogenic testing.

Heart failure therapy based on interventricular mechanics and cardio-vascular communications.

The heart should not be divided in right and left, whether in health nor in disease. However, the morphological and functional differences between the right and left ventricle should be known and the impact of the ventricle's position considered. Further, the parameters beyond heart rate, contractility, pre- and afterload guaranteeing a sufficient systemic cardiac output have to be integrated in therapeutic measures; preferentially the influence of interventricular mechanics. Despite of recent developments of specific drug therapies, heart failure is associated with a high rate of morbidity and mortality in children. During the progression of heart failure, pulmonary vascular disease is the consequence or the reason for further failing. Clinical symptoms are associated with congestion and low cardiac output at rest or exercise. Improved understanding of the pathophysiological mechanisms particularly of ventricular failure has resulted in the development of innovative therapies that target atrial/ventricular/arterial interactions. Recent advances in interventional and surgical approaches provide promising new strategies to deal with right and left ventricular deterioration. These techniques may delay listing for heart and (heart-) lung transplantation or even make redundant in individual cases. The beneficial effects of these ventricular interaction strategies are mainly based on the mechanics of the interventricular septum and improvement of systolic and diastolic ventricular performance.

Hypoplastic Left Heart: Stage-I Will be Performed Interventionally, Soon.

The hypoplasia of left-sided heart structures shows great variability and complexity. What the many variants have in common is that their heart structures are neither fully developed before nor after birth. Fetuses and newborns require an individual therapy depending on anatomy and function of the heart. Fetal interventions focus on improving left heart structures by catheter-based interventions and maternal hyperoxygenation which promotes growth as the left ventricular preload and blood flow within the cavity increase. Stage-I management of newborns with single ventricle physiology is usually based on the Norwood/Sano surgery or the Hybrid approach. Two more steps are required to ultimately achieve a Fontan circulation. Some centers also use the Hybrid approach for subsequent Norwood operation beyond the neonatal period. After the Hybrid approach, a comprehensive stage-II or corrective surgery is performed, the latter if a bi-ventricular circulation is possible. With progressively improved catheter-based interventions, particularly ductal stenting and manipulations of the atrial septum, the next advance is to develop a bespoke flow restrictor that can be easily inserted into the branches of the pulmonary artery. The main goal is to avoid complex heart operations under general anesthesia, followed by substantial intensive care in the neonatal period, especially for patients with complex heart defects. Based on the current state of the art of surgical treatment of hypoplastic left heart syndrome and variants with the Norwood surgery or the Hybrid approach, our main focus is on an alternative percutaneous transcatheter technique in the sense of a completely non-surgical stage-I approach.

Cardiovascular Drug Therapy during Interstage After Hybrid Approach: A Single-Center Experience in 51 Newborns with Hypoplastic Left Heart.

BACKGROUND: Newborns with hypoplastic left heart (HLH) are usually palliated with the Norwood procedure or a hybrid stage I procedure. Hybrid is our preferred approach. Given the critical relationship between stage I, interstage, and comprehensive stage II or advanced biventricular repair, we hypothesized that appropriate drug treatment is a significant therapeutic cornerstone, especially for the management of the high-risk interstage. METHODS: We report a single-center observational study addressing the cardiovascular effects of, in particular, oral ß-blockers and the additional use of angiotensin-converting enzyme (ACE) and mineralocorticoid inhibitors. RESULTS: In total, 51 newborns-30 with HLH syndrome (HLHS) and 21 with HLH complex (HLHC)-with a median bodyweight of 3.0 kg (range 1.9-4.4; nine with bodyweight ≤ 2500 g) underwent an uneventful "Giessen hybrid approach" using a newly approved duct stent. All patients were discharged home with a single, double or triple therapy consisting of ß-blockers, ACE and mineralocorticoid inhibitors; 90% of the patients received bisoprolol, 10% received propranolol, 72% received lisinopril, and 78% received spironolactone. Resting heart rate decreased from 138 bpm (range 112-172; n = 51) at admission to 123 bpm (range 99-139; n = 51) at discharge and 110 bpm before stage II/biventricular repair/heart transplantation (range 90-140; n = 37) accompanied by favorable bodyweight gain. No side effects were evident. CONCLUSION: In view of drug risk/benefit profiles, as well as the variable morphology and hemodynamics, the highly selective ß1-adrenoceptor blocker bisoprolol is our preferred drug for treatment of HLHS/HLHC in the interstage. We avoid using ACE inhibitor monotherapy and exclude potential risks for coronary and cerebral perfusion pressure beforehand.

