Hemodynamic Response to Device Titration in the Shunted Single Ventricle Circulation - A Patient Cohort Modeling Study

Clinical outcomes of ventricular assist device (VAD) support for shunted single ventricle patients trail the larger population due in part to the challenges in optimizing VAD support and balancing systemic and pulmonary circulations. We sought to understand the response to VAD titration in the shunted circulation using a lumped-parameter network modeling six patient-specific clinical cases. Hemodynamic data from six patients (mean body surface area = 0.30 m2) with a systemic-to-pulmonary shunt was used to construct simulated cases of heart failure and hemodynamic response to increasing VAD flow from 5 to 10 L/min/m2. With increasing VAD flow, the pulmonary arterial pressure stayed relatively constant in five patient cases and increased in one patient case. The mean VAD flow needed to attain an arterial-venous O2 saturation difference of 30% was 6.5 ± 1.2 L/min/m2, which is higher than that in the equivalent nonshunted scenario due to the partial diversion of flow to the pulmonary circulation. The hemodynamic responses to VAD support can vary significantly between specific patient cases; therefore hemodynamic modeling may help guide an individualized approach to perioperative VAD management in the shunted single-ventricle circulation and to understand the patients who may benefit the most from VAD support

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

The muscular dystrophies are broadly classified as muscle wasting diseases with myofiber dropout due to cellular necrosis, inflammation, alterations in extracellular matrix composition, and fatty cell replacement. These events transpire and progress despite ongoing myofiber regeneration from endogenous satellite cells. The degeneration/regeneration response to muscle injury/disease is modulated by the proinflammatory cytokine transforming growth factor-β (TGF-β), which can also profoundly influence extracellular matrix composition through increased secretion of profibrotic proteins, such as the matricellular protein periostin. Here we show that up-regulation and secretion of periostin is pathological and enhances disease in the δ-sarcoglycan null (Sgcd(−/−)) mouse model of muscular dystrophy (MD). Indeed, MD mice lacking the Postn gene showed dramatic improvement in skeletal muscle structure and function. Mechanistically, Postn gene deletion altered TGF-β signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-β with a neutralizing monoclonal antibody mitigated the beneficial effects of Postn deletion in vivo. These data suggest that periostin functions as a disease determinant in MD by promoting/allowing the pathological effects of TGF-β, suggesting that inhibition of periostin could represent a unique treatment approach

Genetic Testing in Pediatric Left Ventricular Noncompaction

Background: Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield. Methods and results: One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic pathogenesis, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, pathogenesis, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively; P<0.01). Conclusions: Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases

HVAD to HeartMate 3 left ventricular assist device exchange: Best practices recommendations

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices

Mechanical circulatory support challenges in pediatric and (adult) congenital heart disease

PURPOSE OF REVIEW: Increased miniaturization of ventricular assist devices (VADs) and new mechanical support strategies (MCS) has increased the use of MCS in the pediatric and congenital heart disease (CHD) population. This comes with the need for care providers specialized in this field to determine optimal patient and device selection, and to improve outcomes and decrease complication rates for new innovative strategies. A review of the published literature in this field is timely and relevant. RECENT FINDINGS: There has been a rapid evolution of using adult designed continuous flow VADS to support children and adults with CHD (ACHD). Patient selection for patients with CHD is complex because of patient size and anatomical diversity and, therefore, makes decision-making complex and unique when compared to general adult practice. Outcomes for children depend on size and diagnosis with neonates with single ventricle physiology being the highest risk candidates. This also holds true for ACHD, in which VAD outcomes in patients with two ventricle physiology are comparable to non-ACHD patients. SUMMARY: In children, there is an increased use of continuous flow devices and a growing experience with outpatient management. Patients with CHD especially when associated with single ventricle physiologies, remain a challenge when it comes to MCS/VAD placement but successful durable VAD implantation with discharge home has been reported

ISHLT consensus statement for the selection and management of pediatric and congenital heart disease patients on ventricular assist devices Endorsed by the American Heart Association

Heart failure (HF) is a significant cause of mortality in children and therefore there is interest in understanding the optimal way to support these children with Ventricular Assist Devices (VAD) to improve outcomes. VAD therapy is now regarded as an important treatment option in pediatric HF. The 2019 International Society for Heart and Lung Transplantation (ISHLT) registry report shows that there is an increasing trend towards using VADs as a bridge to transplant (BTT) with currently over one-third of patients transplanted being bridged with a VAD.1 The immediate aim of VAD therapy is to provide hemodynamic stability for a failing circulation unresponsive to medical therapy. The VAD should be implanted before the development of severe end-organ dysfunction in order to optimize clinical outcomes. The goal is to improve tissue and organ perfusion, improve quality of life (QoL) and improve waitlist survival. Importantly, VAD therapy may not only lead to patient stability but may also afford the opportunity for patient rehabilitation prior to heart transplantation (HT). Despite the increase in VAD use within pediatrics over the last decade, the majority of centers implant less than 10 VADs in children per year.2 Thus, local data is limited for analysis of outcomes and therefore multi-center collaboration and consensus is essential in understanding this complex and dynamic field. ISHLT has recognized the importance of a consensus statement on the selection and management of pediatric and congenital heart disease (CHD) patients undergoing VAD implantation. The purpose of this document is to provide expert-consensus derived recommendations and whenever possible, these recommendations shall be guided by evidence. The creation of this consensus document required multiples steps including the engagement of the ISHLT councils, identification and selection of experts in the field, and the development of 13 Tasks Forces. Extensive literature searches were performed but due to the lack of comparative trials in pediatrics, this document was written as a literature review with expert opinion rather than based on level of evidence

Dilated Cardiomyopathy in a 32-Year-Old Woman With Russell-Silver Syndrome

Introduction Russell-Silver Syndrome (RSS) is a genetically determined condition characterized by severe intrauterine and postnatal growth retardation; relative macrocephaly; a small, triangular face; and fifth-finger clinodactyly. The etiology of RSS involves epigenetic regulation through either uniparental disomy or genomic imprinting via DNA methylation. There has been no documented association between RSS and cardiomyopathy. Methods We present an original case of a 32-year-old woman with RSS with dilated a cardiomyopathy who on cardiac biopsy showed occasional hypertrophic and atrophic myocytes with no evidence of inflammation, abnormal sarcomeres and disintegration of the Z bands on ultrastructural analysis, abnormal desmin, and normal C9 immunoreactivity. Conclusion This case represents the first reported association between RSS and cardiomyopathy. Given the complex mechanisms of disease etiology in RSS, this novel case provides insights into the mechanism of progressive dilated cardiomyopathy in an older individual with RSS