Background: Pediatric Heart Failure (HF) cause by Dilated Cardiomyopathy (DCM) is an important cause of morbidity and mortality in childhood. Patients usually undergo mechanical circulatory support (MCS), waiting for heart transplant (HTx), which is a sub-optimal option. Following the Giessen protocol conceived by Schranz et al., since 2015 the Pulmonary Artery Banding (PAB) strategy has been used at our Institution to treat end-stage heart failure (ESHF) in patients with preserved right-ventricle function, as a bridge to transplant or functional recovery. Aim of the study: this study combines both a clinical (1) and experimental (2) research. The former aims to assess the current results of PAB across Europe and Asia. The latter aims to investigate the PAB’s effect on a Sprague-Dawley rat model. Materials and methods: The clinical part (1) is a multicentric retrospective international study enrolling infants and children admitted for ESHF and consequent DCM, not responding to conventional medical management. Among exclusion criteria: biventricular failure, the age over 5 years, the lack of parental consent. Clinical, echocardiographic and CMRI data were collected together on a common database (REDcap). The PAB-efficacy-index was defined as the overall freedom from death/VAD/HTx. Experimentally (2), for the first time in literature, we evaluated, on 46 Sprague-Dawely “young” and “adult” rats, the PAB’s effect in two models of DCM (Doxorubicin-induced one and the temporary surgical LAD-ligation-induced one), through echocardiographic, histological and genetic examinations. In collaboration with the ICGEB of Trieste, we also assessed the PAB-induced cardiomyocyte proliferation on 6 healthy juvenile Sprague-Dawley rats, through the injection of Adeno-Associated-Virus (AAV) vector fluorescent-based reporter systems and a nucleoside analogue (EdU). Results: Part 1. 31 patients (18 males) underwent PAB at a median age of 210d (IQR: 131-357). Complications occurred in 14 pts (47%). Early reinterventions include: ECMO in 1 patient, VAD in 3, delayed chest closure in 7 and surgical PAB tightening in 4. Early deaths were 4 (13%). At a median follow-up of 2,9 years (IQR: 1,20-4,85) one late death and 3 effective HTxs (two preceded by VAD, one by rescue ECMO+VAD) occurred. At the last follow-up echo (median time 32.2 months, IQR: 14.95-55.13), EF improved until the median value of 60% (IQR: 53.75-63.25) from 25% (IQR: 17.5-27.75) on admission (pholm-adj.= 2.69e-09). Left ventricular end-diastolic diameter’s Z-score reduced from a median value of 9.72 (IQR: 6.55-12.63) on admission to 2.52 (IQR: 0.07-3.07) (pholm-adj.= 1.91e-05). The PAB-Efficacy-Index was 74.2%, while overall survival (HTx included) was 84%. Females had greater overall survival from death/VAD/HTx than males (p=0.045). Patients under 12 months of age faced less risk of undergoing VAD application than patients over 12 months of age (p=0.012). Part 2. The DOX-induced rat DCM model is only partially adequate. The impaired contractile function was confirmed through two-dimensional echocardiography, whereas no clear evidence was detected histologically or by molecular tests. Rats undergoing PAB after DOX showed improved contractile function. Instead, temporary LAD-ligation was not sufficient to estabilish a model of rat DCM. The pilot study involving fluorescent reporter systems confirm the PAB-induced cardiomyocyte proliferation in the LV and the myocardial regeneration. Conclusions: PAB, together with aggressive anti-congestive medical management, turned out to be an effective procedure in the treatment of ESHF in infants and children with preserved RV function, serving as a bridge to functional recovery or transplant. Establishing experimental rat DCM models is challenging, but the positive effect of PAB can be confirmed, at least through echo assessment, in the DOX-induced model. PAB-induced cardiomyocyte proliferation in the LV seems corroborated.