Axillary artery access for stenting of aortic coarctation in a 1.2 kg premature newborn with malignant systemic hypertension: a case report.

BACKGROUND: Axillary artery access is rarely used for demanding percutaneous transcatheter interventions. However, there are many clear advantages. CASE SUMMARY: We describe this attractive approach in a 3-week-old premature neonate (bodyweight of 1.2 kg) with severe aortic coarctation. Percutaneous transcatheter intervention was performed with analgo-sedation and local anaesthesia; and a coronary stent was placed with a low fluoroscopy time of 2 min. Malignant systemic hypertension (160/54 mmHg) was effectively treated without any residual blood pressure gradient, with the aim for definitive surgery with stent resection and end-to-end anastomosis at the age of 6-12 months. DISCUSSION: Axillary artery access is an attractive, alternative approach to treat newborns and premature infants with low body weight with complex heart diseases.

Percutaneous Pulmonary Valve Implantation Based on Minimally Invasive Direct Coronary Bypass Surgery.

Approximately 5% of percutaneous pulmonary valve implantations (PPVIs) are at risk for coronary compression. Therefore, PPVI is contraindicated if coronary anomalies and tested coronary flow impairment are observed. Simultaneous right ventricular outflow tract ballooning and coronary angiography are mandatory elucidating contraindications for PPVI. We present the case of a 22-year-old woman who had Rastelli repair with chronic right heart failure. Weighing the risk of several offered surgical options, she underwent successful PPVI after minimally invasive direct coronary artery bypass procedure.

Short-term decrease of left atrial size predicts clinical outcome in patients with severe aortic stenosis undergoing TAVR.

OBJECTIVES: We investigated whether transcatheter aortic valve replacement (TAVR) results in a short-term decrease in left atrium (LA) size and whether such decrease may predict patients' clinical outcome. BACKGROUND: Increased LA size is a hallmark of severe aortic stenosis (AS) and is associated with adverse patients' cardiovascular outcome. Whether TAVR may lead to a decrease in LA size is not known. METHODS AND RESULTS: Hundred and four patients with severe symptomatic AS and dilated LA undergoing TAVR were enrolled. LA volume was assessed by echocardiography before and shortly after TAVR (median time: 7 days). Composite rate of death and hospitalization for acutely decompensated heart failure (HF) was recorded and clinical status was assessed through NYHA-class evaluation at 12 months median follow-up. After TAVR, 49 patients (47%) demonstrated a decrease in LA volume. Despite a similar baseline NYHA class, patients with decrease in LA size had significant better improvement in clinical status respect to patients with unvaried LA size (NYHA post: 1.2 ± 0.6 vs. 1.8 ± 1.1, p = .001; NYHA reduction: -1.6 ± 0.9 vs. -0.9 ± 1.0, p = .002, respectively). Moreover, these patients had a significantly reduced rate of death or HF-hospitalization (4 vs. 29%, p = .001) and a significantly longer event-free-survival from Kaplan-Meier curves (p = .003). COX regression analysis showed that, among echocardiographic parameters, decrease in LA size was an independent predictor of clinical outcome (HR: 0.149, CI: 0.034-0.654, p = .012). CONCLUSIONS: The lack of decrease in LA size shortly after TAVR is associated with significantly higher rates of death and HF-hospitalization, as well as with impaired improvement in clinical status during long-term follow-up.

Comparison of outcomes between complete and incomplete congenital duodenal obstruction.

BACKGROUND: Congenital duodenal obstruction (CDO) can be complete (CCDO) or incomplete (ICDO). To date there is no outcome analysis available that compares both subtypes. AIM: To quantify and compare the association between CCDO and ICDO with outcome parameters. METHODS: We retrospectively reviewed all patients who underwent operative repair of CCDO or ICDO in our tertiary care institution between January 2004 and January 2017. The demographics, clinical presentation, preoperative diagnostics and postoperative outcomes of 50 patients were compared between CCDO (n = 27; atresia type 1-3, annular pancreas) and ICDO (n = 23; annular pancreas, web, Ladd´s bands). RESULTS: In total, 50 patients who underwent CDO repair were enrolled and followed for a median of 5.2 and 3.9 years (CCDO and ICDO, resp.). CCDO was associated with a significantly higher prenatal ultrasonographic detection rate (88% versus 4%; CCDO vs ICDO, P < 0.01), lower gestational age at birth, lower age and weight at operation, higher rate of associated congenital heart disease (CHD), more extensive preoperative radiologic diagnostics, higher morbidity according to Clavien-Dindo classification and comprehensive complication index (all P ≤ 0.01). The subgroup analysis of patients without CHD and prematurity showed a longer time from operation to the initiation of enteral feeds in the CCDO group (P < 0.01). CONCLUSION: CCDO and ICDO differ with regard to prenatal detection rate, gestational age, age and weight at operation, rate of associated CHD, preoperative diagnostics and morbidity. The degree of CDO in mature patients without CHD influences the postoperative initiation of enteral feeding.

