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

The Total Artificial Heart in End-Stage Congenital Heart Disease

The development of durable ventricular assist devices (VADs) has improved mortality rates and quality of life in patients with end stage heart failure. While the use of VADs has increased dramatically in recent years, there is limited experience with VAD implantation in patients with complex congenital heart disease (CHD), despite the fact that the number of patients with end stage CHD has grown due to improvements in surgical and medical care. VAD use has been limited in patients with CHD and end stage heart failure due to anatomic (systemic right ventricle, single ventricle, surgically altered anatomy, valve dysfunction, etc.) and physiologic constraints (diastolic dysfunction). The total artificial heart (TAH), which has right and left sided pumps that can be arranged in a variety of orientations, can accommodate the anatomic variation present in CHD patients. This review provides an overview of the potential use of the TAH in patients with CHD

Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV

Background: Glycogen Storage disease type 4 (GSD4), a rare disease caused by glycogen branching enzyme 1 (GBE1) deficiency, affects multiple organ systems including the muscles, liver, heart, and central nervous system. Here we report a GSD4 patient, who presented with severe hepatosplenomegaly and cardiac ventricular hypertrophy. GBE1 sequencing identified two variants: a known pathogenic missense variant, c.1544G>A (p.Arg515His), and a missense variant of unknown significance (VUS), c.2081T>A (p. Ile694Asn). As a liver transplant alone can exacerbate heart dysfunction in GSD4 patients, a precise diagnosis is essential for liver transplant indication. To characterize the disease-causing variant, we modeled patient-specific GBE1 deficiency using CRISPR/Cas9 genome-edited induced pluripotent stem cells (iPSCs). Methods: iPSCs from a healthy donor (iPSC-WT) were genome-edited by CRISPR/Cas9 to induce homozygous p.Ile694Asn in GBE1 (iPSC-GBE1-I694N) and differentiated into hepatocytes (iHep) or cardiomyocytes (iCM). GBE1 enzyme activity was measured, and PAS-D staining was performed to analyze polyglucosan deposition in these cells. Results: iPSCGBE1-I694N differentiated into iHep and iCM exhibited reduced GBE1 protein level and enzyme activity in both cell types compared to iPSCwt. Both iHepGBE1-I694N and iCMGBE1-I694N showed polyglucosan deposits correlating to the histologic patterns of the patient's biopsies. Conclusions: iPSC-based disease modeling supported a loss of function effect of p.Ile694Asn in GBE1. The modeling of GBE1 enzyme deficiency in iHep and iCM cell lines had multi-organ findings, demonstrating iPSC-based modeling usefulness in elucidating the effects of novel VUS in ultra-rare diseases

Current state of cardiac troponin testing in Duchenne muscular dystrophy cardiomyopathy: review and recommendations from the Parent Project Muscular Dystrophy expert panel

Cardiac disease is now the leading cause of death in Duchenne muscular dystrophy (DMD). Clinical evaluations over time have demonstrated asymptomatic cardiac troponin elevations and acute elevations are associated with symptoms and cardiac dysfunction in DMD. Clinicians require a better understanding of the relationship of symptoms, troponin levels and progression of cardiac disease in DMD. As clinical trials begin to assess novel cardiac therapeutics in DMD, troponin levels in DMD are important for safety monitoring and outcome measures. The Parent Project Muscular Dystrophy convened an expert panel of cardiologists, scientists, and regulatory and industry specialists on 16 December 2019 in Silver Spring, Maryland and reviewed published and unpublished data from their institutions. The panel recommended retrospective troponin data analyses, prospective longitudinal troponin collection using high-sensitivity cardiac troponin I assays, inclusion of troponin in future clinical trial outcomes and future development of clinical guidelines for monitoring and treating troponin elevations in DMD

Current Practices in Treating Cardiomyopathy and Heart Failure in Duchenne Muscular Dystrophy (DMD): Understanding Care Practices in Order to Optimize DMD Heart Failure Through ACTION

Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy 70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679