Innovative management of end-stage heart failure in infants: understanding the mechanism of myocardial rehabilitation after pulmonary artery banding in an experimental rodent model of induced dilated cardiomyopathy

CREA, DOMENICO
2021/2022

Abstract

Background: Pediatric Heart Failure (HF) cause by Dilated Cardiomyopathy (DCM) is an important cause of morbidity and mortality in childhood. Patients usually undergo mechanical circulatory support (MCS), waiting for heart transplant (HTx), which is a sub-optimal option. Following the Giessen protocol conceived by Schranz et al., since 2015 the Pulmonary Artery Banding (PAB) strategy has been used at our Institution to treat end-stage heart failure (ESHF) in patients with preserved right-ventricle function, as a bridge to transplant or functional recovery. Aim of the study: this study combines both a clinical (1) and experimental (2) research. The former aims to assess the current results of PAB across Europe and Asia. The latter aims to investigate the PAB’s effect on a Sprague-Dawley rat model. Materials and methods: The clinical part (1) is a multicentric retrospective international study enrolling infants and children admitted for ESHF and consequent DCM, not responding to conventional medical management. Among exclusion criteria: biventricular failure, the age over 5 years, the lack of parental consent. Clinical, echocardiographic and CMRI data were collected together on a common database (REDcap). The PAB-efficacy-index was defined as the overall freedom from death/VAD/HTx. Experimentally (2), for the first time in literature, we evaluated, on 46 Sprague-Dawely “young” and “adult” rats, the PAB’s effect in two models of DCM (Doxorubicin-induced one and the temporary surgical LAD-ligation-induced one), through echocardiographic, histological and genetic examinations. In collaboration with the ICGEB of Trieste, we also assessed the PAB-induced cardiomyocyte proliferation on 6 healthy juvenile Sprague-Dawley rats, through the injection of Adeno-Associated-Virus (AAV) vector fluorescent-based reporter systems and a nucleoside analogue (EdU). Results: Part 1. 31 patients (18 males) underwent PAB at a median age of 210d (IQR: 131-357). Complications occurred in 14 pts (47%). Early reinterventions include: ECMO in 1 patient, VAD in 3, delayed chest closure in 7 and surgical PAB tightening in 4. Early deaths were 4 (13%). At a median follow-up of 2,9 years (IQR: 1,20-4,85) one late death and 3 effective HTxs (two preceded by VAD, one by rescue ECMO+VAD) occurred. At the last follow-up echo (median time 32.2 months, IQR: 14.95-55.13), EF improved until the median value of 60% (IQR: 53.75-63.25) from 25% (IQR: 17.5-27.75) on admission (pholm-adj.= 2.69e-09). Left ventricular end-diastolic diameter’s Z-score reduced from a median value of 9.72 (IQR: 6.55-12.63) on admission to 2.52 (IQR: 0.07-3.07) (pholm-adj.= 1.91e-05). The PAB-Efficacy-Index was 74.2%, while overall survival (HTx included) was 84%. Females had greater overall survival from death/VAD/HTx than males (p=0.045). Patients under 12 months of age faced less risk of undergoing VAD application than patients over 12 months of age (p=0.012). Part 2. The DOX-induced rat DCM model is only partially adequate. The impaired contractile function was confirmed through two-dimensional echocardiography, whereas no clear evidence was detected histologically or by molecular tests. Rats undergoing PAB after DOX showed improved contractile function. Instead, temporary LAD-ligation was not sufficient to estabilish a model of rat DCM. The pilot study involving fluorescent reporter systems confirm the PAB-induced cardiomyocyte proliferation in the LV and the myocardial regeneration. Conclusions: PAB, together with aggressive anti-congestive medical management, turned out to be an effective procedure in the treatment of ESHF in infants and children with preserved RV function, serving as a bridge to functional recovery or transplant. Establishing experimental rat DCM models is challenging, but the positive effect of PAB can be confirmed, at least through echo assessment, in the DOX-induced model. PAB-induced cardiomyocyte proliferation in the LV seems corroborated.
2021
Innovative management of end-stage heart failure in infants: understanding the mechanism of myocardial rehabilitation after pulmonary artery banding in an experimental rodent model of induced dilated cardiomyopathy
Heart Failure
Infants
Surgery
Myocardial Recovery
Cardiac Regeneration
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/30742