Percutaneous pulmonary valve implantation (PPVI) in non-obstructive right ventricular outflow tract: limitations and mid-term outcomes.

BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) has been established as a safe and effective alternative to surgery treating patients with a failing pulmonary valve conduit. Nevertheless, the majority of patients in need of a valve have a native, non-obstructive right ventricular outflow tract (RVOT). The current approved stent-valves have a balloon-expandable design. Pre-stenting of the RVOT to create a landing zone and also protect the valve stability is usually mandatory; large, non-obstructive RVOTs need pre-stenting to reduce the RVOT-diameter for a balloon-expandable valve implantation. METHODS: A retrospective study design was used to analyze the medium-term outcome after PPVI in a series of 26 patients with native or reconstructed RVOT. RESULTS: PPVI was successfully performed in all, but 1 (96%). Within the follow-up of a minimum of 2 years, the percutaneous implanted valves remained competent; a significant pressure gradient was not detected. Furthermore, no PPVI-related complications such as endocarditis, migration or stent fractures were observed. The electrocardiogram at rest, in particular the QRS duration remained unchanged immediate post-PPVI as well as at medium-term follow-up of 24 months. However, ventricular arrhythmias were documented in 3 patients (11.5%); all patients were successfully treated with antiarrhythmic drugs, utilizing metoprolol. A trial of an invasive catheter based RVOT-ablation in one remained unsuccessful; pre-stented RVOT did not allow a successful intervention. CONCLUSIONS: Medium-term follow-up showed excellent results of the mechanical valve function. PPVI utilizing balloon-expandable stent-valves in a native RVOT remains an off-label use. Despite our encouraging results, advanced manipulations of the patched or native RVOT might be associated with significant ventricular arrhythmias. There is a need for less invasive RVOT reduction devices.

Acute therapy of newborns with critical congenital heart disease.

Critical congenital heart disease (cCHD) is the most common reason for acute cardiac failure in the neonatal period. cCHD, defined by systemic low cardiac output (LCO) and requiring surgery or catheter-based intervention in the first year of life, has an incidence of approximately 15% of CHD and is responsible for up to 25% fatalities of newborn infants. Clinical deterioration develops in most cases due to rapid closure of the ductus arteriosus (DA). Early diagnosis and immediate treatment determinate beneficial outcome. Critical CHD can be classified in duct-dependent systemic flow, duct-dependent pulmonary flow and transposition of the great arteries. The latter two manifest themselves in oxygen resistant cyanosis, whereas CHD with duct-dependent systemic flow may present itself with cardiogenic shock, which can be difficult to differentiate from other causes of shock such as sepsis. Besides prostaglandin therapy for reopening the arterial duct, a balanced parallel pulmonary and systemic circulation should be a therapeutic goal. In CHD with duct-dependent systemic flow a decrease of pulmonary resistance should be avoided; therefore inadequate oxygen therapy, hyperventilation and alkalosis due to excessive treatment of acidosis, should be averted. Volume therapy should be performed carefully. In CHD with duct-dependent pulmonary flow, pulmonary resistance can be decreased, in case of poor pulmonary flow systemic resistance should be increased, mild alkalosis is recommended. Intense volume therapy is in most cases necessary, except if a restrictive atrial communication is present. In addition to intensive care measures, an arsenal of catheter- and surgery-based procedures need to be hold available as back-up for emergency procedures. Transcatheter interventions are nowadays decisive. Atrial-septostomy was the first and still the most utilized high-urgency procedure; DA-stenting is used in prostaglandin-refractory duct stenosis. In the presence of critical aortic valve stenosis, palliation consists of balloon valvuloplasty. In critical aortic coarctation with myocardial failure and no response to prostaglandin, palliative balloon angioplasty may be the method of choice as bridging for corrective surgery.

Pediatric heart failure therapy: why ß1-receptor blocker, tissue ACE-I and mineralocorticoid-receptor-blocker?

Pediatric heart failure (HF) treatment lagged behind the knowledge of pharmacological research and evidence-based clinical experience in adults. Considering the lack of prospective, double blind randomized studies in children, the review is focused on the preferred indication of specific ß1-adrenoreceptor blockers (ARB), mineralocorticoid antagonists and tissue angiotensin-converting enzyme inhibitors (ACE-I). Our recommendations are based on the specificity in children, the effectiveness and the side-effect profile of HF-drugs, the receptor-physiological knowledge and the negative results of the few pediatric HF studies with an "evidence study label". In the interest of our pediatric patients, effective HF treatment has not longer to be postponed by balancing between evidence-based versus pathophysiology-based approach. At our institution, bisoprolol, lisinopril and spironolactone (BLS) are used treating HF in patients with left-right shunt lesions, reduced ejection fraction as well as during the inter-stage after HLHS-Hybrid approach. Chronic use of diuretics and fluid restriction is avoided, if always possible; intravascular volume deficiency stimulates further the neurohumoral axis. Pediatric HF needs to be treated with a strategy respecting the variable pathophysiology and the differences of receptor physiology between children and adult patients. The personalized treatment can be easily proofed by the surrogate parameters as heart rate, breath pattern, weight gain and image-derived parameters as well as biomarkers. Effective HF-therapy is also the basis for novel regenerative strategies in particular for young children with "end-stage" HF avoiding cardiac transplant or death.

Restrictive atrial communication in right and left heart failure.

Heart failure (HF) is usually defined by the dominantly affected heart chamber; therefore, termed right or left HF (RHF or LHF). Pulmonologists understand RHF as a complex syndrome characterized by insufficient delivery of blood from the right ventricle associated with elevated systemic venous pressure at rest or exercise. Cardiologists specify LHF by its clinical functional class and the relation to a reduced (HFrEF), preserved (HFpEF) or mid-range ejection fraction (HFmrEF). Pediatric cardiologist, dealing also with patients with a failing single ventricle, define HF as a condition of insufficient systemic oxygen delivery (DO2). Certainly, pediatricians do not think of the right and left heart, or even a single ventricle as an isolated, independently acting entity. Because of the importance of cardiac interactions, the creation of a restrictive atrial communication aims at a palliative approach with the goal to diminish the congestive consequences of a dysfunctional ventricle; further to serve as a pop-off valve in order to prevent syncope and cardiovascular collapse. This review covers the background, the particular indications, the techniques and preliminary results achieved following the creation of a restrictive atrial septum defect (rASD) in different pathophysiological settings. Based on the institutional experience, percutaneous trans-catheter perforation of the atrial septum, followed by gradual balloon dilatation can be performed at any age and location worldwide. Medical institutions in low resource countries can make use of such palliating procedures in the setting of right as well as LHF independent of their pharmacological facilities.

Transcatheter left atrial decompression in patients with dilated cardiomyopathy: bridging to cardiac transplantation or recovery.

BACKGROUND: Left atrial congestion results from backward failure in dilated cardiomyopathy. We aimed to evaluate feasibility and efficacy of percutaneous atrioseptostomy to create a restrictive atrial septum defect in management of dilated cardiomyopathy.Methods and resultsFrom June 2009 to December 2016, 27 interventions comprised left atria decompressions in 22 dilated cardiomyopathy patients; 9 females; age: 24 days to 36.9 years; weight: 3-50 kg; NYHA-/Ross class IV (n=16). Mean left ventricular ejection fraction was 21.5±9.7% and brain natriuretic peptide was 2291±1992 pg/ml. Dilated cardiomyopathy was classified as chronic (n=9); acute (n=1) myocarditis; idiopathic (n=5); left ventricular non-compaction (n=4); mitochondriopathy, pacemaker induced, and arrhythmogenic (n=3). Atrioseptostomy was concomitantly performed with myocardial biopsies 6.5 days (±11.7) after admission (n=11). Trans-septal puncture was used in 18 patients; foramen ovale dilatation was done in four patients. Mean balloon size was 11 mm (range 7-14 mm); total procedure time was 133±38 minutes. No procedural complications were observed. Mean left atrial pressure decreased from 15.8±6.8 to 12.2±4.8 mmHg (p=0.005), left/right atrial pressure gradient from 9.6±5.6 to 5±3.5 mmHg; brain natriuretic peptide (n=18) decreased from 1968±1606 to 830±1083 pg/ml (p=0.01). One patient unsuitable for heart transplantation died at home despite additionally performed pulmonary artery banding and three further left atrial decompressions; five patients were bridged to transplantation, two died afterwards. Functional recovery occurred in the remaining 14 patients and in six after additional pulmonary artery banding. No patient required assist device. CONCLUSIONS: Percutaneous left atrial decompression is an age-independent, effective palliation treating patients with dilated cardiomyopathy.

Percutaneous closure of perimembranous ventricular septal defects utilizing almost ideal Amplatzer Duct Occluder II: Why limitation in sizes?

AIM: The purpose of this study is to describe the special aspects of perimembranous ventricular septal defects (pmVSD) closure by utilizing Amplatzer Duct Occluder II (ADO II) devices with a rational request for bigger ADO-II sizes, based on our experience in transcatheter device closure of pmVSD. METHODS AND RESULTS: At our institution, placement of an ADO II device was used in 15 patients with pmVSD; the patients' age ranged between 6 months and 20 years. The indications for closure were CHF (n = 4), hemodynamically significant shunt (n = 7), tricuspid regurgitation (n = 3), and high risk for infective endocarditis (n = 2), respectively. The location of the VSD was infracristal in 13 patients, supracristal in 1, and a postsurgical Gerbode VSD in another one. Implantation of the device was successfully performed without embolization, any evidence of an AV block, or other conductance abnormalities during implantation and follow-up in the mean of 2.5 years (range 2 months-6.5 years). CONCLUSIONS: Transcatheter closure of a pmVSD with ADO II is feasible in all pediatric and young adult age groups, by considering the device diameter limitations. The off-label use of ADO II implantation seems to be safe for VSDs closure up to 6 mm of size and feasible for various locations including unusual morphology such as postsurgical Gerbode defect.

Fulminant cytomegalovirus myocarditis in an infant with concomitant large atrial and ventricular septal defects: medical intervention strategy for functional cardiac regeneration.

A cytomegalovirus-associated heart failure in a young infant with atrial and ventricular septal defects is reported in this case report. The patient recovered by an anti-congestive and anti-viral therapy with an extra percutaneous transcatheter treatment strategy. In the context of bi-ventricular predominant right heart failure associated with supra-systemic pulmonary hypertension, the already closed arterial duct was re-opened and stented to unload the right ventricle and thereby augment the systemic blood flow. Either the left-to-right shunting atrial septal defect or bi-directional shunting ventricular septal defect was involved in the disease process and was not able to avoid global heart failure. After clinical improvement, the stented duct was shunted left-to-right and was occluded with an ADO-II-AS. During the same procedure the atrial septal defect was closed with an Amplatzer-ASD occluder, while the peri-membranous ventricular septal defect was closed with an ADO-II occluder 2 months later.

Creation of a restrictive atrial communication in heart failure with preserved and mid-range ejection fraction: effective palliation of left atrial hypertension and pulmonary congestion.

BACKGROUND: Left atrial decompression is considered in patients with symptomatic heart failure with preserved ejection fraction (HFpEF). We aimed to evaluate the feasibility and efficacy of transcatheter generation of a restrictive atrial septum communication to manage HFpEF from infancy to adulthood with cardiomyopathy and congenital heart defect. METHODS AND RESULTS: From June 2009 to December 2016, 24 patients (50% with an age less than 16 years) with HFpEF were palliated; NYHA-/Ross class IV (n = 10); median systemic ventricular ejection fraction 64 (range 35-78) %. Cardiomyopathy was classified as a restrictive (n = 4) or hypertrophic (n = 2). (75% related to congenital heart defects) Three patients had a systemic right ventricle; in the majority of patients, HFpEF was associated to complex congenital heart defects (n = 18). Mean pulmonary arterial pressures (PAP systolic/diastolic) were 56/28 (± 24/13), left atrial pressures (LAP, v-, a-wave, mean) 26/25/20 (± 7/10/6). Trans-septal puncture was used in 22 patients; foramen ovale dilatation in 2 patients. Median balloon size was 12 (range 6-18) mm; procedure time including diagnostic measures 125 (83-221) min. No procedural death or complications were observed. Mean LA-pressures decreased significantly to 19/19/15 ± 6/8/5 mmHg (p = 0.05); median brain natriuretic peptide (BNP) decreased from 392 (range 93-4401) pg/ml median BNP to 314 (range 61-1544) pg/ml (p = 0.05). Three patients died; one patient received orthotopic heart and one patient a heart-lung transplantation. No patient required so far an assist device. Clinical improvement occurred in all patients, in some after additional surgical or interventional approach. CONCLUSIONS: Transcatheter LA decompression is an age-independent, effective palliation treating patients with HFpEF.